APPLICATION FOR REGISTRATION
OF PHARMACEUTICAL PRODUCT
Islamic Republic of Afghanistan
Ministry of Public Health
General Directorate of Pharmaceutical Affairs
Registration and License Issuing Department
ATORVASTATIN TABLETS IP 10 mg
ATORMICK-10 TABLETS
Submitted by:
Niramaya Pharmaceuticals (P) Ltd.
Village Juddi Khurd Barotiwala Road,
Baddi, Distt. Solan, Himachal Pradesh, INDIA
Tel: +
Website:
E-mail:
-1-
INDEX
SECTION
NO.
1
DESCRIPTION
Description of the Finished Pharmaceutical Product
➢Physical characteristic of the product
2
Formulation
➢ Complete formula of the product in a table
3
4
➢ Information on development studies for the product
➢ Literature information for the product
11
In-Vitro Dissolution or Drug Release
29
29
Sites of Manufacture-Finished Product
➢ Manufacturer name, address and responsibility
6
7
8
10
10
11
11
Pharmaceutical Development
➢ In-vitro dissolution study results
5
PAGE
NO.
09
09
30
30
Detailed Description and Validation of the Manufacturing
Procedure for the Finished Product
31
➢ Detail description of the manufacturing procedure
31
➢ Controls of critical steps
37
➢ Description of the manufacturing process
38
➢ Process validation data (manufacturing process,
validation protocol, and manufacturing process
validation report)
Specification for Excipients
45
➢ List of tests and limits for result of excipient
57
57
➢ Test methods
69
Control of the Finished Pharmaceutical Products
1. Specifications for the Finished Pharmaceutical Product
➢ Copy of the FPP specification
99
99
99
➢List of tests and limits for result of the FPP
99
2. Analytical Procedures
100
100
➢ Analytical test procedure and methods
➢ Required for non-compendial method
105
105
4. Batch Analysis
106
3. Validation of Analytical Procedures
-2-
9
➢ Result of the analysis of three batches
106
➢ Copies of the certificates of analysis for these
batches
Container Closure System(s) and Other Packaging
106
➢ Description of the suitability of the container closure
System
➢ Description of container closure system
10
107
107
107
➢ Primary packaging components specification and test methods 114
122
Stability Testing of the Finished Product
122
➢ Stability studies report
➢ Methodology of stability studies
122
➢ A tabulated summary of stability results should be
provided.
Other data, if any
124
➢Summary of Product Characteristics
133
133
13
➢Published Reports on Clinical Trials
157
14
➢Toxicity data
184
11
12
-3-
1. Application Number: (For GDPA use only)
2. Applicant Company Particulars
1. Name of Company (in block
letters)
2. Business Registration Number
3. Company Address and Contact
Information
INDIA
1. Country
2. Province
Himachal
Pardesh
3. City
Baddi
4. Mailing
Address
Village Juddi
Khurd
Barotiwala
Road,
Baddi, Distt.
Solan,
Niramaya Pharmaceutical (P) Ltd.
Village Juddi Khurd Barotiwala
Road, Baddi, Distt. Solan
2.3.6. Fax
Number
2.3.7. Official EMail
Address
2.3.8. Telephone
Number
2.3.9. Company
Website
5. Postal Code
Note:
a. Please enclose a copy of the Letter of Authorization from the
Manufacturer (attached this letter as attachment A)
b. Please attach a copy of the Business Registration Certificate of the
applicant company( attach the registration certificate as attachment B)
3. Applicant Particulars (Person authorized to submit and manage the
application on behalf of the company)
1. First Name
2. Family Name
-4-
3. Designation
4. ID card or Passport Number
5. Official Email Address
6. Telephone Number
7. Fax Number
8. Applicant’s Address
1. Country
2. Province
3. City
3.8.4. Address
line -1
3.8.5. Address
line -1
3.8.6. Address
line -1
4. Product Details
1. Generic Name
2. Proprietary/Brand Name
3. Dosage Form
4. Physical Description of the
Atorvastatin Tablets
Atormick-10
Tablets
White coloured, round shaped,
biconvex,film coated tablet plain on
both side
5. Product Formula (if space is not sufficient, please use a separate piece
of A4 paper):
4.5.1 Component
4.5.2
4.5.3 Strength
4.5.4 Quality
and
Function
standards (e.g.
quality standard
USP,
Quant. %
(and
BP, EP ,IP ,
per
grade, if applicable)
in-house)
unit or
per
mL
<complete with appropriate title e.g. Core tablet, Contents of capsule,
Powder for injection>
attached
Sub total 1
<complete with appropriate title e.g. Film-coating >
attached
-5-
Sub total 2
Total
Note: Please describe the roles of excipients in the respective column
indicated as follows:
F – Flavoring, C – Colorant, P – Preservatives, S – Stabilizers
C10AA05
6. Therapeutic Classification (WHO ATC Code for the
proposed indication[s])
Oral
7. Rout of Administration.
8. Indications (attach information on the indication[s] as attachment C)
9. Recommended Dosage (attach information on the recommended
dosage as attachment D)
10.Proposed Shelf Life
1. Packing, shelf life and storage condition
4.10.1.1.
4.10.1.2.
4.10.1.3.
4.10.1.4.
4.10.1.5.
Container
Quantity per Shelf
Storage
Pack
Closer
Container
Life
Conditions
Size
System
Alu-Alu Strip
10 x 10
2 years
Below 30°c
10 x 10
2. Other shelf life information
N/A
1. Proposed shelf life after first opening
(hours/day/months)
N/A
2. Proposed shelf life after reconstitution
(hours/day/months)
4.11. Forensic Classification in Afghanistan

4.11.1. Prescription Only (PO)
2. Over the Counter (OTC)
12. Regulatory Situation in the Country of Origin & in Other Countries
(provide information, as appropriate) List countries where the product is:
4.12.1.
4.12.2.
4.12.3.
4.12.4. Date
Country
Approved
Registration
(dd/mm/yyyy)
Forensic
Status
Classification
of the Product
Prescription
Authorized
Only
Rejected
Pending
Over the
Withdrawn
Counter (OTC)
-6-
Prescription
Only
Over the
Counter (OTC)
Prescription
Only
Authorized
Rejected
Pending
Withdrawn
Authorized
Rejected
Pending
Withdrawn
Over the
Counter (OTC)
Note: Please enclose one certified copy of the Product License issued by
the relevant authority (attached the certiBicate as attachment E)
13. Proposed Price of the Product:
1. Wholesale Price (US
Dollar)
2. Retail Price (US Dollar)
5. Manufacturer’s Particulars
1. Active Substance Manufacturer
5.1.1. Name of
5.1.2 Name of
Active
Manufacturer
Substance
Atorvastatin
Sigma
1.
5.1.3 Site
Address
Country
5.1.4 Office
Address
5.2.3 Site
Address
Country
5.2.4 Office
Address
Calcium
2.
3.
2. Excipient Manufacturer
5.2.1. Name of
5.2.2 Name of
Excipient
Manufacturer
1.
2.
3.
3. Finished Pharmaceutical Product Manufacturer
5.3.1 Name of Manufacturer
Country
5.3.3 Site
5.3.4 Office
Address
Address
Niramaya
Village Juddi
1.
Pharmaceutical
(P) Ltd.
Khurd
Barotiwala
Road, Baddi,
Distt. Solan,
-7-
6. Certification by a Responsible Person in the Applicant Company
On behalf of [
], I hereby declare that:
1.All of the information in this application is true.
2.Information in all of the annexes attached to this application is true and
complete.
All available data, reports, and information relevant to the benefit/risk
assessment of the product have been provided.
3.[ ] agree to abide by the Afghanistan Medicines Law and
Manufacturing and Importing Medicine and Medical Appliances
Regulation.
4.[
] agree to notify the General Directorate of Pharmaceutical
Affairs, Ministry of Public Heath, of any change in the information
submitted in this application and of any new safety information during
the course of the evaluation of this application and as long as the product
remains on the market.
5.[
] confirms that it has a standard operating procedure for handling
adverse reaction reports for its products.
6.[
] confirms that it has a standard operating procedure for handling
batch recalls of its products.
I understand that any false statement is an offence under the laws of
Afghanistan and that all documents submitted for evaluation will not be
returned.
Submitted by:
Name (in block letters):
Position in the Applicant Company (in block letters):
Date:
Signature:
Company Stamp
Received by (GDPA):
Name (in block letters):
Position (in block letters):
Date:
Signature:
Note: all pages of the application form must be signed and stamped.
-8-
1. Description of the Finished Pharmaceutical Product
➢Physical characteristic of the product
Product Name
:
ATORMICK-10 TABLETS
Generic Name
:
Atorvastatin Tablet IP
Composition
:
Each Film Coated Tablet Contains:
Atorvastatin calcium IP
Equivalent to Atorvastatin 10 mg
Colour: Titanium dioxide IP
Shelf Life
:
2 years
Packing
:
Alu-Alu
Batch Size
:
100000 tablets
Description
:
White coloured, round shaped, biconvex,
film coated tablet plain on both side
Identification
:
Positive for Atorvastatin
Average Weight
:
Uncoated 175 mg ± 7.5%,
Coated 181 mg ± 7.5%
Dissolution
:
Not less than 75% of the stated amount
Assay
:
90.0 to 110.0% of the stated amount.
Storage
:
Store below 30°C. Protect from light.
-9-
2. Formulation
➢ Complete formula of the product in a table
Each Film Coated Tablet Contains:
Atorvastatin calcium IP
Equivalent to Atorvastatin 10 mg
Colour: Titanium dioxide IP
Batch size
: 100000 Tablets.
List of all required Ingredients, active and inactive with its specification and
exact quantities as per unit dose:
Ingredient
Specification
Qty
/Tablet
Overage
Qty./Batch
Active Ingredient
Atorvastatin calcium
I.P.
11.10 mg
=
10.0 mg
Atorvasta
tin
--
1.110 kg
I.P.
I.P.
30.00 mg
122.0 mg
---
I.P.
I.P.
I.P.
-5.0 mg
5.0 mg
-------
10.00 liters
0.500 kg
0.500 kg
2.0 mg
---
0.200 kg
Inactive Ingredient
Maize Starch
Microcrystalline
cellulose
Purified Water
Purified Talc
Sodium Starch
Glycollate
Colloidal Anhydrous
Silica
Film Coating
Titanium Dioxide
Hydoxypropyl
methylcellulose
Povidone
Methylene Chloride
Isopropyl alcohol
I.P.
3.00 kg
12.20 kg
I.P.
I.P.
1.0 mg
4.0 mg
0.100 kg
0.400 kg
I.P.
B.P.
I.P.
1.0 mg
---
0.100 kg
4.0 liters
7.0 liters
- 10 -
3. Pharmaceutical Development
➢ Information on development studies for the product
➢ Literature information for the product
Systematic approach:
A Systematic approach to Atorvastatin Tablet design and product development
activities were sub divided in to literature search, formulation development and
process development. The various studies carried out during these phases were
given below.
Literature search:
Preliminary activities in a drug product development project started with a
comprehensive review of authoritative reference books on the pharmaceutical
and analytical parameters and attributes of the chosen drug.
Reference books, the current British pharmacopoeia, United States
Pharmacopoeia, Physician’s Desk Reference, Martindale and Merck Index
were thoroughly reviewed on physical and chemical properties of the active
ingredient and its potential formulations.
An extensive internet online search relating to drug and the drug product was
done.
- 11 -
Components of the Drug Product
Drug Substance
Active ingredient:
Atorvastatin calcium
Synonym:
Atorvastatin
Chemical name:
[R-(R*, R*)]-2-(4-fluorophenyl)-β, δ -dihydroxy-5- (1-methylethyl)-3-phenyl4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1)
trihydrate
Molecular formula:
(C33H34 FN2O5)2Ca•3H2O
Molecular weight:
1155.36
Molecular structure:
Physical properties:
A white to off-white, crystalline powder
Biological properties:
Lipid modifying agents, HMG-CoA-reductase inhibitors,
- 12 -
Compatibility of Drug Substance for Combination Products
None
Compatibility of Drug Substance with Excipients
The excipients used in the tablet manufacture are Starch, Micro Crystalline
Cellulose, Purified talc, Sodium Starch Glycollate, Aerosil (Colloidal
anhydrous silica), Hydoxypropyl methylcellulose, Povidone, Titanium Dioxide,
Isopropyl Alcohal and Methylene Chloride
It could be observed that the excipients- Starch, Micro Crystalline Cellulose,
Purified talc, Sodium Starch Glycollate, Aerosil (Colloidal anhydrous silica),
Hydoxypropyl methylcellulose, Povidone, Titanium Dioxide, Isopropyl
Alcohal and Methylene Chloride are used in the Applicant’s formulation were
present in the reference product as well. Further, stability data provided in the
dossier also supports that there is no incompatibility of active ingredient in the
presence of the above listed excipient.
Selection of Excipients
Based on the Physical and chemical properties of the drug and the experience
gained during the development of the drug products, Excipients those found to
be compatible are used in the formulation.
Formulation contains Starch, Micro Crystalline Cellulose, Purified talc,
Sodium Starch Glycollate, Aerosil (Colloidal anhydrous silica), Hydoxypropyl
methylcellulose, Povidone, Titanium Dioxide, Isopropyl Alcohal and
Methylene Chloride as excipients
Excipients used are Pharmacopoeial, mainly complying with the Indian/British
Pharmacopoeia.
Quality Characteristics of the Excipients have been discussed below.
Starch: Starch is used in the formulation as a binder
Micro Crystalline Cellulose Powder: Micro Crystalline Cellulose Powder is
used in the formulation as a diluent
Purified Talc: Purified Talc is used in the formulation as a lubricant
- 13 -
Sodium Starch Glycollate: Sodium Starch Glycollate is used in the
formulation as a disintegrant
Aerosil (Colloidal anhydrous silica): Aerosil (Colloidal anhydrous silica)is
used in the formulation as a glidant
Hydoxypropyl methylcellulose: Hydoxypropyl methylcellulose is used in
the formulation as a film coating material
Povidone: Povidone is used in the formulation as a film coating material
Titanium Dioxide: Titanium Dioxide is used in the formulation as a colour
Isopropyl Alcohol: Isopropyl Alcohol is used in the formulation as a solvent
for film coating material
Methylene Chloride: Methylene Chloride is used in the formulation as a
solvent for film coating material
Optimization of excipients
The aim of the formulation development was to develop a formulation of
Atorvastatin Tablet containing Atorvastatin
The excipients – Starch, Micro Crystalline Cellulose, Purified talc, Sodium
Starch Glycollate, Aerosil (Colloidal anhydrous silica), Hydoxypropyl
methylcellulose, Povidone, Titanium Dioxide, Isopropyl Alcohal and
Methylene Chloride were optimized in such a way that the resulting tablet have
similar specification comparable to that of reference product, besides being
stable with respect to assay content.
Drug Product
Formulation Development
Summary of development of drug product
The aim was to develop a robust generic formulation of Atorvastatin Tablet
that is comparable to the reference product.
The finished product should demonstrate similar characteristics compare to
reference product.
Overages
No overages were added
- 14 -
Physiochemical and Biological Properties
Physiochemical Properties
Product Name
:
ATORMICK-10 TABLETS
Generic Name
:
Atorvastatin Tablet IP
Composition
:
Each Film Coated Tablet Contains:
Atorvastatin calcium IP
Equivalent to Atorvastatin 10 mg
Colour: Titanium dioxide IP
Shelf Life
:
2 years
Packing
:
Alu-Alu
Batch Size
:
100000 tablets
Description
:
White coloured, round shaped, biconvex,
film coated tablet plain on both side
Identification
:
Positive for Atorvastatin
Average Weight
:
Uncoated 175 mg ± 7.5%,
Coated 181 mg ± 7.5%
Dissolution
:
Not less than 75% of the stated amount
Assay
:
90.0 to 110.0% of the stated amount.
Storage
:
Store below 30°C. Protect from light.
- 15 -
Manufacturing Process Development
175 mg granular powder containing active and inactive ingredients are
compressed as round, biconvex tablet using tablet compression machine.
Selection of manufacturing process
The Main Steps of the Manufacturing Process are as below
1. Sifting
2. Dry Mix
3. Preparation of Starch Paste
4. Wet Granulation
5. Wet Screening
6. Drying
7. Dry Screening milling
8. Lubrication
9. Sampling
10. Machine Release
11. Compression
12. In- Process Check
13. Sampling of compressed Tablets
14. Visual Inspection
15. Preparation of coationg
16. Coating
17. Packaging
Laboratory experimental trials were carried over to select the suitable formula
and process for in order to meet the tentative specifications mentioned above
and the summary of trials with flow diagram are given in the following pages
with details of final formulation & manufacturing process.
- 16 -
Container Closure System
Suitability for the Intended Use
Every proposed packaging system should be shown to be suitable for its
intended use: it should adequately protect the dosage form; it should be
compatible with the dosage form; and it should be composed of materials that
are considered safe for use with the dosage form and the route of
administration. If the packaging system has a performance feature in addition
to containing the product, the assembled container closure system should be
shown to function properly.
General issues concerning protection, compatibility, safety and performance of
packaging components and/or systems are discussed below. In this guidance,
component functionality and drug delivery will also be addressed in connection
with specific dosage forms and routes of administration.
Table 1
Examples of packaging Concerns for Common Classes of Drug
Products
Degree of
Concern
Associated
with the Route
of
Administration
Likelihood of Packaging Component-Dosage
Form Interaction
Highest
Inhalation
Aerosols and
Solutions;
Injections and
Injectable
Suspensionsa
High
Ophthalmic
Solutions and
High
Medium
Sterile
Powders and
Powders for
Injection;
Inhalation
Powders
- 17 -
Low
Suspensions;
Transdermal
Ointments and
Patches; Nasal
Aerosols and
Sprays
Low
Topical
Solutions and
Suspensions;
Topical and
Lingual
Aerosols; Oral
Solutions and
Suspensions
Topical
Powders; Oral
powders
Oral Tablets
and Oral (Hard
and Soft
Gelatin)
Capsules
a
For the purposes of this table, the term sterile powder for injection is used
mean a after constituting with Sterile water for injection or any other
suitable diluents it can be administered in the pharmaceutical sense.
A) Protection
Container closure system should provide the dosage form with adequate
protection from factors (e.g., temperature, light) that can cause degradation in
the quality of that dosage form over its shelf life. Common causes of such
degradation are: exposure to light, loss of solvent, exposure to reactive gases
(e.g., oxygen), absorption of water vapor, and microbial contamination. A drug
product can also suffer an unacceptable loss in quality if it is contaminated by
filth.
Atorvastatin tablet is packed in Alu-Alu strip of aluminium foil to protect the
quality of the dosage form.
B) Compatibility
Packaging components aluminium foil and Rigid PVC film does not interact
sufficiently to cause unacceptable changes in the quality of the dosage form.
Examples of interactions include loss of potency due to absorption or
adsorption of the active drug substance, or degradation of the active drug
substance induced by a chemical entity leached from a packaging component;
reduction in the concentration of an excipient due to absorption, adsorption or
leachable-induced degradation; precipitation; changes in drug product pH;
- 18 -
discoloration of either the dosage form or the packaging component; or
increase in brittleness of the packaging component.
Some interactions between a packaging component and dosage form will be
detected during qualification studies on the container closure system and its
components. Others may not show up except in the stability studies. Therefore,
any change noted during a stability study that may be attributable to interaction
between the dosage form and a packaging component should be investigated
and appropriate action taken, regardless of whether the stability study is being
conducted for an original application, a supplemental application, or as
fulfillment of a commitment to conduct post approval stability studies.
Atorvastatin tablet is packed in Alu-Alu strip of aluminium foil is checked for
its stability during its shelf life. On the basis of Stability studies report the drug
is found stable and does interacted with drug component. No potency loss &
colour changes were observed during storage.
C) Safety
Packaging components should be constructed of materials that will not leach
harmful or undesirable amounts of substances to which a patient will be
exposed when being treated with the drug product. This consideration is
especially important for those packaging components which may be in direct
contact with the dosage form, but it is also applicable to any component from
which substances may migrate into the dosage form (e.g., an ink or adhesive).
Making the determination that a material of construction used in the
manufacture of a packaging component is safe for its intended use is not a
simple process, and a standardized approach has not been established. There is,
however, a body of experience which supports the use of certain approaches
that depend on the route of administration and the likelihood of interactions
between the component and the dosage form (see Table 1).
The approach for toxicological evaluation of the safety of extractables should
be based on good scientific principles and take into account the specific
container closure system, drug product formulation, dosage form, route of
administration, and dose regimen (chronic or short-term dosing).
For drug products that undergo clinical trials, the absence of adverse reactions
traceable to the packaging components is considered supporting evidence of
material safety.
Based upon above conducted tests, Atorvastatin tablet is found to be safe and
non toxic on storage in Alu-Alu packing
- 19 -
D) Performance
Performance of the container closure system refers to its ability to function in
the manner for which it was designed. A container closure system is often
called upon to do more than simply contain the dosage form. When evaluating
performance, two major considerations are container closure system
functionality and drug delivery.
Container Closure System Functionality
The container closure system may be designed to improve patient compliance.
Drug Delivery
Drug delivery refers to the ability of the packaging system to deliver the dosage
form in the amount or at the rate described in the package insert. Some
examples of a packaging system for which drug delivery aspects are relevant
are a prefilled syringe, a transdermal patch, a metered tube, a dropper or spray
bottle, a dry powder inhaler, and a metered dose inhaler.
Container closure system functionality and/or drug delivery are compromised
when the packaging system fails to operate as designed. Failure can result from
misuse, faulty design, manufacturing defect, improper assembly, or wear and
tear during use. Tests and acceptance criteria regarding dosage form delivery
and container closure system functionality should be appropriate to the
particular dosage form, route of administration, and design features.
E) Summary
Table 2 summarizes typical packaging suitability considerations for common
classes of drug products.
Table 2
Typical Suitability Considerations for Common Classes of Drug Products
(This table is a general guide, and is not comprehensive)
Route of
Administration/
Dosage Form
Inhalation Aerosols and
Solutions, Nasal Sprays
SUITABILITYa
Protection Compatibility
L, S, M,
W, G
Case 1c
- 20 -
Safety
Performance/Drug
Delivery
Case 1s
Case 1d
Inhalation Powders
L, W, M
Case 3 c
case 5s
Case 1d
Injections, Injectable
Suspensionsb
L, S, M, G
Case 1c
Case 2s
Case 2d
Sterile Powders and
Powders for Injection
L, M, W
Case 2c
Case 2s
Case 2d
Ophthalmic Solutions and
Suspensions
L, S, M, G
Case 1c
Case 2s
Case 2d
Topical Delivery Systems
L, S
Case 1c
Case 3s
Case 1d
Topical Solutions and
Suspensions, and Topical
and Lingual Aerosols
L, S, M
Case 1c
Case 3s
Case 2d
Topical Powders
L, M, W
Case 3c
Case 4s
Case 3d
Oral Solutions and
Suspensions
L, S, M
Case 1c
Case 3s
Case 2d
Oral Powders
L, W
Case 2c
Case 3s
Case 3d
Oral Tablets and Oral
(Hard and Soft Gelatin)
Capsules
L, W
Case 3c
Case 4s
Case 3d
*
If there is a special performance function built into the drug product it is of
importance for any dosage form/route of administration to show that the
container closure system performs that function properly.
Explanation of Codes in Table 2:
Protection:
L (protects from light, if appropriate)
S (protects from solvent loss/leakage)
M (protects sterile products or those with microbial limits
from microbial contamination)
W (protects from water vapor, if appropriate)
G (protects from reactive gases, if appropriate)
- 21 -
Compatibility: Case 1c: Liquid-based dosage form that conceivably could
interact with its container closure system components (see
examples
described
in
section
III.B.1)
Case 2c: Solid dosage form until reconstituted; greatest
chance for interacting with its container closure system
components
occurs
after
it
is
reconstituted.
Case 3c: Solid dosage form with low likelihood of interacting
with its container closure system components.
Safety:
Case 1s: Typically provided are USP Biological Reactivity
Test data, extraction/toxicological evaluation, limits on
extractables, and batch-to-batch monitoring of extractables.
Case 2s: Typically provided are USP Biological Reactivity
Test data and possibly extraction/toxicological evaluation.
Case 3s: Typically, an appropriate reference to the indirect
food additive regulations is sufficient for drug products with
aqueous-based solvents. Drug products with non-aqueous
based solvent systems or aqueous based systems containing
co-solvents generally require additional suitability information
(see section III.F).
Case 4s: Typically, an appropriate reference to the indirect
food additive regulations is sufficient.
Case 5s: Typically, an appropriate reference to the indirect
food additive regulations for all components except the
mouthpiece for which USP Biological Reactivity Test data is
provided.
Performance:
Case 1d: Frequently a consideration
Case 2d: May be a consideration
Case 3d: Rarely a consideration
Atorvastatin tablet is packed in Alu-Alu strip of aluminium foil.
There was no interaction between Primary Packing material and drug
product, which ensured the safety of aluminium foil and Rigid PVC film as
primary packaging material.
Both the Primary and Secondary Packaging materials are duly tested as per the
following Specifications in Quality Control Laboratory & only those
complying with the set In – House specifications are used.
- 22 -
Packaging material is routinely studied for Compatibility and Stability and the
results have indicated that there is no interaction between Primary Packaging
Material and the Drug Product.
Final proposed formula
Ingredient
Specification
Qty
/Tablet
Overage
Qty./Batch
Active Ingredient
Atorvastatin calcium
I.P.
11.10 mg
=
10.0 mg
Atorvasta
tin
--
1.110 kg
I.P.
I.P.
30.00 mg
122.0 mg
---
I.P.
I.P.
I.P.
-5.0 mg
5.0 mg
-------
10.00 liters
0.500 kg
0.500 kg
2.0 mg
---
0.200 kg
Inactive Ingredient
Maize Starch
Microcrystalline
cellulose
Purified Water
Purified Talc
Sodium Starch
Glycollate
Colloidal Anhydrous
Silica
Film Coating
Titanium Dioxide
Hydoxypropyl
methylcellulose
Povidone
Methylene Chloride
Isopropyl alcohol
I.P.
3.00 kg
12.20 kg
I.P.
I.P.
1.0 mg
4.0 mg
0.100 kg
0.400 kg
I.P.
B.P.
I.P.
1.0 mg
---
0.100 kg
4.0 liters
7.0 liters
- 23 -
Manufacturing Steps-Flow Chart
PROCESS FLOW CHART:
Actives & Diluents
# 30, 16, 100 mesh
Binder Paste
Dry Mixing
Granulation in RMG &
Drying
Oscillator & Multimill
Sizing
Blending
Compression of Tablets
Coating
Packing
- 24 -
Sifted
Excipients
Manufacturing Methods
S.No.
Operation
Procedure
1.
Weight
Checking
Check the weight of all the ingredients and record in
the flow - sheet of batch production record (BMR).
2.
Sifting
Pass all the raw materials through mechanical sifter
mesh # 30, separately to avoid foreign materials if any.
Mentioned in the dispensing sheet.
3.
Preparation
of Paste
Measure 10.00 liters Purified water in SS container,
add Maize Starch and stir well to make slurry & sift
from 100 # SS sieve.
4.
Dry mixing
and
granulation
Load the sifted material In RMG and Dry mix the
material for 10 minutes with Mixer at slow speed and
keep the Chopper OFF.
Charge the paste of above step slowly in RMG, with
impeller at slow speed and chopper at OFF position.
Continue the mixing with Mixer and Chopper at slow
speed. Rack the material then continue the mixing.
Mix with impeller and Chopper at fast speed for 5
minutes, till desired wet mass achieved. IF required
add additional purified Water.
Unload the wet mass in FBD bowl impeller and
Chopper at slow speed.
5.
Drying
Air dries the wet mass for 10 minutes.
Then continue the drying at Inlet temperature 70 to 80
°c till the outlet temperature reaches to 50 to 55°C.
Check moisture content and if required continue
drying till LOD not more than 1.5 to 2.5% w/w at
105°c.
Record the observations in given table. Time taken for
drying of each lot 45 minutes.
6.
Sifting and
Milling
Sift the dried granules through 16# SS Sieve fitted to
the sifter, collect the sifted granules in cleaned plastic
container lined with polythene bag and affix proper
status label.
Mill the granules retained on sieve through 2.50 mm
SS Screen fitted to the Multimill, collect the milled
granules in cleaned plastic container lined with
- 25 -
polythene bag.
Record the sifting and milling activity in given table.
Check the weight of sifted and milled granules and
record in BMR
7.
Lubrication
Transfer the sifted and milled granules of step F to the
blending area.
Transfer the sifted lubricants of step B to the blending
area.
Record the observation in given table Time of
Lubrication -10 minutes
Unload the lubricated granules in containers lined with
double polythene bags.
Check the weight of lubricated granules and record the
observation in given table.
Check the physical parameter of lubricated granules
and record the observation in the BMR.
8.
Sampling
Store the weighed lubricated material in well closed
containers lined with polyethylene and intimate the
Quality Assurance Department to draw a sample for
assay and moisture content determination. Determine
the percentage yields of the granules.
9.
Machine
Release
The tableting cabin must be free from left outs of the
previous batch and incorporate machine release report
in BMR.
10.
: 27 Station / Rotary
Compression Machine
Fix the standard dies and punches set on the
compression machine. Bring approved lubricated
granules to the machine.
Load the hopper of the compression machine with
granules & adjust the tablet parameters detailed below
for the compressed tablets.
Weight of 20 tablets
Average Weight
D. T.
: 3.50 gm
: 175 mg
: Not more than 15
minutes
Friability
: Not more than
1.00%
Weight Variation
:  7.5%
Check the average weight, weight variation, hardness,
friability & disintegration time as per standard
- 26 -
operating procedure for compression & record on the
compression sheet.
After the compress job is over, weigh the compressed
tablets and record in the BMR and calculate yield
11.
In- Process
Check
Intimate the Quality Assurance Department to check
the average weight, weight variation, hardness,
friability and disintegration time.
Resume compression after obtaining the approval from
in- process supervisor. Store the compressed tablets in
polyethylene lined drum.
12.
Sampling of
compressed
Tablets
During the compression, intimate the Quality
Assurance Department to draw the sample of
compressed tablets for complete analysis.
13.
Visual
Inspection
Send the tablets to the inspection table for inspection
of tablets.
14.
Preparation
of coating
suspension
Charge the Methylene chloride in a S.S. Container.
Add Hydoxypropyl methyl cellulose, Povidone and
Titanium Dioxide stir well.
Dilute this solution by Isopropyl alcohol stir well for
20 minutes, pass through colloid mill to form a
uniform solution.
15.
Coating
Transfer the uncoated tablets to the coating area.
Charge the uncoated tablets in the cleaned coating pan
Set the coating pan RPM in between 2-8 RPM.
Start the Inlet temperature, set the inlet temperature for
40 – 60 °C.
Preheat the tablets using air temperature till the bed
temperature reaches to 45- 55°C
Fit the 1.8 mm nozzle to the spray gun. Add the
coating solution to solution tank.
16.
Packaging
Batch is released for packing after getting approval
from Quality Assurance Department.
17.
Total No. of Record the total number of units packed in BMR.
Units packed
18.
Stability
Test the tablet for stability every six months as per
shelf life.
- 27 -
19.
Control
Sample
Original pack. Twice the quantity required for
complete analysis for a period of additional six months
to expiry.
20.
Release for
sale
The release of product should be under the signature of
Mfg. Chemist and it has to be countersigned by
Analytical Chemist.
Final conclusion:
Based on the above experiments, the following are concluded:
This process is finalized for the manufacturing process.
- 28 -
4. In-Vitro Dissolution or Drug Release
➢ In-vitro dissolution study results
Enclosed
- 29 -
5. Sites of Manufacture-Finished Product
➢ Manufacturer name, address and responsibility
Niramaya Pharmaceuticals (P) Ltd.
Village Juddi Khurd Barotiwala Road,
Baddi, Distt. Solan, Himachal Pradesh, INDIA
- 30 -
6. Detailed Description and Validation of the Manufacturing Procedure
for the Finished Product
➢ Detail description of the manufacturing procedure
FLOW CHART FOR THE MANUFACTURING
Actives & Diluents
# 30, 16, 100 mesh
Binder Paste
Dry Mixing
Granulation in RMG &
Drying
Oscillator & Multimill Sizing
Blending
Compression of Tablets
Coating of Tablets
Packing
- 31 -
Sifted
Excipients
EQUIPMENT USED IN MANUFACTURING
Sr. No
Department
1
Granulation
Name of
Machine /
Equipment
30” S.S. Sifter
2
Granulation
S.S. Multi mill
3
Granulation
4
Granulation
5
Granulation
6
Granulation
7
Compression
8
Compression
Jacketed Steam
Kettle
Rapid Mixer
Granulator- 160
Kg.
Fluid Bed Dryer160 kg
Octagonal
Blender
320 kg
Compression
machine
Dedusters
9
Compression
Dust Extractor
10
Coating
Auto coater
11
Packing
Alu-Alu packing
machine
- 32 -
Equip.
I.D. No
Cleaned as per
SOP No.
MG/PDP/SIF001
PDP/11
MG/PDP/MLM0
01
MG/PDP/PST00
1
MG/PDP/RMG0
01
PDP/27
MG/PDP/FBD00
1
MG/PDP/OGB00
1
PDP/24
MG/PDP/COM0
01
MG/PDP/DED00
1
MG/PDP/DUD00
1
MG/PDP/AUC00
1
MG/PDP/BLS00
1
PDP/31
PDP/23
PDP/21
PDP/26
PDP/32
PDP/33
PDP/34
PDP/47
Quality Control of Raw Material
Check list for In-Process
RAW MATERIAL STORE
1. The doors are closed of all stores
(under Test, Approved, etc.)
: Checked after each operation
2. To collect sample requisition slip
from raw material store
: Slip collected and duly filled.
3. Each and every room of store is
sufficiently cleaned and free from
environment for microbes
: Check for cleanliness and
environmental microbes
4. After collecting requisition slip
: Lab. records duly maintained.
inform immediately to the laboratory
5. Under Test sticker are there on
container or not
: Test striker checked.
6. Sample is done by stipulated plans
: Performed
7. To ensure all containers received
: Check for container condition and
are in good condition and not damage replaced the damaged ones.
and if it is immediately informed to Q.A.
Manager and his decision is final
8. To ensure all containers bear proper
: Container identification slip
identification slips having all necessary checked
details
9. In case all details are not there then : Availability of bills checked and Q.A.
take from bills and in case still not
manager informed.
available then bring such matters in
notice of Q.A. Manager
10. Open container with the help of
: Check for temper proof packing.
helper and confirm the inner packing
are all intact. In case of tempering
inform Q.A. Manager
11. Physically check all materials for
any odour black particles etc.
: The physical characteristics are
duly taken care for any discrepancies.
- 33 -
12. Sampling is done by completely
mixing the material with the use
of spoon etc.
: Checked the spoon for any foreign
matter
13. Sampling is done in self looked
: Check the polythene bag
polythene bags having all necessary
details
14. After sampling the containers are
not left open properly tied
: Check for proper closure of container
after use.
15. After material is approved /rejected : Performed accordingly.
by Q.A. Manager and giving all
details of A.R. numbers and date and
stock approved sample or rejection one
and transfer in respective room
16. Humidity is properly checked
: Should not be more than 45%
- 34 -
MANUFACTURING PROCESS
Cleaning Instructions
Ensure the following before commencing the production:
1. The floor and ceilings of the area should be thoroughly cleaned and should
not contain any foreign material attached to these.
2. All equipments are cleaned and washed thoroughly.
No material of
previously run material should stick to these. When machine is ready for
use, approval should be obtained from the quality Assurance Department
after checking the wash-water content.
3. The raw material required must be previously checked for labels and
weight.
4. Proper temprature and humidity records should be maintained throughout
the processing as per the instructions.
5. Equipments and containers should be labelled at each and every stage of
manufacturing.
Process Instructions
1. All processing should be carried out under the strict supervision of a
Qualified Competent Staff.
2. Production personnel should wear gloves and masks before they enter the
mixing area and while handling material.
3. Temperature and Relative Humidity (RH) should be recorded.
- 35 -
MANUFACTURING INSTRUCTIONS
I.
Good Manufacturing Practices:
To ensure a quality production, all current manufacturing practices should be
followed such as :
1.
Area and Equipments
1.
The area should be free from unwanted material as well as material from
the last batch
2.
The equipments to be used should be labelled for product batch no. and
date o prior to use.
3.
The equipments to be used must bear a “clear equipment’ tag and wash
water analysis report releasing the equipment in case of product change
over.
II.
Personnel
1.
All personnel should be of good health and should practice good
sanitation habits.
2.
Persons engaged in the manufacture, processing, packing or holding of
drug product should bear protective apperen such as head, face, hand and
arm covering necessary to protect the product from contamination.
III.
Raw Material & Packing Material
1.
All ingredients and packing material must be tested for conformance to
written specifications.
2.
Weight and volume of the ingredients should be checked by the
authorised persons.
IV
Production and Process Control
1.
Production record must be complete and accurate reflecting all the
procedure and process adopted during production
2.
Batch should be fabricated strictly as per the written procedure and any
deviation in the process should be approved by Q.A.
- 36 -
➢ Controls of critical steps
IN-PROCESS PRODUCT SPECIFICATION
STANDARD SPECIFICATIONS
Sr.
No.
1.
2.
3.
4.
5.
6.
Tests
Specification
Description
White coloured, round shaped, biconvex,
uncoated tablet plain on both side
Average weight of a tablet 175.0 mg
Uniformity of weights
 7.5 % of avg. wt of tablets
Disintegration Time
NMT 15 minutes.
Identification
Positive for Atorvastatin calcium
Assay
Each uncoated tablet contains
Atorvastatin calcium
(NLT 90.0% & NMT 110.0%)
Equivalent to Atorvastatin 10 mg 9.0 mg to 11.0 mg
STANDARD SPECIFICATIONS
Sr.
No.
1.
2.
3.
4.
5.
6.
Tests
Specification
Description
White coloured, round shaped, biconvex,
film coated tablet plain on both side
Average weight of a tablet 181.0 mg
Uniformity of weights
 7.5 % of avg. wt of tablets
Disintegration Time
NMT 30 minutes.
Identification
Positive for Atorvastatin calcium
Assay
Each film coated tablet contains
Atorvastatin calcium
(NLT 90.0% & NMT 110.0%)
Equivalent to Atorvastatin 10 mg
9.0 mg to 11.0 mg
- 37 -
➢ Description of the manufacturing process
Manufacturing Methods
S.No.
Operation
Procedure
1.
Weight
Checking
Check the weight of all the ingredients and record in
the flow - sheet of batch production record (BMR).
2.
Sifting
Pass all the raw materials through mechanical sifter
mesh # 30, separately to avoid foreign materials if any.
Mentioned in the dispensing sheet.
3.
Preparation
of Paste
Measure 10.00 liters Purified water in SS container,
add Maize Starch and stir well to make slurry & sift
from 100 # SS sieve.
4.
Dry mixing
and
granulation
Load the sifted material In RMG and Dry mix the
material for 10 minutes with Mixer at slow speed and
keep the Chopper OFF.
Charge the paste of above step slowly in RMG, with
impeller at slow speed and chopper at OFF position.
Continue the mixing with Mixer and Chopper at slow
speed. Rack the material then continue the mixing.
Mix with impeller and Chopper at fast speed for 5
minutes, till desired wet mass achieved. IF required
add additional purified Water.
Unload the wet mass in FBD bowl impeller and
Chopper at slow speed.
5.
Drying
Air dries the wet mass for 10 minutes.
Then continue the drying at Inlet temperature 70 to 80
°c till the outlet temperature reaches to 50 to 55°C.
Check moisture content and if required continue
drying till LOD not more than 1.5 to 2.5% w/w at
105°c.
Record the observations in given table. Time taken for
drying of each lot 45 minutes.
6.
Sifting and
Milling
Sift the dried granules through 16# SS Sieve fitted to
the sifter, collect the sifted granules in cleaned plastic
container lined with polythene bag and affix proper
status label.
Mill the granules retained on sieve through 2.50 mm
- 38 -
SS Screen fitted to the Multimill, collect the milled
granules in cleaned plastic container lined with
polythene bag.
Record the sifting and milling activity in given table.
Check the weight of sifted and milled granules and
record in BMR
7.
Lubrication
Transfer the sifted and milled granules of step F to the
blending area.
Transfer the sifted lubricants of step B to the blending
area.
Record the observation in given table Time of
Lubrication -10 minutes
Unload the lubricated granules in containers lined with
double polythene bags.
Check the weight of lubricated granules and record the
observation in given table.
Check the physical parameter of lubricated granules
and record the observation in the BMR.
8.
Sampling
Store the weighed lubricated material in well closed
containers lined with polyethylene and intimate the
Quality Assurance Department to draw a sample for
assay and moisture content determination. Determine
the percentage yields of the granules.
9.
Machine
Release
The tableting cabin must be free from left outs of the
previous batch and incorporate machine release report
in BMR.
10.
: 27 Station / Rotary
Compression Machine
Fix the standard dies and punches set on the
compression machine. Bring approved lubricated
granules to the machine.
Load the hopper of the compression machine with
granules & adjust the tablet parameters detailed below
for the compressed tablets.
Weight of 20 tablets
Average Weight
D. T.
Friability
Weight Variation
- 39 -
: 3.50 gm
: 175 mg
: Not more than 15
minutes
: Not more than
1.00%
:  7.5%
Check the average weight, weight variation, hardness,
friability & disintegration time as per standard
operating procedure for compression & record on the
compression sheet.
After the compress job is over, weigh the compressed
tablets and record in the BMR and calculate yield
11.
In- Process
Check
Intimate the Quality Assurance Department to check
the average weight, weight variation, hardness,
friability and disintegration time.
Resume compression after obtaining the approval from
in- process supervisor. Store the compressed tablets in
polyethylene lined drum.
12.
Sampling of
compressed
Tablets
During the compression, intimate the Quality
Assurance Department to draw the sample of
compressed tablets for complete analysis.
13.
Visual
Inspection
Send the tablets to the inspection table for inspection
of tablets.
14.
Preparation
of coating
suspension
Charge the Methylene chloride in a S.S. Container.
Add Hydoxypropyl methyl cellulose, Povidone and
Titanium Dioxide stir well.
Dilute this solution by Isopropyl alcohol stir well for
20 minutes, pass through colloid mill to form a
uniform solution.
15.
Coating
Transfer the uncoated tablets to the coating area.
Charge the uncoated tablets in the cleaned coating pan
Set the coating pan RPM in between 2-8 RPM.
Start the Inlet temperature, set the inlet temperature for
40 – 60 °C.
Preheat the tablets using air temperature till the bed
temperature reaches to 45- 55°C
Fit the 1.8 mm nozzle to the spray gun. Add the
coating solution to solution tank.
16.
Packaging
Batch is released for packing after getting approval
from Quality Assurance Department.
17.
Total No. of Record the total number of units packed in BMR.
Units packed
- 40 -
18.
Stability
Test the tablet for stability every six months as per
shelf life.
19.
Control
Sample
Original pack. Twice the quantity required for
complete analysis for a period of additional six months
to expiry.
20.
Release for
sale
The release of product should be under the signature of
Mfg. Chemist and it has to be countersigned by
Analytical Chemist.
- 41 -
MASTER PACKING PROCEDURE
PACKAGING PROGRESS
GENERAL
Packing should be completed within 8 days after checking as per
1
specified lead time for various manufacturing process.
2
Check the Alu-Alu packing machine and packaging area for any leftover
packaging material belonging to previous product / batch. Area should be
clean, tidy and free from any dust.
3
Set the machine as per Standard Operating Procedure for Alu-Alu
Packing Machine (SOP/MO-036) using correct change parts. Set the
temperature of rollers between 135 to 140 C. Maintain the strip sealing
room at temperature between 25-30 C and relative humidity between
45-55% RH. Operate the machine as per Standard Operating Procedure
for Alu-Alu Packing Machine (SOP/MO-036). In case of product change
over machine is set as per Standard Operating Procedure for setting of
Alu-Alu packing machine at the time of product change over (SOP/MO036).
4
Transfer the tablets from tablets quarantine to packaging area. Weigh the
tablets and record the weight in BMR.
5
Line Clearance: Get the line clearance from IPQC chemist as per
Standard Operating Procedure (SOP/DOC-14) after above mentioned
setting. Set the machine using printed aluminium foil
6
Get correct rubber stereos for the batch and fix them on printing unit.
Destroy the stereos after completion of the batch. Refer Standard
Operating Procedure for Rubber Stereos (SOP/DOC/BM-01).
Print the batch details such as batch number, manufacturing date, expiry
date & price (in case of sample pack price shall not be appear) and
manufacturing license number (if it is not preprinted) using violet ink and
print ‘PHYSICIAN’S SAMPLE NOT TO BE SOLD’ red line (for
sample pack). Adjust the printing quality of sharpness of letters.
7
8
Check the printing details as per batch record, sign and get them
counterchecked and sign by IPQC Chemist.
9
Attach one sample overprinted foil to BMR. The sample should be
checked and signed by packaging supervisor and IPQC Chemist.
- 42 -
10
Check the relative humidity and room temperature every two hours and
record.
11
Start the machine and get some strips (total number of tablets should be
equal to the number of cavities of the roller initially) and subject them to
leak test as per standard operating procedure for leak test of Alu-Alu and
Strips (SOP/DOC-61).
12
Wipe the tested strips with dry cloth and check the Alu-Alu for moisture
penetration by carefully cutting all the pockets.
13
If leak test is O.K. run the machine. If leak test is not satisfactory, rectify
the problem, recheck for leak test and only after, all the Alu-Alu comply
for leak test, that Alu-Alu sealing shall be continued.
14
Perform the leak test every 2 hours and discard the leak tested tablets.
Record the observation in BMR.
15
Similar procedure is adopted and Alu-Alu for sample pack is done by
using different change parts so as to give a Alu-Alu of 4 tablets, after
removing price and using stereos for P.S. legend, ’PHYSICIAN’S
SAMPLE NOT TO BE SOLD’ (to be printed on plain alu foil ).
SALES PACK 10 x 10 Tablets
1
Draw the cartons and other packaging materials from the stores as per
Packaging Material Requirements, raising Material Requisition Slip as per
standard operating procedure for Receipt & Issue of Raw Material /
Packaging Material (SOP/DOC-52).
2
Line Clearance: Get the Line Clearance from IPQC Chemist as per
standard operating procedure (SOP/DOC-14) before commencing
overprinted activity. The area should be free from leftover cartons or any
other material of earlier product/batch. Respective stereos should be fixed
to get required printing details.
3
Overprint the cartons with batch details (batch number, manufacturing
date, expiry date, manufacturing license number, price) as per standard
operating procedure for Overprinting M/c-Hand / electrical, (SOP/MO030).
- 43 -
4
Check the details as per batch record and get them counterchecked by
IPQC Chemist. Sign and attach one such sample to Batch Manufacturing
Record and one to overprinting registers.
5
Check the Alu-Alu of 10 tablets for any defect like cut pockets, improper
printing, improper sealing etc.
6
Pack 10 x 10 in each carton along with one literature.
7
Pack these cartons in a printed duplex board box.
8
Check the printed details on the box (product name, batch number, mfg.,
and Exp. Date, quantity, address, packer’s name) and seal the box with 2
inch printed BOPP tape.
9
Overprint 7 Ply corrugated boxes with batch number, quantity and put box
number and packer’s name on the boxes.
10
Check the printed details on the box (product name, batch number, mfg.,
and Exp. Date, quantity, address, box number, packer’s name) and seal the
box with BOPP tape.
11
Inform IPQC chemist to collect sample for analysis. Q.C. shall carry out
complete analysis on final pack.
12
Destroy excess overprinted packaging materials if any in presence of IPQC
chemist as per standard operating procedure for Distruction of Rejection
(SOP/DOC-08). Record and reconcile the quantities after returning the
balance quantities of unprinted packaging material to the stores.
Remove the control sample (4 x 10 x 10 tablets) and sample it as “Control
Sample-Not for Sale”.
13
14
Record the total quantity packed and reconcile the yield.
15
Prepare internal Transfer Note and transfer the packed goods to BSR.
NOTE: In case the yield is within 2% of the standard norm, the batch shall
be released by Q. A. M, provided he is satisfied with the
justification given by Production Manager. If the yield is below 2%
of the standard norm of 97.5% and 2% above the standard norm of
99.8%, the batch shall not be released unless authorization is
obtained from V.P.(Operation). The detailed investigation should be
carried out for the deviation in the yield, observation should be
recorded and authorization obtained from V.P.(Operations), on the
form ‘Justification for Deviation in Yield’.
- 44 -
➢ Process validation data (manufacturing process, validation protocol, and
manufacturing process validation report)
OBJECTIVES
The intention of this validation exercise is to demonstrate that the equipment
and formulation process employed by Niramaya Pharmaceuticals (P) Ltd.
at Village Juddi Khurd Barotiwala Road, Baddi, Distt. Solan, Himachal
Pradesh, for Atorvastatin Tablets consistently produces material, which meets
the required specification.
Further, more supporting activities will ensure the conditions and procedures
are maintained to a level that guarantees compliance with the expectations of
Good Manufacturing Practice and Safety, Health and Environmental
requirements.
The Validation Master Plan describes the process by which the exercise will be
managed and documented.
SCOPE AND BACKGROUND
The scope of this protocol is limited to first three consecutive commercial scale
batches manufactured with specific batch size and specified equipment and
operating parameters for Atorvastatin Tablets.
A project team has been formed to complete the task and their roles and
document responsibilities have been defined.
RESPONSIBILITY
The project team for the process validation will perform the validation and
make a report of the data generated during validation process.
The production team will prepare the validation protocol, execute the
validation batches as per the batch production records and will compile the
report.
Quality assurance will review and approve the process validation protocol and
report.
Quality control will review the validation protocol and report; analyze the
samples collected during validation study.
Engineering department will support the study by providing the necessary
utilities.
- 45 -
Following are the members of the process validation team.
1.
Sr. Manager (Quality Assurance)
2.
Manager (Operations)
3.
Manager (Engineering)
4.
Dy. Manager (Quality Assurance)
5.
Manager (Quality Control)
6.
Dy. Manager (Quality Control)
REVALIDATION
The validation process shall be re-validated on account of following cases:
1. When there is change or major preventive maintenance of the equipment.
2. When there is change in processing equipment.
3. When there is a product failure.
4. When there is change in cleaning equipment.
5. When there is change in raw material or change of raw material itself.
6. When there is change in procedures.
Revalidation shall be done at least one time in a year.
VALIDATION TECHNIQUE
The objective of the whole exercise is to show that the process operated by and
the facilities used by Niramaya Pharmaceuticals (P) Ltd. can routinely
produce Atorvastatin Tablets that meets the required specification.
The process is sufficiently controlled to ensure that is operated within the
specified conditions and yield of product is within the expected range.
The validation will be controlled by this VMP, a series of protocols and
subsequent reports.
The protocols describe the activities to be completed and the acceptance
criteria. These documents must be available in advance of any activity.
All protocols will be written and approved by the staff indicated in Appendix 1.
Similarly any changes to the protocol must be documented, justified and
authorized.
Upon completion of each phase (DQ, IQ, OQ, PQ, CV) a report will be issued
by the responsible person, QA Manager.
At the end of the complete exercise a validation summary report will be
prepared covering all stages of the project. This will include conclusions from
each phase, comments on supporting activities e.g. Training, Calibration, and
actions from any GMP audits together with a final statement on the validation
status of the process.
- 46 -
The project is divided into a number of phases, the activities and requirements
for each phase are outlined below.
Design Qualification (DQ)
The objective of this section is to show that the design of the plant (and
supporting utilities) are such that they will allow the consistent formulation of
Atorvastatin Tablets to the requirements of the process description.
A DQ protocol will be produced and approved prior to commencement of the
exercise. Upon completion a DQ certificate will be issued. Any revisions to the
plant will be subjected to formal change control.
An "as built" Engineering Line Diagram (ELD) will be in place and signed by
responsible staff of the appropriate disciplines (including QA) to show that the
plant meets the needs of the process.
An equipment list of main plant items will be prepared from the ELD together
with equipment specifications. These will be identified and listed.
Installation Qualification (IQ)
The objective of this section is to show that the system has been installed in
line with the finalized ELD's. This is achieved by engineering completing
checklist.
As part of the IQ confirmation will be made that all critical instruments have
been calibrated within the acceptable ranges and entered into a calibration
schedule. In addition a planned preventive maintenance schedule will be in
place for the key equipment.
A protocol will be written and approved prior the exercise. Upon completion a
report and certificate will be prepared and authorized.
Operational Qualification (OQ)
The objective of this section of the validation is to show that the plant operates
in such a manner as to be able to routinely provide and control the parameters
required by the process. This would have been achieved by solvent
"simulation", i.e. processing without raw materials and reagents. However, this
has been declared redundant as the plant is already in an operation state and i.e.
checks for leaks and correct configuration arc already demonstrated.
Furthermore the OQ phase ensures that formulation documentation is prepared
and of an appropriate standard, that relevant SOP's are available and that the
staff has been adequately trained to conduct the process and supporting
activities.
- 47 -
A protocol will be written and approved prior to the exercise. Based on the
acceptance criteria written in the protocol a report and certificate will be
written and authorized.
Process Performance Qualification (PQ)
The objective of this exercise is to show that the defined process, when
performed in qualified equipment, will generate product which consistently
meets the specification. This is achieved by checking, very closely, three
batches from VGT-1301 to VGT-1303 shows that the product has been
formulated within the defined process parameters and meets all the quality
specifications.
Prior to the PQ phase a protocol will be prepared by QA based on critical
process parameters.
The documentation used during the PQ will essentially consist of the normal
production and analytical procedures, batch sheets and specifications.
Prior to PQ it is essential that all raw materials used in the process have been
approved and that analytical methods used for assessing the product are
suitably in validated state.
Sampling plans for the exercise should also be documented.
The PQ will be deemed to have been successful once the plant performance,
process performance, product quality and plant capacity requirements have
been met.
Cleaning validation
The objective of this section of the validation is to demonstrate the capacity of
the cleaning process.
The validation process will take place in 3 cleaning processes and will end until
the completion of this 3 cleaning processes. Criteria will be evaluated and
checked for acceptance.
Deviations /Planned Changes
The existence of deviations in any of the qualification exercises does not
exclude successful validation. However they must be fully documented and a
QA review must show them to be acceptable for the exercise.
Exceptions / Reservations
Throughout the various phases of the exercise there will be a number of
observations which will give rise to "reservations".
All of these exceptions should be documented and reviewed by QA. The bulk
of exceptions should be completed prior to close out the following phase.
- 48 -
However in some instances these may be deferred until agreed al later date.
This is only being done with full QA approval.
EQUIPMENT USED IN MANUFACTURING
Sr. No
Department
1
Granulation
Name of
Machine /
Equipment
30” S.S. Sifter
2
Granulation
S.S. Multi mill
3
Granulation
4
Granulation
5
Granulation
6
Granulation
7
Compression
8
Compression
Jacketed Steam
Kettle
Rapid Mixer
Granulator- 160
Kg.
Fluid Bed Dryer160 kg
Octagonal
Blender
320 kg
Compression
machine
Dedusters
9
Compression
Dust Extractor
10
Coating
Auto coater
11
Packing
Alu-Alu packing
machine
- 49 -
Equip.
I.D. No
Cleaned as per
SOP No.
MG/PDP/SIF001
PDP/11
MG/PDP/MLM0
01
MG/PDP/PST00
1
MG/PDP/RMG0
01
PDP/27
MG/PDP/FBD00
1
MG/PDP/OGB00
1
PDP/24
MG/PDP/COM0
01
MG/PDP/DED00
1
MG/PDP/DUD00
1
MG/PDP/AUC00
1
MG/PDP/BLS00
1
PDP/31
PDP/23
PDP/21
PDP/26
PDP/32
PDP/33
PDP/34
PDP/47
PROCEDURES
Following procedures to be followed to validate the manufacturing process of
Atorvastatin Tablets to optimize the efforts needed for collection, compilation
and evaluation of the complete process of manufacturing of Atorvastatin
Tablets.
1. Ensure that correct and approved procedures are available
2. Plan three consecutive validation batches
3. Each step to be reviewed and evaluated with observations and conclusions
4. Appropriate samples to be drawn from each validation batches for testing
and stability studies
5. Validation report shall be compiled after completion of validation study and
complete analysis of last batch.
Manufacturing Stage:
Granulation Stage:
A) Parameters to be checked after dry mix :
Dry mix time
Blend uniformity (assay of Active(s)
* - Indicates approximate position of the sampling point
No. of Samples
: 9
Quantity
: 10 g/sample
Sample Identification : Ta, Tb, Ta,
Ma, Mb, Mc
Ba, Bb, Bc
B) Parameters to be checked during Granulation in RMG:
Granulation Started on: Date and Time
Granulation completed on: Date and Time
Temperature of Binder paste added
Quantity of extra water added (if any)
Time after addition of binder paste at slow speed
Time after addition of binder paste at fast speed
Load of RMG in ampere at the stage when granules are ready
Whether chopper is used while discharging from bowl
- 50 -
C) Parameters to be checked during drying in Glatt:
1. Inlet air temp.
2. Outlet air temp.
3. Drying temp.
D) LOD of granules after sizing (by I. R. at 600c/ 5 min)
Blending
Parameters to be checked during blending stage:
1
Blending time
Tests to be carried out on blended granules:
1.
Bulk density (untapped)
2.
Sieve analysis ( by 20, 40 & 60 )
3.
Angle of Repose
4.
LOD (by I. R. at 1050c for 5 min)
5.
Assay of active(s)
For test no. 1 to 4 remove the required quantity of sample from top and bottom
of the each container and make on composite sample for the tests.
- 51 -
Compression Stage:
Before starting the run, collect 20 tablets from right and left discharge chute by
Running the compression machine at slow (12-15 rpm double rotary); medium
(25-28 rpm double rotary) and high speed (35-40 rpm double rotary) with
keeping compression pressure constant. Record the RPM and Tablets per
minute. Carry all physical parameter test on these samples ( test no. 1 to 7 ) and
decide the optimum running speed of the machine for the regular run.
Tests to be carried out on compressed tablets:
1
Appearance
2
Weight variation
3
Assay of active(s)
4
Disintegration time
5
Water content by K.F.
Compression Speed (as tablets per minute) to be recorded at least three times
during the compression run (i.e. from start to end of compression).
Approx. 20 tablets to be collected from Left & Right discharge chute at evenly
spaced interval so that minimum 9 or 12 samples shall be obtained considering
the total compression run. Record the date & time of each sample is collected.
Carry all physical parameter test on these samples.
From these samples, prepare three pulled samples representing the initial,
middle & end of the compression run. Carry test no. 4 & 5 on the pooled
samples.
Total No. of pulled samples: 3
Quantity of sample
: 50 tablets / sample
- 52 -
Interpretation of Results:
Results of this study shall be compared with norms given in the Doc. No.:
& with product specification limits as per DOC No QCT-FPInterpretation of all the results shall be done by QA personal & it shall be
reviewed by Manager Production.
Release of the batch shall be with respect to the specifications for finished
product.
ACCEPTANCE CRITERIA:
Stage of Process
Limits
►
Dry Mix stage
 5 % of the Labelled Amount
►
Blended granules stage
 5 % of the Labelled Amount
►
Compression (Chemical Tests)
(Physical Tests)
As per cited STP & MFR
For all the above stages % CV shall be as per SOP no.
Reference Documents
1. Standard testing procedures
2. Standard operating procedures
3. Specification of raw material and finish products
4. DQ, IQ, OQ, PQ of machines
5. Calibration of all laboratories instrument
ACCEPTANCE CRITERIA
All monitoring and testing of the key process steps will be completed and
approved. The process qualification is performed on all processing steps to
ensure and document the consistency and / or effectiveness of the operation.
1. All raw materials must meet quality control specifications
2. All critical process parameters must be within the ranges specified in the
batch records.
3. The final yield must be within the ranges specified in the batch records.
4. All in-process tests must meet specifications as per batch records.
5. Final product must meet quality control specifications / pharmacopoeia
specifications.
- 53 -
VALIDATION REPORT AND APPROVAL
Refer Annexure - 1 to 2 for detail.
Summarize data in tabular form.
Compare all results to acceptance criteria.
Attach completed process monitoring data sheets, completed analytical test
results or additional support documentation, if any.
TYPE OF VALIDATION AND ANNEXURES
Concurrent Validation
Annexure – 1
BATCHES UNDER STUDY
Product / Brand Name
Batch No.
Batch Size
Mfg. Date
Exp. Date
Atorvastatin Tablets
MT-1421
APR- 2014
MAR -2016
Atorvastatin Tablets
MT-1422
APR- 2014
MAR -2016
Atorvastatin Tablets
MT-1423
100000
Tablets
100000
Tablets
100000
Tablets
APR- 2014
MAR -2016
- 54 -
ANNEXURE – 2
Specification and Results of Final Products
PARAMETER
SPECIFICATION
Description
Identification
White coloured, round
shaped, biconvex, film coated
tablet plain on both side
Positive for Atorvastatin
Average weight
Uniformity of weight
Disintegration Time
Dissolution
Related substances
Assay
Each film coated
tablet contains :
Atorvastatin calcium
Equivalent to
Atorvastatin 10 mg
OBSERVATION
B.NO.
B.NO.
B.NO.
MT-1421
MT-1422
MT-1423
Complies
Complies
Complies
Positive
Positive
Positive
181.0 mg
± 7.5% of average weight
180.0 mg
Complies
182.0 mg
Complies
180.2 mg
Complies
NMT 30 minutes
4 min.30 4 min 45 4 min 35 sec
sec
sec
91.15%
92.30%
90.35%
Complies
Complies
Complies
99.82%
99.78%
99.90%
NLT 75%
Complies as per IP
90.0 to 110.0% of the stated
amount
- 55 -
Annexure – 3
CLEANING VALIDATION
The cleaning validation is done as per standard protocol.
Annexure – 4
AVERAGE WEIGHT RECORD AND YIELD IN UNIT PER BATCH
PARAMETER
SPECIFICATION
B.NO.
MT-1421
Average Weight
Yield (In %/Batch)
180.0 mg
181.0 mg
Minimum 97%
98.45%
OBSERVATION
B.NO.
B.NO.
MT-1422
MT-1423
182.0 mg
98.30%
Annexure – 5
Observation
Finished Product AtorvastatinTablet is within the limit in assay, yield
(Minimum 97%) and Average weight within the limit.
Summary and Conclusion
Report shall be prepared based on the acceptance criteria established and data
collected during validation studies. All results shall be verified against the
established acceptance criteria and defined specifications. This report will state
that the process is validated.
LIST OF ABBREVIATIONS
CV Cleaning validation
DQ Design Qualification
ELD Engineering Line Diagram
GMP’s Good Manufacturing Practices
IQ
Installation Qualification
OI’s Operation Instructions
OP’s Operating Procedures
OQ Operation Qualification
PQ Process Performance Qualification
QA Quality Assurance
R&D Research & Development
SOP’s Standard Operating Procedure
VMP Validation Master Plan
VSR Validation Summary Report
- 56 -
180.2 mg
98.55%
7. Specification for Excipients
➢ List of tests and limits for result of excipient
TECHNICAL SPECIFICATION FOR ACTIVE SUBSTSNCE
NAME: ATORVASTATIN CALCIUM
SPECIFICATION: I.P.
Sr.
No.
1
2
Test Performed
Specification
Description
Identification
3
Specific rotation
A white to off White crystalline powder
Determine by infrared absorption spectrophotometry.
Compare the spectrum with that obtained with
atorvastatin calcium RS or with the reference
spectrum of atorvastatin calcium.
Between -6.0° to -12.0°
4
Related Substance
5
6
7
Heavy metal
Water
Assay
Single Maximum impurity: Not more than 0.5 %
Total Impurity: Not more than 2.0 %
Not more than 20 ppm
3.0 % to 7.0 %
NLT 98.0 % w/w and NMT 102.0 % w/w. calculated
on the anhydrous basis
- 57 -
Specification and Method of Analysis of Excipients
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: MAIZE STARCH
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
Acidity
4
5
Iron
Fluorescence
6
7
Oxidising substances
Microbial
Contamination
Sulphated ash
Loss on drying
8
9
Specification
A very fine, white or slightly yellowish
powder or irregular white masses which are
readily reducible to powder, creaks when
pressed between the fingers; odourless and
tasteless.
A. Polyhedral granules, 2 to 23 μm in size, or
rounded granules, 25 to 32 μm in diameter.
The central hilum consists of a distinct cavity
or two- to five-rayed cleft;
no concentric striations. Viewed between
crossed nicol prisms, a distinct black cross is
seen intersecting at the hilum.
B. Heat to boiling for 1 minute a suspension of
1 g in 50 ml of water and cool; a thin and
cloudy mucilage is produced with all starches
except potato starch which gives a thick and
more
transparent mucilage.
C. To 10 ml of the mucilage obtained in test B
add 0.05 ml of 0.01 M iodine; a dark blue
colour is produced, which disappears on
heating and reappears on cooling.
Not more than 2.0 ml is required to change the
colour of the solution.
NMT 40 ppm
No fluorescence should be visible under
screened ultra-violet light
No distinct brown or blue colour is observed.
1 g is free from Escherichia coli and
salmonellae
NMT 0.6 %
NMT 15.0%
- 58 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: MICROCRYSTALLINE CELLULOSE
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
4
pH
Starch and dextrins
5
Organic impurities
6
Water-soluble
substances
Arsenic
Heavy metals
Sulphated ash
Loss on drying
Assay
7
8
9
10
11
Specification
A fine or granular, white or almost white powder;
odourless
A. To about 1 mg add 1 ml of phosphoric acid,
heat on a water-bath for 30 minutes, add 4 ml of a
0.2 per cent w/v solution of catechol in phosphoric
acid and heat for further 30 minutes;
a red colour is produced.
B. To 50 mg add 2 ml of iodine solution, allow to
stand for 5 minutes and remove the excess reagent
with the aid of a filter paper and add 1 or 2 drops of
sulphuric acid (66 per cent v/v); a blue-purple
colour is produced.
C. Mix 30 g with 270 ml of water, mix in a blender
at 18,000 rpm for 5 minutes, transfer 100 ml of the
mixture to a 100-ml graduated cylinder and allow
to stand for 3 hours. A white, opaque,
bubble-free dispersion is obtained that does not
produce a supernatant liquid.
5.0 to 7.5
Mix 0.1 g with 5 ml of water by vigorous shaking
and add 2 to 3 drops of iodine solution; no blue or
brownish-red colour is produced
Place 10 mg on a watch-glass and add 0.05 ml of a
freshly prepared solution of 0.1 g of phloroglucinol
in 5 ml of hydrochloric acid; no red colour is
produced
NMT 0.2 %
NMT 2 ppm
NMT 10 ppm
NMT 0.2%
NMT 6.0%
NLT 97.0 % and NMT 102.0 % of cellulose,
calculated on the dried basis.
- 59 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: PURIFIED WATER
SPECIFICATION: I.P.
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
Test Performed
Specification
Description
Acidity or alkalinity
Ammonium
Calcium and
magnesium
Heavy metals
Chloride
Nitrate
Sulphate
Oxidisable substances
Residue on
evaporation
Aluminum
Bacterial endotoxins
A clear, colourless liquid; odourless and
tasteless
To Comply as per IP
NMT 0.2 ppm
To Comply as per IP
NMT 0.1 ppm
To Comply as per IP
NMT 0.2 ppm
To Comply as per IP
To Comply as per IP
NMT 0.001%
NMT 10 ppb
NMT 0.25 Endotoxin Unit per ml
- 60 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: PURIFIED TALC
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
4
5
7
Acidity or alkalinity
Iron
Acid-soluble
substances
Water-soluble
substances
Carbonates
8
9
Chloride
Organic compounds
10
Loss on Drying
6
Specification
A white or almost white powder, free
from grittiness; readily adheres to the
skin; unctuous to the touch; odourless
A. When examined microscopically,
shows irregular plates, the majority less
than 50 μm in length.
B. By Reaction; a white, crystalline
precipitate is produced.
C. Gives the reaction of silicates
To Comply as per IP
NMT 10 ppm
NMT 2.0%.
To Comply as per IP
To 1 g add 20 ml of dilute hydrochloric
acid; no effervescence is produced
NMT 250 ppm
The residue obtained in the test for Loss
on drying is not more than slightly
yellow or grey.
NMT 1.0 %
- 61 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: SODIUM STARCH GLYCOLATE
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
4
5
6
7
8
pH .
9
10
Heavy metals
Iron
Sodium chloride
Sodium glycollate
Microbial
Contamination
Loss on Drying
Assay
Specification
A very fine, white or off-white, freeflowing powder; odourless or almost
odourless.
A. Determine by infrared absorption
spectrophotometry
Compare the spectrum with that
obtained with sodium starch glycollate
RS or with the reference spectrum of
sodium starch glycollate.
B.By Reaction; a dark blue colour is
produced.
C. The solution obtained in the test for
Heavy metals gives the reactions of
sodium salts
5.5 to 7.5.
NMT 20 ppm
NMT 20 ppm
NMT 10% w/w
To Comply as per IP
1.0 g is free from Escherichia coli and
Salmonellae
NMT 10.0 %
Contains NLT 2.8 % and NMT 4.5 % of
sodium, Na
- 62 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: COLLOIDAL ANHYDROUS SILICA
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
4
5
6
7
8
pH .
Arsenic
Heavy metals
Chlorides
Loss on ignition
Assay
Specification
A light, fine, white, amorphous powder.
It has a particle size of about 15 nm
About 20 mg gives the reaction of
silicates
3.5 to 2.5.
NMT 8 ppm
NMT 25 ppm
NMT 250 ppm
NMT 5.0%
NLT 99.0 % and NMT 100.5 % of
SiO2, calculated on the ignite basis.
- 63 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: TITANIUM DIOXIDE
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
Appearance of
solution.
4
5
Acidity or alkalinity
Water-soluble
substances
Arsenic
Barium
Heavy metals
Iron
Assay
6
7
8
9
10
Specification
A white or almost white, infusible
powder; odourless
A. When strongly heated it becomes
pale yellow; the colour is discharged on
cooling.
B. By Reaction;an orange-red colour is
produced.
C. To 5 ml of solution A add 0.5 g of
zinc, in granules; after 45 minutes a
violet-blue colour is produced.
Solution A is not more opalescent than
opalescence
standard
OS2,
and
colourless
To Comply as per IP
NMT 0.5%
NMT 5 ppm
To Comply as per IP
NMT 20 ppm
NMT 200 ppm
NLT 98.0 % and NMT 100.5 % of
TiO2
- 64 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: HYDROXYPROPYLMETHYLCELLULOSE
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
4
pH
Appearance of
Solution
5
6
7
8
9
Apparent viscosity
Heavy metals
Chlorides
Sulphated ash
Loss on drying
Specification
A white or yellowish white, fibrous or
granular powder; almost odourless;
hygroscopic after drying
A) By Reaction- Should Comply
B) By Reaction- Should Comply
C) By Reaction- Should Comply
D) By Reaction- Should Comply
E) By Reaction- Should Comply
5.5 to 8.0
Solution A is not more opalescent than
opalescence standard OS3, and not
more intensely coloured than reference
solution YS6
75 to 140 per cent of the stated value
NMT 20 ppm
NMT 0.5%
NMT 3.0%
NMT 10.0%
- 65 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: POVIDONE
SPECIFICATION: I.P.
Sr.
No.
1
2
3
4
5
6
7
8
9
10
11
12
Test Performed
Description
Identification
Appearance of
Solution
Heavy metals
Aldehydes
Vinylpyrrolidone
Sulphated ash
Water
K-value
Nitrogen
Water
Specification
A white or yellowish white powder or
flakes; odourless or almost odourless;
hygroscopic.
A) By Infrared absorption
spectrophotometry
B) By Reaction- Should Comply
C) By Reaction- Should Comply
D) By Reaction- Should Comply
Solution A is clear, and not more
intensely coloured than reference
solution BS6 or BYS6
NMT 10 ppm
NMT 0.2%
NMT 0.2%
NMT 0.1 per cent
NMT 5.0 per cent
To Comply as per IP
To Comply as per IP
NMT 5.0 per cent
- 66 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: METHYLENE CHLORIDE (DICHLOROMETHANE)
SPECIFICATION: B.P.
Sr.
No.
1
2
Test Performed
Description
Solubility
3
Identification
4
Appearance of
solution
Acidity
Relative density
Refractive index
Ethanol, 2-methylbut2-ene and other
related substances
Free chlorine
5
6
7
8
9
10
11
12
Heavy metals
Residue on
evaporation
Water
Specification
A clear, colourless, volatile liquid
sparingly soluble in water, miscible
with alcohol
A)By Relative Density Should Comply.
B)By Refractive Index Should Comply
C)By Comparison of chromatogram
D)By Reaction Should Comply
E) By Reaction Should Comply
Should Comply
Should Comply
1.320 to 1.332.
1.423 to 1.425.
By gas chromatography- Should
Comply
Should Comply
NMT 1 ppm.
NMT 20 ppm.
NMT 0.05%
- 67 -
TECHNICAL SPECIFICATION FOR EXCEPIENTS
NAME: ISOPROPYL ALCOHOL
SPECIFICATION: I.P.
Sr.
No.
1
Test Performed
Description
2
Identification
3
4
Acidity or alkalinity
Distillation range
5
6
7
Refractive index
Weight per ml
Aldehydes and
ketones
Benzene and related
substances
Non-volatile matter
Water-insoluble
matter
Water
Specification
A clear, colourless liquid; odour,
characteristic and spirituous; flammable
A) By Reaction- Should Comply
B) By Reaction- Should Comply
To Comply as per IP
NLT 95.0 %t v/v distils between 81°
and 83°.
1.377 to 1.378,
. 0.782 g to 0.786 g
To Comply as per IP
NMT 03%
NMT 0.002%
Mix 1 volume with 19 volumes of
water; no opalescence is produced
NMT 0.5%
- 68 -
➢ Test methods
Method of Analysis of Active Raw Material
ATORVASTATIN CALCIUM
Protocol: I.P.
Atorvastatin Calcium is calcium salt of [βR,8R]-2-(4-fluorophenyl)-α, δ –
dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole1-heptanoic acid trihydrate
Atorvastatin Calcium contains not less than 98.0 per cent and not more than
102.0 per cent of C66H68 Ca F2N4O10, calculated with reference to the
anhydrous basis.
Description
A white to off White crystalline powder
Identification
Determine by Infrared absorption Spectrophotometry (2.4.6). Compare the
spectrum with that obtained with Atorvastatin Calcium RS or with reference
spectrum of Atorvastatin Calcium
Tests
Specific Optical Rotation (2.4.22) -6.0° to -12.0°, determined in 1.0 percent
w/v solution in dimethylsulphoxide
Related Substances. Determine by liquid chromatography (2.4.14)
Solvent mixture. A mixture of 40 volumes of acetonitrile and 60 volume of
water
Test Solution. Dissolve 50 mg the substance under examination in 10 ml of
methanol and dilute to 100 ml with the solvent mixture
- 69 -
Reference Soultion. (a). A 0.5 percent w/v solution of atorvastatin calciumRS
in methanol. Dilute 5 ml of the solution to 50 ml with the solvent mixture
Reference Soultion. (b). Dilute 1 ml of reference solution (a) to 100 ml with the
solvent mixture
Chromagrahic system
- a stainless steel column 25 cm x 4.6 mm, packed with octadecylsilane bonded
to porous silica (5 µm)
- Mobile phase: A. a mixture of 92.5 volumes of Acetonitrile and 7.5 volume
tetrahydrofuran.
B. a mixture of 58 volumes of a buffer solution prepared by
dissolving 5.75 g of ammonium dihydrogen orthophosphate in 1000 ml of
water and 42 volumes of mobile phase A
C. a mixture of 20 volumes of the buffer solution 20 volumes of
mobile phase A and 60 volumes of methanol
- a linear gradient porgramme using the condition given below
- spectrophotometer set at 246 mm
- 20µl loop injector
- injection delay 10 minutes
Time
Flow rate
(in min.)
0
20
35
40
55
60
(ml per min.)
1.8
1.8
1.5
1.5
1.5
1.8
Mobile
Phase B
(percent v/v)
100
100
25
25
0
100
Mobile
Phase C
(percent v/v)
0
0
75
75
100
0
Inject reference solution (a). The test is not valid unless the column efficiency
is not less than 10000 theoretical plates and tailing factor is not more than 1.5
Inject alternatively the test solution and reference solution (b).In the
chromatogram obtained with test solution, the area of any secondary peak is
not more than the area of the peak in the chromatogram obtained with the
reference solution (b) (0.5 percent) and the sum of the area of all the secondary
peaks is not more than 2 times the area of the peak in the chromatogram
obtained with the reference solution (b) (2.0 percent)
- 70 -
Ignor any peak with an area less than0.05 times the area of the peak obtained in
the chromatogram obtained with the reference solution (b) (0.05 percent)
Heavy metals (2.3.13). 1.0 g complies with the limit testfor heavy metals,
Method A (20 ppm)
Water (2.3.43) 3.0 percent to 7.0 percent determined on 3.0 g
Assay. Determine by liquid chromatography (2.4.14)
Solvent mixture. A mixture of 40 volumes of acetonitrile and 60 volume of
water
Test Solution. Dissolve 80 mg the substance under examination in 20 ml of
methanol and dilute to 200 ml with the solvent mixture. Dilute this solution
with the solvent mixture to produce a solution containing 0.008 percent w/v of
Atorvastatin calcium
Reference Soultion. Dissolve 20 mg of Atorvastatin calcium in 5 ml of
methanol and dilute to 50 ml with the solvent mixture. Dilute this solution with
the solvent mixture to produce a solution containing 0.008 percent w/v of
Atorvastatin calcium
Chromagrahic system
- a stainless steel column 25 cm x 4.6 mm, packed with octadecylsilane bonded
to porous silica (5 µm)
- Mobile phase: a mixture of 58 volumes of a buffer solution prepared by
dissolving 5.75 g of ammonium dihydrogen orthophosphate in 1000 ml of
water and 42 volumes of a mixture of 92.5 volumes of Acetonitrile and 7.5
volume tetrahydrofuran.
- flow rate 1.8 ml per minute
- spectrophotometer set at 246 mm
- 20µl loop injector
Inject the reference solution. The test is not valid unless the relative standard
deviation for replicate injections is not more than 2.0 percent
Inject alternatively the test solution and reference solution
Clculate the content of C66H68 CaF2N4O10
Storage.Store protected from light at a temperature not exceeding 30°
- 71 -
Method of Analysis of Excipients
STARCH
Protocol: I.P.
Starch consists of polysaccharide granules obtained from the caryopsis of
maize or corn, Zea mays Linn., or of rice, Oryza sativa Linn., or of wheat,
Triticum aestivum Linn., or from the tuber of potato, Solanum tuberosum Linn.,
or from the rhizomes of tapioca, Manihot utilissima Pohl.
Description. A very fine, white or slightly yellowish powder or irregular white
masses which are readily reducible to powder, creaks when pressed between
the fingers; odourless and tasteless. The presence of granules showing cracks or
edge irregularities is exceptional in starches other than wheat starch; wheat
starch may contain granules with cracks on the edges.
Identification
A. Corn or maize starch — Polyhedral granules, 2 to 23 μm in size, or rounded
granules, 25 to 32 μm in diameter. The central hilum consists of a distinct
cavity or two- to five-rayed cleft; no concentric striations. Viewed between
crossed nicol prisms, a distinct black cross is seen intersecting at the hilum.
Potato starch — Single granules, either irregular, ovoid or pear-shaped, 30 to
100 μm in size, or rounded, 10 to 35 μm in size; compound granules consisting
of groups of two to four elements are rare. Eccentric hilum; clearly visible
concentric striations. Viewed between crossed nicol prisms, a distinct black
cross is seen intersecting at the hilum.
Rice starch — Polyhedral granules, 2 to 5 μm in size, either isolated or
aggregated in ovoid masses, 10 to 20 μm in size. Central hilum poorly visible;
no concentric striations. Viewed between crossed nicol prisms, a distinct black
cross is seen intersecting at the hilum.
Tapioca starch — Principally simple granules, sub-spherical, muller-shaped or
rounded polyhedral; smaller granules 5 to 10 μm, larger granules 20 to 35 μm
in diameter; hilum, central, punctate, linear or triradiate; striations, faint,
concentric; compound granules, few, of two to three unequal components.
Wheat starch — Large discoid or, more rarely, reniform granules, 10 to 45 μm
in size; profile, elliptical and fusiform, slit along the main axis. Small rounded
or polyhedral granules, 2 to 10 μm in size. Granules of intermediate size very
rarely occur. Hilum and striations invisible or barely visible. Viewed between
crossed nicol prisms, a distinct black cross is seen intersecting at the hilum.
- 72 -
B. Heat to boiling for 1 minute a suspension of 1 g in 50 ml of water and cool;
a thin and cloudy mucilage is produced with all starches except potato starch
which gives a thick and more transparent mucilage.
C. To 10 ml of the mucilage obtained in test B add 0.05 ml of 0.01 M iodine; a
dark blue colour is produced, which disappears on heating and reappears on
cooling.
Tests
Acidity. Add 10.0 g to 100 ml of ethanol (70 per cent) previously neutralised
to phenolphthalein solution, shake for 1 hour, filter and titrate 50 ml of the
filtrate with 0.1 M sodium hydroxide. Not more than 2.0 ml is required to
change the colour of the solution.
Iron (2.3.14). Dissolve the residue obtained in the test for sulphated ash in 4 ml
of hydrochloric acid with the aid of gentle heat, dilute with water to 50 ml and
mix; 25 ml of the resulting solution complies with the limit test for iron (40
ppm).
Fluorescence. No fluorescence should be visible under screened ultra-violet
light.
Oxidising substances. To 5.0 g add 10 ml of water and 1 ml of acetic acid and
stir until a homogeneous suspension is obtained. Add 0.5 ml of a freshly
prepared saturated solution of potassium iodide, mix and allow to stand for 5
minutes; no distinct brown or blue colour is observed.
Microbial Contamination (2.2.9). 1 g is free from Escherichia coli and
salmonellae.
Sulphated ash (2.3.18). Not more than 0.6 per cent (for all starches except rice
starch) and not more than 0.8 per cent (for rice starch), determined on 2.0 g.
Loss on drying (2.4.19). Not more than 15.0 per cent (for all starches except
potato starch) and not more than 20.0 per cent (for potato starch), determined
on 0.2 g by drying in an oven at 105º.
Storage. Store protected from light and moisture.
Labelling. The label states the type of starch.
- 73 -
MICROCRYSTALLINE CELLULOSE
Protocol: I.P.
Microcrystalline Cellulose is purified, partially depolymerised cellulose
prepared from alpha cellulose.
Microcrystalline Cellulose contains not less than 97.0 per cent and not more
than 102.0 per cent of cellulose, calculated on the dried basis.
Description. A fine or granular, white or almost white powder; odourless.
Identification
A. To about 1 mg add 1 ml of phosphoric acid, heat on a water-bath for 30
minutes, add 4 ml of a 0.2 per cent w/v solution of catechol in phosphoric acid
and heat for further 30 minutes; a red colour is produced.
B. To 50 mg add 2 ml of iodine solution, allow to stand for 5 minutes and
remove the excess reagent with the aid of a filter paper and add 1 or 2 drops of
sulphuric acid (66 per cent v/v); a blue-purple colour is produced.
C. Mix 30 g with 270 ml of water, mix in a blender at 18,000 rpm for 5
minutes, transfer 100 ml of the mixture to a 100-ml graduated cylinder and
allow to stand for 3 hours. A white, opaque, bubble-free dispersion is obtained
that does not produce a supernatant liquid.
Tests
pH (2.4.24). 5.0 to 7.5, determined on the supernatant liquid obtained by
shaking 2.0 g with 100 ml of carbon dioxide-free water for 5 minutes and
centrifuging.
Starch and dextrins. Mix 0.1 g with 5 ml of water by vigorous shaking and
add 2 to 3 drops of iodine solution; no blue or brownish-red colour is produced.
Organic impurities. Place 10 mg on a watch-glass and add 0.05 ml of a
freshly prepared solution of 0.1 g of phloroglucinol in 5 ml of hydrochloric
acid; no red colour is produced.
Water-soluble substances. Shake 5.0 g with about 80 ml of water for 10
minutes, filter through a filter paper (Whatman No 42 or equivalent) into a
tared beaker and evaporate the filtrate to dryness and dry the residue at 105° for
1 hour. The residue weighs not more than 10 mg (0.2 per cent).
Arsenic (2.3.10). Mix 5.0 g with 3 g of anhydrous sodium carbonate, add 10
ml of bromine solution and mix thoroughly. Evaporate to dryness on a waterbath, gently ignite and dissolve the cooled residue in a mixture of 15 ml of
- 74 -
hydrochloric acid containing 0.15 ml of bromine solution and 45 ml of water.
Add 2 ml of stannous chloride solution AsT. The resulting solution complies
with the limit test for arsenic (2 ppm).
Heavy metals (2.3.13). 2.0 g complies with the limit test for heavy metals,
Method B (10 ppm).
Sulphated ash (2.3.18). Not more than 0.2 per cent.
Loss on drying (2.4.19). Not more than 6.0 per cent, determined on 0.5 g by
drying in an oven at 105°.
Assay. Weigh accurately about 0.125 g and transfer to a 300-ml conical flask
with the aid of about 25 ml of water. Add 50.0 ml of 0.083 M potassium
dichromate, mix, carefully add 100 ml of sulphuric acid and heat to boiling.
Remove from heat, allow to stand at room temperature for 15 minutes, cool and
transfer to a 250-ml volumetric flask. Dilute with water almost to volume, cool
to 25°, dilute with water to volume and mix. Titrate 50.0 ml of the resulting
solution with 0.1 M ferrous ammonium sulphate using 2 to 3 drops of ferroin
sulphate solution as indicator. Repeat the procedure without the substance
under examination. The difference between the titrations represents the amount
of ferrous ammonium sulphate required.
1 ml of 0.1 M ferrous ammonium sulphate is equivalent to 0.000675 g of
cellulose.
Storage. Store protected from light and moisture
- 75 -
PURIFIED WATER
H2 O
Protocol: I.P.
Mol. Wt. 18.0
Purified Water is prepared by distillation, by means of ion exchange or by any
other appropriate means from suitable potable water that complies with all
relevant statutory regulations.
During production and subsequent storage, it is recommended that adequate
measures are taken to ensure that the microbial quality is controlled and
monitored. Appropriate alert and
action limits are set so as to detect adverse trends. Under controlled conditions,
an appropriate action limit is a total viable count (2.2.9) of 100 microorganisms per ml, determined by membrane filtration. In addition, the test for
oxidisable substances (given below) is carried out. The adequacy of these
measures may be determined by carrying out the test for conductivity (2.4.9)
off-line or in-line.
Description. A clear, colourless liquid; odourless and tasteless.
Tests
Acidity or alkalinity. To 10 ml, freshly boiled and cooled in a borosilicate
glass flask, add 0.05 ml of methyl red solution; the resulting solution is not red.
To 10 ml add 0.1 ml of bromothymol blue solution; the resulting solution is not
blue.
Ammonium. To 20 ml add 1 ml of alkaline potassium mercuriiodide solution,
and allow to stand for 5 minutes. When viewed vertically the solution is not
more intensely coloured than a solution prepared at the same time by adding 1
ml of alkaline potassium mercuri-iodide solution to a mixture of 4.0 ml of
ammonium standard solution (1 ppm NH4) and 16.0 ml of ammonia-free water
(0.2 ppm).
Calcium and magnesium. To 100 ml add 2 ml of ammonia buffer pH 10.0, 50
mg of mordant black II mixture and 0.5 ml of 0.01 M disodium edetate; a pure
blue colour is produced.
Heavy metals (2.3.13). Evaporate 150 ml to 15 ml on a water bath; 12 ml of
the solution complies with the limit test for heavy metals, Method D (0.1 ppm).
Use lead standard solution (1 ppm Pb) to prepare the standard.
Chlorides (2.3.12). To 10 ml add 1 ml of 2 M nitric acid and 0.2 ml of 0.1 M
silver nitrate; the appearance of the solution does not change for at least 15
minutes.
- 76 -
Nitrates. To 5 ml in a test-tube immersed in ice add 0.4 ml of a 10 per cent w/v
solution of potassium chloride, 0.1 ml of diphenylamine solution and, drop
wise with shaking, 5 ml of sulphuric acid. Transfer the tube to a water-bath at
50° and allow to stand for 15 minutes. Any blue colour in the solution is not
more intense than that in a solution prepared at the same time and in the same
manner using a mixture of 4.5 ml of nitrate-free water and 0.5 ml of nitrate
standard solution (2 ppm NO3) (0.2 ppm).
Sulphates (2.3.17). To 10 ml add 0.1 ml of 2 M hydrochloric acid and 0.1 ml
of barium chloride solution. The appearance of the solution does not change
for at least 1 hour.
Oxidisable substances. To 100 ml add 10 ml of 1 M sulphuric acid and 0.1 ml
of 0.02 M potassium permanganate and boil for 5 minutes; the solution
remains faintly pink.
Residue on evaporation. Evaporate 100 ml to dryness on a water-bath and dry
to constant weight at 105°. The residue weighs not more than 1 mg (0.001 per
cent).
Purified Water intended for use in the manufacture of dialysis solutions and
also without a further procedure for the removal of bacterial endotoxins
complies with the following additional requirements.
Aluminium (2.3.8). Not more than 10 ppb, determined using the following
solutions.
Test solution. To 400 ml of the water under examination add 10 ml of acetate
buffer solution pH 6.0 and 100 ml of distilled water.
Reference solution. Mix 2 ml of aluminium standard solution (2 ppm Al), 10 ml
of acetate buffer solution pH 6.0 and 98 ml of distilled water.
Blank solution. Mix 10 ml of acetate buffer solution pH 6.0 and 100 ml of
distilled water.
Bacterial endotoxins (2.2.3). Not more than 0.25 Endotoxin Unit per ml.
Storage. Store protected from light.
- 77 -
TALC
Protocol: I.P.
Purified Talc; Talcum
Talc is a powdered, selected natural hydrated magnesium silicate. It may
contain varying amounts of aluminium and iron in forms insoluble in 1M
sulphuric acid.
Description. A white or almost white powder, free from grittiness; readily
adheres to the skin; unctuous to the touch; odourless.
Identification
A. When examined microscopically, shows irregular plates, the majority less
than 50 μm in length. The particles are not notably stained by a 0.1 per cent
w/v solution of Methylene blue in ethanol (95 per cent).
B. Melt 0.5 g in a metal crucible with 1 g of potassium nitrate and 3 g of
anhydrous sodium carbonate, add 20 ml of boiling water, mix and filter. Wash
the residue with 50 ml of water. Mix the residue with a mixture of 0.5 ml of
hydrochloric acid and 5 ml of water and filter. To the filtrate add 1 ml of 9 M
ammonia and 1 ml of ammonium chloride solution and filter. To the filtrate add
1 ml of disodium hydrogen phosphate solution; a white, crystalline precipitate
is produced.
C. Gives the reaction of silicates (2.3.1).
Tests
Acidity or alkalinity. Shake 5.0 g with 25 ml of carbon dioxide free water for
1 minute, filter and add to the filtrate 0.5 ml of bromothymol blue solution; the
solution is not acid and requires not more than 0.3 ml of 0.1 M hydrochloric
acid to make it acid.
Iron (2.3.14). Boil 4.0 g with 25 ml of water for 30 minutes, replacing the
water lost by evaporation, and filter. The filtrate, after the addition of 5 ml of
nitric acid, complies with the limit test for iron (10 ppm).
Acid-soluble substances. Not more than 2.0 per cent, determined by the
following method. Digest 2.0 g with 40 ml of dilute hydrochloric acid for 15
minutes, filter, evaporate the filtrate; to the residue add 0.1 ml of sulphuric acid
and ignite to constant weight.
Water-soluble substances. Shake 5.0 g with 25 ml of water for 1 minute,
filter, evaporate the filtrate and dry to constant weight; the residue weighs not
more than 10 mg.
- 78 -
Carbonates. To 1 g add 20 ml of dilute hydrochloric acid; no effervescence is
produced.
Chlorides (2.3.12). Suspend 2.0 g in 10 ml of water, add 10 ml of 2 M nitric
acid, shake for 15 minutes and filter. 10 ml of the filtrate complies with the
limit test for chlorides (250 ppm).
Organic compounds. The residue obtained in the test for Loss on drying is not
more than slightly yellow or grey.
Loss on drying (2.4.19). Not more than 1.0 per cent, determined on 1.0 g by
drying in an oven at 180º for 1 hour.
Storage. Store protected from moisture.
- 79 -
SODIUM STARCH GLYCOLLATE
Protocol: I.P.
Sodium Carboxymethyl Starch
Sodium Starch Glycollate is the sodium salt of a poly-aglucopyranose in which
some of the hydroxyl groups are in the form of carboxymethyl ether.
Sodium Starch Glycollate contains not less than 2.8 per cent and not more than
4.5 per cent of sodium, Na, calculated on the material washed with Ethanol (95
per cent) and dried as described under Assay.
Description. A very fine, white or off-white, free-flowing powder; odourless
or almost odourless.
Identification
A. Determine by infrared absorption spectrophotometry (2.4.6).
Compare the spectrum with that obtained with sodium starch
glycollate RS or with the reference spectrum of sodium starch glycollate.
B. To 5 ml of a 2 per cent w/v dispersion in water add 0.05 ml of 0.005 M
iodine; a dark blue colour is produced.
C. The solution obtained in the test for Heavy metals gives the reactions of
sodium salts (2.3.1).
Tests
pH (2.4.24). 5.5 to 7.5, determined in a 2.0 per cent w/v dispersion in carbon
dioxide-free water.
Heavy metals (2.3.13). To 4.0 g in a silica or platinum dish add 2 ml of a 50
per cent w/v solution of sulphuric acid, heat in a water-bath and then cautiously
over a flame at about 600º.
Continue heating until all black particles have disappeared, allow to cool, add
0.1 ml of 1 M sulphuric acid, heat to ignition once again and allow to cool.
Add 0.1 ml of 2 M ammonium carbonate, evaporate to dryness and cautiously
ignite. To the residue add 5 ml of hydrochloric acid, evaporate to dryness on a
water-bath and dissolve the residue in 100 ml of water. 25 ml of a solution
complies with the limit test for heavy metals, Method A (20 ppm).
Iron (2.3.14). 50 ml of the solution obtained in the test for Heavy metals
complies with the limit test for iron (20 ppm).
Sodium Chloride. Not more than 10.0 per cent, determined by the following
method. To 1.0 g add 20.0 ml of 0.1 M silver nitrate and 30 ml of nitric acid
and boil carefully for 30 minutes.
- 80 -
Cool and add a sufficient volume of a saturated solution of potassium
permanganate to change the colour of the solution to red. Discharge the colour
by the dropwise addition of hydrogen peroxide solution (10 vol), add 3 ml of
dibutyl phthalate and titrate with 0.1 M ammonium thiocyanate using ferric
ammonium sulphate solution as indicator, shaking vigorously after each
addition of titrant. Carry out a blank titration.
1 ml of 0.1 M silver nitrate is equivalent to 0.005844 g of NaCl.
Sodium glycollate. To 0.2 g add 5 ml of glacial acetic acid, mix well and add
5 ml of water, stirring occasionally until solution is complete. Slowly add 50
ml of acetone with stirring and then add 1 g of sodium chloride. Filter, wash
the residue with acetone and dilute the filtrate to 100 ml with acetone.
Transfer 2 ml of this solution to an open flask, heat on a water bath for exactly
20 minutes, cool, add 5 ml of naphthalenediol reagent and mix thoroughly.
Add a further 15 ml of the same reagent, mix, cover the flask with aluminium
foil and heat on a water-bath for 20 minutes. Cool and dilute to 25 ml with
sulphuric acid. The absorbance (2.4.7) of the resulting solution at the
maximum at about 540 nm using water as the blank, is not more than that of a
solution prepared in the following manner. To 5 ml of a 0.062 per cent w/v
solution of glycolic acid, previously dried at a pressure not exceeding 2 kPa for
16 hours, add 5 ml of glacial acetic acid, dilute to 100 ml with acetone and
complete the procedure described above beginning at the words “Transfer 2
ml....” (2.0 per cent).
Microbial Contamination (2.2.9). 1.0 g is free from Escherichia coli and
Salmonellae.
Loss on drying (2.4.19). Not more than 10.0 per cent, determined on 0.5 g by
drying in an oven at 105º.
Assay. Weigh accurately about 4.0 g, add 350 ml of a mixture of 4 volumes of
ethanol (95 per cent) and 1 volume of water, add 0.25 ml of phenolphthalein
solution and mix. Add 1 M sodium hydroxide dropwise until the colour of the
suspension becomes faintly pink, shake for 30 minutes and decant through a
sintered glass crucible. Repeat the extraction three times, or until a test for
chloride ions is negative. Transfer the bulk of the residue to the crucible, wash
the residue with ethanol (95 per cent) and dry at 110º to constant weight.
Weigh accurately 0.5 g of the residue, add 80 ml of anhydrous glacial acetic
acid, heat under a reflux condenser for 2 hours, cool.
Titrate with 0.1 M perchloric acid, determining the end-point
potentiometrically (2.4.25).
1 ml of 0.1 M perchloric acid is equivalent to 0.0023 g of Na.
Storage. Store protected from light and moisture.
- 81 -
COLLOIDAL SILICON DIOXIDE
Protocol: I.P.
Colloidal Anhydrous Silica
SiO2
Mol. Wt. 60.1
Colloidal Silicon Dioxide is a submicroscopic fumed silica prepared by the
vapour-phase hydrolysis of a silicon compound.
Colloidal Silicon Dioxide contains not less than 99.0 per cent and not more
than 100.5 per cent of SiO2, calculated on the ignite basis.
Description. A light, fine, white, amorphous powder. It has a particle size of
about 15 nm.
Identification
About 20 mg gives the reaction of silicates (2.3.1).
Tests
pH (2.4.24). 3.5 to 5.5, determined in a suspension of 1.0 g in 30 ml of carbon
dioxide-free water.
Arsenic (2.3.10). To 2.5 g contained in a round-bottomed flask add 50 ml of 3
M hydrochloric acid and heat under a reflux condenser for 30 minutes. Cool,
filter with the aid of suction and transfer the filtrate to a 100-ml volumetric
flask. Wash the filter with several portions of hot water and add the washings
to the volumetric flask. Cool, dilute to volume with water and mix. To 50.0 ml
of the solution add 3 ml of hydrochloric acid; the resulting solution complies
with the limit test for arsenic (8 ppm).
Heavy metals (2.3.13). Suspend 2.5 g in sufficient water to produce a semifluid slurry and dry at 140º. When the dried substance is white, break up the
mass using a glass rod, add 25 ml of 1 M hydrochloric acid, boil gently for 5
minutes, stirring frequently with the glass rod, centrifuge for 20 minutes and
filter the supernatant liquid through a membrane filter. To the residue in the
centrifuge tube add 3 ml of 2 M hydrochloric acid and 9 ml of water, boil,
centrifuge for 20 minutes and filter the supernatant liquid through the same
membrane filter. Wash the residue with small quantities of water, combine the
filtrates and washings and dilute to 50.0 ml with water. To 20.0 ml of the
solution add 50 mg of L-ascorbic acid and 1 ml of strong ammonia solution,
neutralise with 2 M ammonia and dilute to 25 ml with water. 12 ml of the
solution complies with the limit test for heavy metals, Method D (25 ppm). Use
lead standard solution (1 ppm Pb) to prepare the standard.
Chlorides (2.3.12). To 1.0 g add a mixture of 20 ml of 2 M nitric acid and 30
ml of water, heat on a water-bath for 15 minutes, shaking frequently, dilute to
- 82 -
50 ml with water if necessary, filter and cool. The filtrate complies with the
limit test for chlorides (250 ppm).
Loss on ignition (2.4.20). Not more than 5.0 per cent, determined on 0.2 g by
igniting at 900º in a platinum crucible for 2 hours.
Assay. To the residue obtained in the test for Loss on ignition add 0.2 ml of
sulphuric acid and sufficient ethanol (95 percent) to moisten the residue
completely, add 6 ml of hydrofluoric acid and evaporate to dryness on a hot
plate at 95º to 105º, avoiding loss from sputtering. Wash the sides of the dish
with 6 ml of hydrofluoric acid, evaporate to dryness in a well-ventilated hood,
ignite at 1000º, allow to cool in a desiccator and weigh. The difference between
the weight of
the final residue and that of the residue obtained in the test for Loss on ignition
represents the amount of SiO2 in the amount of the substance taken for the test
for Loss on ignition.
Storage. Store protected from light.
- 83 -
TITANIUM DIOXIDE
TiO2
Protocol: I.P.
Mol. Wt. 79.9
Titanium Dioxide contains not less than 98.0 per cent and not more than 100.5
per cent of TiO2.
Description. A white or almost white, infusible powder; odourless.
Identification
A. When strongly heated it becomes pale yellow; the colour is discharged on
cooling.
B. To 0.5 g add 5 g of anhydrous sodium sulphate and 10 ml of water and mix.
Add 10 ml of sulphuric acid and boil gently until clear; cool, add slowly 30 ml
of a 25 per cent v/v solution
of sulphuric acid and dilute with water to 100 ml (solution A). To 5 ml of
solution A add 0.1 ml of strong hydrogen peroxide solution; an orange-red
colour is produced.
C. To 5 ml of solution A add 0.5 g of zinc, in granules; after 45 minutes a
violet-blue colour is produced.
Tests
Appearance of solution. Solution A is not more opalescent than opalescence
standard OS2 (2.4.1), and colourless (2.4.1).
Acidity or alkalinity. Shake 5.0 g with 50 ml of carbon dioxide free water for
5 minutes and centrifuge until a clear solution is obtained. To 10 ml of the
solution add 0.1 ml of bromothymol blue solution. Not more than 1.0 ml of
either 0.01 M hydrochloric acid or 0.01 M sodium hydroxide is required to
change the colour of the solution.
Water-soluble substances. Not more than 0.5 per cent, determined by the
following method. Boil 10.0 g for 5 minutes with 150 ml of water containing
0.5 g of ammonium sulphate.
Cool, dilute to 200 ml with water and filter until a clear solution is obtained.
Evaporate 100 ml of the filtrate to dryness ignite and weigh.
Arsenic (2.3.10). To 0.2 g in a 100-ml Kjeldahl flask add 2 g of anhydrous
sodium sulphate, 7 ml of sulphuric acid and 5 ml of nitric acid. Heat gently
until a clear solution is obtained,
cool, add 10 ml of water, cool again and add 5 g of hydrazine reducing mixture
and 10 ml of hydrochloric acid. Immediately attach an air condenser and distil
- 84 -
into 15 ml of cooled water until a total volume of 30 ml is obtained. Rinse the
condenser with 5 ml of water and dilute the combined distillate and rinsings to
40 ml with water. 20 ml of the resulting solution complies with the limit test
for arsenic. Use a mixture of 0.5 ml of arsenic standard solution (1 ppm As)
and 24.5 ml of water to prepare the standard (5 ppm).
Barium. Shake 20.0 g with 30 ml of hydrochloric acid, add 100 ml of distilled
water and boil. Filter while hot through a hardened filter paper until a clear
filtrate is obtained. Wash the filter with 60 ml of distilled water and dilute the
combined filtrate and washings to 200 ml with distilled water. To 10 ml of this
solution add 1 ml of 1 M sulphuric acid. After 30 minutes any opalescence is
not more intense than that of a mixture of 10 ml of the test solution and 1 ml of
distilled water.
Heavy metals (2.3.13). Dilute 10 ml of the solution prepared in the test for
Barium to 20 ml with water. 12 ml of the solution complies with the limit test
for heavy metals, Method D (20 ppm).
Iron. To 8 ml of solution A add 4 ml of water, mix and add 0.05 ml of bromine
water, allow to stand for 5 minutes, remove the excess of bromine with a
current of air and add 3 ml of potassium thiocyanate solution. Any colour in
the solution is not more intense than that in a standard prepared at the same
time and in the same manner using a mixture of 4 ml of iron standard solution
(2 ppm Fe) and 8 ml of a 20 per cent w/v solution of sulphuric acid (200 ppm).
Assay. Weigh accurately about 0.5 g, transfer to a 300-ml Kjeldahl flask, add 5
g of anhydrous sodium sulphate and 10 ml of water, mix and add 10 ml of
sulphuric acid. Boil gently until clear, cool, add slowly 40 ml of cooled
sulphuric acid (25 per cent), cool again and dilute with water to 100.0 ml
(solution B). To 300 g of zinc, in granules, add 300 ml of a 2 per cent w/v
solution of mercuric nitrate and 2 ml of nitric acid, shake for 10 minutes and
wash with water. Pack the zinc
amalgam into a glass tube (400 mm x 20 mm) fitted with a tap and a filter
plate. Pass through the column, at a rate of about 3 ml per minute, 100 ml of 1
M sulphuric acid followed by 100 ml of water, ensuring that the amalgam is
covered withliquid throughout. Pass slowly through the column, at a rate of
about 3 ml per minute, 200 ml of 0.5 M sulphuric acid followed by 100 ml of
water. Collect the combined eluates in a 500-ml conical flask containing 50 ml
of a 15 per cent w/v solution of ferric ammonium sulphate in sulphuric acid (25
per cent) and titrate immediately with 0.1 M ceric ammonium nitrate using
ferroin solution as indicator until a greenish colour is obtained (n1 ml). Pass
slowly through the column 100 ml of 0.5 M sulphuric acid followed by 20.0 ml
of solution B, wash with 100 ml of 0.5 M sulphuric acid followed by 100 ml of
water. Collect the combined eluates in a 500-ml conical flask containing 50 ml
of a 15 per cent w/v solution of ferric ammonium sulphate in sulphuric acid (25
- 85 -
per cent), rinse the lower end of the column with water and titrate immediately
with 0.1 M ceric ammonium nitrate using ferroin
solution as indicator until a greenish colour is obtained (n2 ml). Calculate the
percentage content of TiO2 from the expression 3.99(n2 - n1)/w
Where, w is the weight, in g, of the substance under examination used in the
preparation of solution A.
Storage. Store protected from moisture. Avoid contact with aluminium.
- 86 -
HYDROXYPROPYLMETHYLCELLULOSE
Protocol: I.P.
Cellulose, 2-Hydroxypropylmethyl Ether;
Hypromellose
Hydroxypropylmethylcellulose is a cellulose having some of the hydroxyl
groups in the form of the methyl ether and some in the form of the 2hydroxypropyl ether. The various grades commercially available are
distinguished by a number indicative of the apparent viscosity in millipascal
seconds of a 2 per cent w/v solution measured at 20°.
Description. A white or yellowish white, fibrous or granular powder; almost
odourless; hygroscopic after drying.
Identification
A. With constant stirring add a quantity containing 1 g of the dried substance
into 50 ml of carbon dioxide-free water previously heated to 90°. Allow to
cool, dilute to 100 ml with carbon dioxide-free water and continue stirring until
solution is complete (solution A). Heat 10 ml of solution A in a water bath with
stirring. At temperatures above 50° the solution becomes cloudy or a flocculent
precipitate is formed. On cooling, the solution becomes clear or slightly
opalescent.
B. To 10 ml of solution A add 10 ml of 1 M sodium hydroxide or 1 M
hydrochloric acid; in either case the mixture remains stable.
C. To 10 ml of solution A add 0.3 ml of 2 M acetic acid and 2.5 ml of a 10 per
cent w/v solution of tannic acid; a yellowish white, flocculent precipitate is
produced which dissolves in 6 M ammonia.
D. Without heating completely dissolve 0.2 g in 15 ml of a 70 per cent w/w
solution of sulphuric acid, pour the solution with stirring into 100 ml of iced
water. In a test-tube kept in ice, mix thoroughly 1 ml of the solution with 8 ml
of sulphuric acid, added dropwise. Heat in a water-bath for exactly 3 minutes
and cool immediately in ice. When the mixture is cool, carefully add 0.6 ml of
a solution containing 3 g of ninhydrin in 100 ml of a 4.55 per cent w/v solution
of sodium metabisulphite, mix well and allow to stand at 25°; a pink colour is
produced immediately which becomes violet within 100 minutes.
E. Place 1 ml of solution A on a glass plate. After evaporation of the water a
thin film is produced.
Tests
- 87 -
pH (2.4.24). 5.5 to 8.0, determined in solution A.
Appearance of solution. Solution A is not more opalescent than opalescence
standard OS3 (2.4.1), and not more intensely coloured than reference solution
YS6 (2.4.1).
Apparent viscosity. 75 to 140 per cent of the stated value, determined by the
following method. Weigh accurately a quantity equivalent to 2.0 g of the dried
substance and add, with constant stirring, to 50 ml of water previously heated
to 90°. Allow to cool, dilute to 100 ml with water and continue stirring until
solution is complete. Adjust the weight of the solution to 100 g and centrifuge
the solution to expel any trapped air. Determine the viscosity, Method C, at 20°
using a shear rate of 10 s-1 (2.4.28).
Heavy metals (2.3.12). 1.0 g complies with the limit test for heavy metals,
Method B (20 ppm).
Chlorides (2.3.12). Dilute 5.0 ml of solution A to 15 ml with water. The
resulting solution complies with the limit test for chlorides (0.5 per cent).
Sulphated ash (2.3.18). Not more than 3.0 per cent.
Loss on drying (2.4.19). Not more than 10.0 per cent, determined on 0.5 g by
drying in an oven at 105°.
Storage. Store protected from moisture.
Labelling. The label states the apparent viscosity in millipascal seconds of a 2
per cent w/v solution.
- 88 -
POVIDONE
Protocol: I.P.
Polyvinylpyrrolidone; Polyvidone
(C6H9NO)n
Mol. Wt. (111.2)n
Povidone is poly(2-oxopyrrolidin-1-ylethylene) and consists of linear polymers
of 1-vinylpyrrolidin-2-one. The different types of Povidone are characterised
by their viscosity in solution, expressed as K-value, in the range 10 to 95.
Povidone with a nominal K-value of 15 or less has a K-value of not less than
85.0 per cent and not more than 115.0 per cent of the declared value. The Kvalue of povidone with a nominal K-value of more than 15, or a nominal Kvalue range with an average of more than 15, is not less than 90.0 per cent and
not more than 107.0 per cent of the declared value or of the average of the
declared range. It contains not less than 11.5 per cent and not more than 12.8
per cent of nitrogen, N, calculated on the anhydrous basis.
Description. A white or yellowish white powder or flakes; odourless or almost
odourless; hygroscopic.
Identification
Test A may be omitted if tests B, C and D are carried out. Tests B and C may
be omitted if tests A and D are carried out.
A. Determine by infrared absorption spectrophotometry (2.4.6).
Compare the spectrum with that obtained with povidone RS.
B. Add 2.5 g in small portions to a suitable volume of carbon dioxide-free
water, stirring with a magnetic stirrer, and dilute to 25 ml with the same solvent
(solution A). To 0.4 ml of solution
A add 10 ml of water, 5 ml of 2 M hydrochloric acid and 2 ml of potassium
dichromate solution; an orange-yellow precipitate is produced.
- 89 -
C. To 1 ml of solution A add 0.2 ml of dimethylaminobenzaldehyde reagent
and 0.1 ml of sulphuric acid; a pink colour is produced.
D. To 0.1 ml of solution A add 5 ml of water and 0.2 ml of 0.05 M iodine; a red
colour is produced.
Tests
Appearance of solution. Solution A is clear (2.4.1), and not more intensely
coloured than reference solution BS6 or BYS6 (2.4.1).
Heavy metals. Mix 2.0 g with 0.5 g of magnesium oxide in a silica crucible.
Ignite to dull red heat until a homogeneous white or greyish white mass is
produced. Heat at 800º for about 1 hour, dissolve the residue using two
quantities, each of 5 ml, of 5 M hydrochloric acid, add 0.1 ml of
phenolphthalein solution and strong ammonia solution until a pink colour is
produced. Cool, add glacial acetic acid until the solution is decolorised and add
a further 0.5 ml. Filter if necessary and dilute the solution to 20 ml with water.
To 12 ml of the resulting solution add 2 ml of acetate buffer pH 3.5, mix, add
1.2 ml of thioacetamide reagent, mix immediately and allow to stand for 2
minutes. Any brown colour produced is not more intense than that obtained by
treating in the same manner a mixture of 2 ml of the test solution obtained
above and 10 ml of the 20 ml of solution obtained by repeating the procedure
using 2 ml of lead standard solution (10 ppm Pb) in place of the substance
under examination, adding 0.5 g of magnesium oxide in a silica crucible and
continuing as described above beginning at the words “Ignite to dull red
heat....” (10 ppm).
Aldehydes. Boil 20.0 g in 180 ml of a 25 per cent v/v solution of sulphuric
acid in a ground-glass-stoppered flask under a reflux condenser for 45 minutes
and allow to cool. Fit a distillation head, distil and collect 60 ml of the distillate
in 20 ml of a 7.0 per cent w/v solution of hydroxylamine hydrochloride,
previously adjusted to pH 3.1 using 1 M sodium hydroxide, and cooled in ice.
Titrate with 0.1 M sodium hydroxide to pH 3.1. Carry out a blank titration. Not
more than 9.1 ml of 0.1 M sodium hydroxide is required (0.2 per cent,
calculated as acetaldehyde, C2H4O).
Vinylpyrrolidone. Dissolve 10.0 g in 80 ml of water and add 1 g of sodium
acetate. Titrate with 0.05 M iodine until a persistent colour is obtained and add
a further 3.0 ml of the iodine solution. Allow to stand for 10 minutes and titrate
the excess of iodine with 0.1 M sodium thiosulphate using 3 ml of starch
solution, added towards the end of the titration, as indicator. Repeat the
operation without the substance under examination using the same total volume
of 0.05M iodine. The difference between the titrations represents the amount of
iodine consumed by the vinylpyrrolidone monomer that may be present. Not
more than 3.6 ml of 0.05 M iodine is required (0.2 per cent).
- 90 -
Sulphated ash (2.3.18). Not more than 0.1 per cent.
Water (2.3.43). Not more than 5.0 per cent determined on 0.5 g.
K-value. For Povidone with a stated K-value of 18 or less, prepare a 5.0 per
cent w/v solution. For Povidone with a declared K-value of more than 18,
prepare a 1.0 per cent w/v
solution. Allow the solution to stand for 1 hour and carry out Method B for the
determination of viscosity (2.4.28), at 25º ± 0.2º using a size no. 1 viscometer
with a minimum flow time of
100 seconds. Calculate the K-value (Ko) from the expression
where c is the percentage concentration w/v of the substance under
examination, calculated on the anhydrous basis, and z is the viscosity of the
solution relative to that of water.
Nitrogen (2.3.30). Follow Method C, using 0.3 g, accurately weighed and 11
ml of nitrogen-free sulphuric acid. For complete destruction of organic matter
repeat the addition of hydrogen peroxide (10 vol) (usually 3 to 6 times) until a
clear, light-green solution is obtained, then heat for a further 4 hours.
Storage. Store protected from moisture.
Labelling. The label states the viscosity in terms of a K-value or K-range.
- 91 -
METHYLENE CHLORIDE
Protocol: B.P.
(Methylene Chloride, Ph Eur monograph 0932)
CH2Cl2
84.9
75-09-02
Action and use
Pharmaceutical aid.
DEFINITION
Methylene chloride is dichloromethane. It may contain not more than 2.0 per
cent V/V of ethanol and/or not more than 0.03 per cent V/V of 2-methylbut-2ene as stabiliser.
CHARACTERS
A clear, colourless, volatile liquid, sparingly soluble in water, miscible with
alcohol.
IDENTIFICATION
First identification
Second identification
B, C.
A, D, E.
A. It complies with the test for relative density (see Tests).
B. It complies with the test for refractive index (see Tests).
C. Examine the chromatograms obtained in the test for ethanol, 2methylbut-2-ene and other related substances. The retention time and size of
the principal peak in the chromatogram obtained with test solution (b) are
approximately the same as those of the principal peak in the chromatogram
obtained with reference solution (a).
D. Heat 2 ml with 2 g of potassium hydroxide R and 20 ml of alcohol R
under a reflux condenser for 30 min. Allow to cool. Add 15 ml of dilute
sulphuric acid R and filter. To 1 ml of the filtrate add 1 ml of a 15 g/l solution
of chromotropic acid, sodium salt R, 2 ml of water R and 8 ml of sulphuric
acid R. A violet colour is produced.
E. 2 ml of the filtrate obtained in identification test D gives reaction (a) of
chlorides (2.3.1).
- 92 -
TESTS
Appearance
It is clear (2.2.1) and colourless (2.2.2, Method II).
Acidity
To 50 ml of methanol R previously neutralised to 0.1 ml of bromothymol blue
solution R1, add 50 g of the substance to be examined. Not more than 0.15 ml
of 0.1 M sodium hydroxide is required to change the colour of the indicator to
blue.
Relative density (2.2.5)
1.320 to 1.332.
Refractive index (2.2.6)
1.423 to 1.425.
Ethanol, 2-methylbut-2-ene and other related substances
Examine by gas chromatography (2.2.28).
Test solution (a)
The substance to be examined.
Test solution (b)
Dilute 0.5 ml of test solution (a) to 100.0 ml with water R.
Reference solution (a)
with water R.
Dilute 0.5 ml of methylene chloride CRS to 100.0 ml
Reference solution (b)
R.
Dilute 2.0 ml of test solution (b) to 10.0 ml with water
Reference solution (c) To 20.0 ml of ethanol R, add 0.3 ml of 2-methylbut-2ene R and dilute to 100.0 ml with test solution (a). Dilute 1.0 ml of the solution
to 10.0 ml with test solution (a).
Reference solution (d) Dilute 0.1 ml of methanol R and 0.1 ml of methylene
chloride CRS to 100.0 ml with water R.
The chromatographic procedure may be carried out using:
—a glass column 2 m long and 2 mm in internal diameter, packed with
ethylvinylbenzene-divinylbenzene copolymer R (136 µm to 173 µm),
- 93 -
—nitrogen for chromatography R as the carrier gas at a flow rate of 30
ml/min,
—a flame-ionisation detector,
maintaining the temperature of the column at 90 °C until injection, then raising
the temperature at a rate of 4 °C per minute to 190 °C and maintaining at 190
°C for 15 min and maintaining the temperature of the injection port and the
detector at 240 °C.
Inject 1 µl of reference solution (d). If a recorder is used, adjust the sensitivity
of the detector such that the height of the peak due to methanol is not less than
25 per cent of the full scale of the recorder. The test is not valid unless: in the
chromatogram obtained with reference solution (d), the resolution between the
peaks corresponding to methanol and methylene chloride is at least 3.0.
Inject twice 2 µl of reference solution (c). If the peaks obtained show an area
difference greater than 1.0 per cent, verify the repeatability by making four
separate injections of reference solution (c); the test is not valid unless the
relative standard deviation of the peak area is not more than 5.0 per cent.
Inject 2 µl of test solution (a), 2 µl of reference solution (b) and 2 µl of
reference solution (c). In the chromatogram obtained with test solution (a): the
areas of any peaks corresponding to ethanol and 2-methylbut-2-ene
respectively are not greater than the difference between the areas of the peaks
due to ethanol and 2-methylbut-2-ene in the chromatogram obtained with
reference solution (c) and those of the peaks due to ethanol and 2-methylbut-2ene in the chromatogram obtained with test solution (a) (2.0 per cent and 0.03
per cent, respectively).
In the chromatogram obtained with test solution (a), the sum of the areas of
any peaks apart from the principal peak and any peaks due to ethanol and 2methylbut-2-ene, is not greater than the area of the principal peak in the
chromatogram obtained with reference solution (b) (0.1 per cent).
Free chlorine
Place 5 ml in a ground-glass-stoppered tube. Add 5 ml of a 100 g/l solution of
potassium iodide R and 0.2 g of soluble starch R. Shake for 30 s and allow to
stand for 5 min. No blue colour develops.
Heavy metals (2.4.8)
Evaporate 25.0 g to dryness on a water-bath. Allow to cool. Add 1 ml of
hydrochloric acid R and evaporate again. Dissolve the residue in 1 ml of acetic
- 94 -
acid R and dilute to 25 ml with water R. 12 ml of the solution complies with
limit test A for heavy metals (1 ppm). Prepare the standard using 10 ml of lead
standard solution (1 ppm Pb) R.
Residue on evaporation
Evaporate 50.0 g to dryness on a water-bath and dry at 100 °C to 105 °C for 30
min. The residue weighs not more than 1 mg (20 ppm).
Water (2.5.12)
Not more than 0.05 per cent m/m, determined on 10.00 g by the semi-micro
determination of water.
STORAGE
Store in an airtight container , protected from light.
LABELLING
The label states the name and the concentration of any stabilisers.
IMPURITIES
A. carbon tetrachloride,
B. chloroform,
C. ethanol,
D. methanol,
E. 2-methylbut-2-ene.
- 95 -
ISOPROPYL ALCOHOL
Protocol: I.P.
2-Propanol; Propan-2-ol
C3H8O
Mol. Wt. 60.1
Isopropyl Alcohol is propan-2-ol.
Description. A clear, colourless liquid; odour, characteristic and spirituous;
flammable.
Identification
A. Mix 1 ml of a 10 per cent v/v solution with 2 ml of mercuric sulphate
solution and heat just to boiling; a white or yellowish white precipitate is
produced.
B. Gently heat 1 ml with 4 ml of dilute potassium dichromate solution and 1 ml
of sulphuric acid; acetone, recognisable by its odour, is evolved.
Tests
Acidity or alkalinity. Gently boil 25 ml for 5 minutes with 25 ml of carbon
dioxide-free water and cool, taking precautions to exclude carbon dioxide. Not
more than 0.06 ml of 0.1 M sodium hydroxide is required to make the resulting
solution alkaline to phenolphthalein solution.
Distillation range (2.4.8). Not less than 95.0 per cent v/v distils between 81°
and 83°.
Refractive index (2.4.27). 1.377 to 1.378, determined at 20°.
Weight per ml (2.4.29). 0.782 g to 0.786 g, determined at 20°.
Aldehydes and ketones. Mix in a cylinder 25 ml with 25 ml of water and 50
ml of hydroxylamine solution, allow to stand for 5 minutes and titrate with 0.1
M sodium hydroxide until the colour is the same as that of a mixture of 50 ml
of hydroxylamine solution and 50 ml of water contained in a similar cylinder,
- 96 -
each being viewed down the vertical axis of the cylinder. Not more than 2.0 ml
of 0.1 M sodium hydroxide is required.
Benzene and related substances. Determine by gas chromatography (2.4.13).
Test solution. The substance under examination.
Reference solution (a). A 0.1 per cent v/v solution of 2- butanol reagent in the
substance under examination.
Reference solution (b). A solution containing 0.1 per cent v/v of each of 2butanol reagent and 1-propanol in the substance under examination.
Reference solution (c). A 0.0002 per cent v/v solution of benzene in the
substance under examination.
Chromatographic system
– a glass column 1.8 m x 2 mm, packed with acid-washed diatomaceous
support (80 to 100 mesh) coated with 15 per cent w/w of polyethylene glycol
400,
– temperature:
column.50°,
inlet port.150°,
– flow rate. 30 ml per minute of the carrier gas,
– flame ionisation detector at 200°.
Inject separately 2 μl of each of the test solution and reference solution (a). The
chromatogram obtained with the test solution shows no peak with retention
time similar to the peak due to 2butanol (retention time relative to isopropyl alcohol, about 1.5) obtained with
solution (2). Inject 2 μl of reference solution (b) and adjust the sensitivity of the
system so that the heights of the peaks due to 2-butanol and 1-propanol in the
chromatogram obtained with reference solution (b) are not less than 50 per cent
of the full scale of the recorder. The test is not valid unless the resolution
between the peaks due to 2- butanol and 1-propanol in the chromatogram
obtained with reference solution (b) is at least 1.2.
Inject alternately 2 μl each of the test solution and reference solution (c). The
area of any peak due to benzene in the chromatogram obtained with the test
solution is not greater than the difference between the area of the peak due to
benzene in the chromatogram obtained with reference solution (c) and that of
the peak due to benzene in the chromatogram obtained with the test solution.
In the chromatogram obtained with reference solution (a) the sum of areas of
any peaks other than the principal peak and the peaks due to 2-butanol is not
greater than 3 times the area of the peak due to 2-butanol (0.3 per cent).
Non-volatile matter. Not more than 0.002 per cent w/v, determined by
evaporating 100 ml on a water-bath and drying the residue at 105°.
- 97 -
Water-insoluble matter. Mix 1 volume with 19 volumes of water; no
opalescence is produced.
Water (2.3.43). Not more than 0.5 per cent, determined on 5 g.
- 98 -
8. Control of the Finished Pharmaceutical Products
1. Specifications for the Finished Pharmaceutical Product
➢ Copy of the FPP specification
➢List of tests and limits for result of the FPP
SPECIFICATION FOR ATORMICK-10 TABLETS
(Atorvastatin Tablets IP 10 mg)
Sr.
No.
1
Test Performed
Specification
Description
2
Identification
3
4
5
Wt. of 20 tablets
Average weight
Uniformity of weight
White coloured, round
shaped, biconvex, film coated
tablet plain on both side
In the Assay, the principal peak in the
chromatogram obtained with the test
solution corresponds to the peak in the
chromatogram obtained with the
reference solution.
NLT 3.340 gms, NMT 3.900 gms
NLT 0.1670 gms, NMT 0.1950 gms
± 7.5 %
6
7
8
9
10
Thickness
Diameter
Hardness
Disintegration time
Dissolution
11
12
Related substances
Assay
Each film coated tablet contains:
Atorvastatin calcium
Equivalent to Atorvastatin 10
mg
3.40 mm ± 0.3 mm
8.0 mm ± 0.3 mm
NLT 3.0 kg/cm2
NMT 30 minutes
Not less than 75 percent of the stated
amount of C66H68 F2N4O10
Complies as per IP
Limit:
(NLT 90.0% & NMT 110.0%)
9.0 mg to 11.0 mg
- 99 -
2. Analytical Procedures
➢ Analytical test procedure and methods
ATORMICK-10 Tablets
(Atorvastatin Tablets IP 10 mg)
Protocol: I.P.
Description:
White coloured, round shaped, biconvex, film coated tablet plain on both side
Composition:
Each film coated tablet contains:
Atorvastatin calcium
Equivalent to Atorvastatin 10 mg
Content of Atorvastatin, C66H68 F2N4O10:
Atorvastatin Tablets contain not less than 90.0 percent and not more than 110.0
percent of the stated amount of Atorvastatin, (C66H68 F2N4O10).
Average weight / Uniformity of weights:
Weight 20 tablets selected at random and calculate the average weight .Not
more than two of the individual weights deviate from the average weight by
more than the percentage ± 5, and none deviates by more than twice that
percentage.
1.
(Upper weight —Average weight) X 100
------------------------------------------------Average weight
=
2.
(Lower weight — Average weight) X 100
------------------------------------------------Average weight
=
+ deviation in %
— deviation in %
Disintegration time: Not more than 30 minutes.
Method:
This test determines whether tablet disintegrate within a prescribed time when
placed in liquid medium.
- 100 -
Introduce one tablet into each of six tubes of the basket, add a disc to each tube
and suspend the assembly in the beaker containing water maintained at 37 +
2C, operate the apparatus for 30 minutes left the basket out of water and
observe. The tablet passes the test if all of them are disintegrated, i.e. in all the
tubes no part of the tablet is left. If 1 or 2 tablets fail to disintegrate completely,
repeat the test on 12 additional tablets, not less than 16 of the total of 18 tablets
tested should disintegrate completely.
Identification
In the Assay, the principal peak in the chromatogram obtained with the test
solution corresponds to the peak in the chromatogram obtained with the
reference solution.
Tests
Dissolution (2.5.2)
Apparatus: 1
Medium: 900 ml of phosphate buffer pH 6.8
Speed and time: 75 rpm for 30 minutes
Test Solution. Use the filterate, diluted if necessary, with the dissolution
medium
Reference Soultion. Weigh a suitable quantity of atorvastatin calcium RS and
dissolve in sufficient methanol to produce a solution containing 0.088 percent
w/v of Atorvastatin. Dilute 10.0 ml of the resulting solution to 100.0 ml with
the medium
Use the chromatographic system described under the assay
Inject reference solution. The test is not valid unless the column efficiency is
not less than 7000 theoretical plates and tailing factor is not more than 1.5 and
the relative standard deviation for replicate injections is not more than 2.0
percent
Clculate the content of C66H68 F2N4O10
D.Not less than 70 percent of the stated amount of C66H68 F2N4O10
Related Substances. Determine by liquid chromatography (2.4.14)
Solvent mixture. A mixture of 40 volumes of acetonitrile and 60 volume of the
buffer solution
- 101 -
Test Solution. Weigh accurately a quantity of the powdered tablets containing
50 mg of atorvastatin, disperse in 10 ml of methanol add 20 mlof solvent
mixture, disperse with the aid of ultrasound, if required, and dilute to 100 ml
with the solvent mixture and filter
Reference Soultion. (a). Weigh accurately a suitable quantity of atorvastatin
calcium RS, dissolve in 5 ml of methanol and dilute to 50 ml with the solvent
mixture to produce 0.05 percent of Atorvastatin.
Reference Soultion. (b). Dilute 1 ml of reference solution (a) to 100 ml with the
solvent mixture
Chromagrahic system
- a stainless steel column 25 cm x 4.6 mm, packed with octadecylsilane bonded
to porous silica (5 µm)
- Mobile phase: A. a mixture of 92.5 volumes of Acetonitrile and 7.5 volume
tetrahydrofuran.
B. a mixture of 58 volumes of a buffer solution prepared by
dissolving 5.75 g of ammonium dihydrogen orthophosphate in 1000 ml of
water and 42 volumes of mobile phase A
C. a mixture of 20 volumes of the buffer solution 20 volumes of
mobile phase A and 60 volumes of methanol
- a linear gradient porgramme using the condition given below
- spectrophotometer set at 246 mm
- 20µl loop injector
- injection delay 10 minutes
Time
Flow rate
(in min.)
0
20
35
40
55
60
(ml per min.)
1.8
1.8
1.5
1.5
1.5
1.8
Mobile
Phase B
(percent v/v)
100
100
25
25
0
100
Mobile
Phase C
(percent v/v)
0
0
75
75
100
0
Inject reference solution (a). The test is not valid unless the column efficiency
is not less than 10000 theoretical plates and tailing factor is not more than 1.5
Inject alternatively the test solution and reference solution (b).In the
chromatogram obtained with test solution, the area of any secondary peak is
- 102 -
not more than the area of the peak in the chromatogram obtained with the
reference solution (b) (1.0 percent) and the sum of the area of all the secondary
peaks is not more than 4 times the area of the peak in the chromatogram
obtained with the reference solution (b) (4.0 percent)
Ignor any peak with an area less than 0.05 times the area of the peak obtained
with the reference solution (b) (0.05 percent)
Assay. Determine by liquid chromatography (2.4.14)
Solvent mixture. A solution prepared by dissolving 6.8 g of potassium
dihydrogen orthophosphate and 0.9 g of sodium hydroxide in 1000 ml of water
and adjusting the pH to 6.8 with phosphoric acid or sodium hydroxide
Test Solution. Weigh and powder 20 tablets.Weigh accurately a quantity of the
powdered tablets containing about 80 mg of atorvastatin and disperse in
sufficient methanol to produce a solution containing 0.016 percent w/v of
Atorvastatin, disperse with the aid of ultrasound, if required, and filter. Dilute
the filterate with sufficientof the solvent mixture to produce a solution
containing 0.008 percent w/v of Atorvastatin
Reference Soultion. Weigh accurately a suitable quantity of atorvastatin
calcium RS, dissolve in sufficient methanol to produce a solution containing
0.008 percent w/v of Atorvastatin. To 5 ml of this solution, add 20 ml of
methanol and dilute to 50 ml with the solvent mixture to produce a solution
containing 0.08 percent w/v of Atorvastatin
Chromagrahic system
- a stainless steel column 25 cm x 4.6 mm, packed with octadecylsilane bonded
to porous silica (5 µm)
- Mobile phase: a mixture of 50 volumes of a buffer solution prepared by
dissolving 1.54 g of ammonium acetate in 1000 ml of water and adjusting the
pH to 4.0 with glacial acetic acid and 50 volumes of a mixture of 92.5 volumes
of Acetonitrile and 7.5 volume tetrahydrofuran.
- flow rate 2.0 ml per minute
- spectrophotometer set at 246 mm
- a 20µl loop injector
Inject reference solution. The test is not valid unless the column efficiency is
not less than 7000 theoretical plates and tailing factor is not more than 1.5 and
the relative standard deviation for replicate injections is not more than 1.0
percent
Inject alternatively the test solution and reference solution
Clculate the content of C66H68 F2N4O10 in the tablets
- 103 -
Storage.Store protected from moisture at a temperature not exceeding 30°
Labelling. The label statesthe strength in terms of the equivalent amount of
atorvastatin
- 104 -
3. Validation of Analytical Procedures
➢ Required for non-compendial method
Analytical method of Atorvastatin tablet is compendial method and described
in many Pharmacopoeias viz. (BP. USP. EP. IP etc), the specification of the
ATORMICK-10 (Atorvastatin) tablet is as per IP, Hence the method validation
is not discussed
- 105 -
4. Batch Analysis
➢ Result of the analysis of three batches
➢ Copies of the certificates of analysis for these batches
Enclosed
- 106 -
9. Container Closure System(s) and Other Packaging
➢ Description of the suitability of the container closure System
➢ Description of container closure system
Suitability for the Intended Use
Every proposed packaging system should be shown to be suitable for its
intended use: it should adequately protect the dosage form; it should be
compatible with the dosage form; and it should be composed of materials that
are considered safe for use with the dosage form and the route of
administration. If the packaging system has a performance feature in addition
to containing the product, the assembled container closure system should be
shown to function properly.
General issues concerning protection, compatibility, safety and performance of
packaging components and/or systems are discussed below. In this guidance,
component functionality and drug delivery will also be addressed in connection
with specific dosage forms and routes of administration.
Table 1
Examples of packaging Concerns for Common Classes of Drug
Products
Degree of
Concern
Associated
with the Route
of
Administration
Likelihood of Packaging Component-Dosage
Form Interaction
Highest
Inhalation
Aerosols and
Solutions;
Injections and
Injectable
Suspensionsa
High
Medium
Sterile
Powders and
Powders for
Injection;
Inhalation
Powders
- 107 -
Low
High
Ophthalmic
Solutions and
Suspensions;
Transdermal
Ointments and
Patches; Nasal
Aerosols and
Sprays
Low
Topical
Solutions and
Suspensions;
Topical and
Lingual
Aerosols; Oral
Solutions and
Suspensions
Topical
Powders; Oral
powders
Oral Tablets
and Oral (Hard
and Soft
Gelatin)
Capsules
a
For the purposes of this table, the term sterile powder for injection is used
mean a after constituting with Sterile water for injection or any other
suitable diluents it can be administered in the pharmaceutical sense.
A) Protection
Container closure system should provide the dosage form with adequate
protection from factors (e.g., temperature, light) that can cause degradation in
the quality of that dosage form over its shelf life. Common causes of such
degradation are: exposure to light, loss of solvent, exposure to reactive gases
(e.g., oxygen), absorption of water vapor, and microbial contamination. A drug
product can also suffer an unacceptable loss in quality if it is contaminated by
filth.
Atorvastatin tablet is packed in Alu-Alu strip of aluminium foil to protect the
quality of the dosage form.
B) Compatibility
Packaging components aluminium foil and Rigid PVC film does not interact
sufficiently to cause unacceptable changes in the quality of the dosage form.
Examples of interactions include loss of potency due to absorption or
adsorption of the active drug substance, or degradation of the active drug
substance induced by a chemical entity leached from a packaging component;
- 108 -
reduction in the concentration of an excipient due to absorption, adsorption or
leachable-induced degradation; precipitation; changes in drug product pH;
discoloration of either the dosage form or the packaging component; or
increase in brittleness of the packaging component.
Some interactions between a packaging component and dosage form will be
detected during qualification studies on the container closure system and its
components. Others may not show up except in the stability studies. Therefore,
any change noted during a stability study that may be attributable to interaction
between the dosage form and a packaging component should be investigated
and appropriate action taken, regardless of whether the stability study is being
conducted for an original application, a supplemental application, or as
fulfillment of a commitment to conduct post approval stability studies.
Atorvastatin tablet is packed in Alu-Alu strip of aluminium foil is checked for
its stability during its shelf life. On the basis of Stability studies report the drug
is found stable and does interacted with drug component. No potency loss &
colour changes were observed during storage.
C) Safety
Packaging components should be constructed of materials that will not leach
harmful or undesirable amounts of substances to which a patient will be
exposed when being treated with the drug product. This consideration is
especially important for those packaging components which may be in direct
contact with the dosage form, but it is also applicable to any component from
which substances may migrate into the dosage form (e.g., an ink or adhesive).
Making the determination that a material of construction used in the
manufacture of a packaging component is safe for its intended use is not a
simple process, and a standardized approach has not been established. There is,
however, a body of experience which supports the use of certain approaches
that depend on the route of administration and the likelihood of interactions
between the component and the dosage form (see Table 1).
The approach for toxicological evaluation of the safety of extractables should
be based on good scientific principles and take into account the specific
container closure system, drug product formulation, dosage form, route of
administration, and dose regimen (chronic or short-term dosing).
For drug products that undergo clinical trials, the absence of adverse reactions
traceable to the packaging components is considered supporting evidence of
material safety.
- 109 -
Based upon above conducted tests, Atorvastatin tablet is found to be safe and
non toxic on storage in Alu-Alu packing
D) Performance
Performance of the container closure system refers to its ability to function in
the manner for which it was designed. A container closure system is often
called upon to do more than simply contain the dosage form. When evaluating
performance, two major considerations are container closure system
functionality and drug delivery.
Container Closure System Functionality
The container closure system may be designed to improve patient compliance.
Drug Delivery
Drug delivery refers to the ability of the packaging system to deliver the dosage
form in the amount or at the rate described in the package insert. Some
examples of a packaging system for which drug delivery aspects are relevant
are a prefilled syringe, a transdermal patch, a metered tube, a dropper or spray
bottle, a dry powder inhaler, and a metered dose inhaler.
Container closure system functionality and/or drug delivery are compromised
when the packaging system fails to operate as designed. Failure can result from
misuse, faulty design, manufacturing defect, improper assembly, or wear and
tear during use. Tests and acceptance criteria regarding dosage form delivery
and container closure system functionality should be appropriate to the
particular dosage form, route of administration, and design features.
E) Summary
Table 2 summarizes typical packaging suitability considerations for common
classes of drug products.
Table 2
Typical Suitability Considerations for Common Classes of Drug Products
(This table is a general guide, and is not comprehensive)
Route of
Administration/
Dosage Form
SUITABILITYa
Protection Compatibility
- 110 -
Safety
Performance/Drug
Delivery
Inhalation Aerosols and
Solutions, Nasal Sprays
L, S, M,
W, G
Case 1c
Case 1s
Case 1d
Inhalation Powders
L, W, M
Case 3 c
case 5s
Case 1d
Injections, Injectable
Suspensionsb
L, S, M, G
Case 1c
Case 2s
Case 2d
Sterile Powders and
Powders for Injection
L, M, W
Case 2c
Case 2s
Case 2d
Ophthalmic Solutions and
Suspensions
L, S, M, G
Case 1c
Case 2s
Case 2d
Topical Delivery Systems
L, S
Case 1c
Case 3s
Case 1d
Topical Solutions and
Suspensions, and Topical
and Lingual Aerosols
L, S, M
Case 1c
Case 3s
Case 2d
Topical Powders
L, M, W
Case 3c
Case 4s
Case 3d
Oral Solutions and
Suspensions
L, S, M
Case 1c
Case 3s
Case 2d
Oral Powders
L, W
Case 2c
Case 3s
Case 3d
Oral Tablets and Oral
(Hard and Soft Gelatin)
Capsules
L, W
Case 3c
Case 4s
Case 3d
*
If there is a special performance function built into the drug product it is of
importance for any dosage form/route of administration to show that the
container closure system performs that function properly.
Explanation of Codes in Table 2:
Protection:
L (protects from light, if appropriate)
S (protects from solvent loss/leakage)
M (protects sterile products or those with microbial limits
from microbial contamination)
- 111 -
W (protects from water vapor, if appropriate)
G (protects from reactive gases, if appropriate)
Compatibility: Case 1c: Liquid-based dosage form that conceivably could
interact with its container closure system components (see
examples
described
in
section
III.B.1)
Case 2c: Solid dosage form until reconstituted; greatest
chance for interacting with its container closure system
components
occurs
after
it
is
reconstituted.
Case 3c: Solid dosage form with low likelihood of interacting
with its container closure system components.
Safety:
Case 1s: Typically provided are USP Biological Reactivity
Test data, extraction/toxicological evaluation, limits on
extractables, and batch-to-batch monitoring of extractables.
Case 2s: Typically provided are USP Biological Reactivity
Test data and possibly extraction/toxicological evaluation.
Case 3s: Typically, an appropriate reference to the indirect
food additive regulations is sufficient for drug products with
aqueous-based solvents. Drug products with non-aqueous
based solvent systems or aqueous based systems containing
co-solvents generally require additional suitability information
(see section III.F).
Case 4s: Typically, an appropriate reference to the indirect
food additive regulations is sufficient.
Case 5s: Typically, an appropriate reference to the indirect
food additive regulations for all components except the
mouthpiece for which USP Biological Reactivity Test data is
provided.
Performance:
Case 1d: Frequently a consideration
Case 2d: May be a consideration
Case 3d: Rarely a consideration
Atorvastatin tablet is packed in Alu-Alu strip of aluminium foil.
There was no interaction between Primary Packing material and drug
product, which ensured the safety of aluminium foil and Rigid PVC film as
primary packaging material.
- 112 -
Both the Primary and Secondary Packaging materials are duly tested as per the
following Specifications in Quality Control Laboratory & only those
complying with the set In – House specifications are used.
Packaging material is routinely studied for Compatibility and Stability and the
results have indicated that there is no interaction between Primary Packaging
Material and the Drug Product.
- 113 -
➢ Primary packaging components specification and test methods
Packaging:
(a)
Type of package, its shape, size, color:
1 x 10 Tablets in Alu-Alu pack
10 x 10 Tablets strip in cardboard carton
(b)
Nature of packaging material:
Atorvastatin Tablets are to be packed in 1x 10 Tablets in Alu-Alu pack
and then Such 10 x 10 strip packed in a unit cartons With an insert.
These cartons are to be packed in a shipper carton depending on the type
of packing details. All the boxes are sealed within the shipper with a
poly lining, which protects the cartons from humidity and other
damages.
The shipper cartons are made of export worthy material and are sealed
with a BOPP tape.
(c)
Pack size:
Stage
Packing Description
1
1 x 10 Tablets in Alu-Alu pack
2
10 x 10 Tablets strip in cardboard carton
- 114 -
TECHNICAL SPECIFICATION FOR PACKING MATERIAL
NAME: ALU-ALU FOIL
SPECIFICATION: IN HOUSE
Sr.
No.
1
Test Performed
Specification
Description
Silver coloured alu-alu foil.
2
Material
Aluminium
3
Width in (mm)
115 mm
4
Thickness in (mm)
132 mm. ± 5 mm
5
grammage (g/m2)
250 GSM ± 5%
6
Pin Holes
Should be absent.
‫ ٭‬GRAMMAGE:
Bet. 65 gm/m2 to 75 gm/m2
Cut and perfect square piece of 5cm *5cm and weigh . Calculate as per the
Grams per sq. meter
Wt. In mg x 100 x100
.
L in cm x B in cm x1000
Cut this test on 10 sample foil individually. The test passes as per specification
with tolerance of ±10% Note it in the report sheet.
- 115 -
TECHNICAL SPECIFICATION FOR PACKING MATERIAL
NAME: ALUMINIUM FOIL
SPECIFICATION: IN HOUSE
Sr.
No.
1
Test Performed
2
3
4
5
Description
i) Appearance
ii) Print colour
Width
egammarG ‫٭‬
Thickness
Printed Matter
6
7
8
Pinhole Test
Ink Lifting Test
Suitability
9
Defects
10
Supply
11
Storage
12
Toxicity
Specification
Thick aluminum alloy soft temper foil with bright finish
with specimen colour printing
115 mm
Bet. 65 gm/m2 to 75 gm/m2
Bet. 0.025 mm to 0.0275 mm
To comply as per
approved specimen, should be sharp & readable
Should be absent
Should be Satisfactory
1.Winding of rolls should not be loose or telescopic.
2.Rolls should be free from dents, creasing/wrinkles and
damaged/collapsed core
3.Ink used for printing should be HR grade & withstand
temp. up to 180°C, there should not be lifting or fading
of ink during Strip sealing
Sample size of 5% rolls to be inspected at random for
corroded or oxidized surface, improper coating, and
improper winding & incorrect diameter of roll.
Rolls should be individually wrapped in polythene film
followed by brawn paper. Rolls should properly label
with item name, quantity & supplied by.
Store in air-conditioned room at temp. 20-30°C & RH
45-65%.
It is Food Grade. It is non toxic
‫ ٭‬GRAMMAGE:
Bet. 65 gm/m2 to 75 gm/m2
Cut and perfect square piece of 5cm *5cm and weigh . Calculate as per the
Grams per sq. meter
Wt. In mg x 100 x100
.
L in cm x B in cm x1000
Cut this test on 10 sample foil individually. The test passes as per specification
with tolerance of ±10% Note it in the report sheet.
- 116 -
TECHNICAL SPECIFICATION FOR PACKING MATERIAL
NAME: CARTON
SPECIFICATION: IN HOUSE
Sr.
No.
1.
Test Performed
3
Description
i) Color
ii) Shape
iii) Material of
Construction
Dimension: (Outer)
i) Length
ii) Breadth
iii) Height
iv) Grammage
Printed Matter
4
Suitability
5
Supply
6
Storage
2.
Specification
As per artwork / standard.
Rectangular, top opening, reverse tuck
Printed / unprinted, art card.
120.0 mm ± 2 mm
115.0 mm ± 2 mm
90.0 mm ± 2 mm
330.0 gsm  10%
Sharp & elegant as per artwork
The inks used for printing should be scuff-proof and
rub resistant. Cartons should pass the test when
checked on scuff-proof tester.
Banded in bundles of 100nos. and such 10 bundles
wrapped in brown paper clearly marked with item
name, quantity & supplied by.
Material should be stored in clean, dry warehouse.
- 117 -
TECHNICAL SPECIFICATION FOR PACKING MATERIAL
NAME: PACKAGING INSERTS
SPECIFICATION: IN HOUSE
Sr.
No.
1.
Test Performed
Specification
Description
Packaging inserts printed in black ink as per approved
text.
2.
Dimension:
175 x 100 ± 2 mm
3.
Grammage
50 ± 10% GSM
4
5
Material
Supply
6
Storage
Map litho paper
1000 nos. should be packed in brawn paper, properly
labeled with item name, quantity & supplied by.
Material should be stored in clean, dry warehouse.
- 118 -
TECHNICAL SPECIFICATION FOR PACKING MATERIAL
NAME: CORRUGATED BOX (SHIPPER)
SPECIFICATION: IN HOUSE
Sr.
No.
1.
2.
Test Performed
Description
Specification
7 Ply Brown color corrugated box having printed with
black color.
3.
Dimension:
i) Length
ii) Breadth
iii) Height
egammarG ‫٭‬
490 mm ± 1mm
460 mm ± 1mm
295 mm ± 1 mm
160 .02 GSM Outer
4.
Text Matter
Clear & readable
5.
Cleanliness check
Cleanliness ok.
6.
Foldlines /flaps
Working proper
7.
Bursting strength
 kg/cm
‫ ٭‬GRAMMAGE:
Select one corrugated boxes cut and perfect square piece of 12cm *12cm
approximately ,and dip in a hot water bath for several hours till the ply ‘s are
separated .Then dry in a oven and cut a perfect square of 10cm x 10 cm of each
ply in a sequence and weigh . Calculate as per the
Grams per sq. meter
Wt. In mg x 100 x100
.
L in cm x B in cm x1000
The test passes with limits of not less than 100 GSM per each ply.
- 119 -
TECHNICAL SPECIFICATION FOR PACKING MATERIAL
NAME: BOPP TAPE (SELF ADHESIVE TAPE)
SPECIFICATION: IN HOUSE
Sr.
No.
1
2
3
4
Test Performed
Specification
Transparent self-adhesive BOPP tape printed as per
approved text and design in Approved colour.
Description
Dimension:
i) Width
ii) Thickness of BOPP
iii) Total Thickness
Grammage
72 ± 1 mm
25-30 microns
50-55 microns
50 ± 10%
Diameter 75 ± 1 mm
5
Core
Internal
Adhesive
6
Adhesion test
7
Supply
8
Storage
Should be uniform, printed surface should pass tape
test.
Seal the flaps in length on corrugated fiber box the tape
using a hand dispenser or manually. Ensure no
wrinkles/air bubbles are formed while pasting and
proper pressure should be applied. Leave the box for
10minutes and try to separate the tape from the end.
Tape should separate with fiber tearing.
Supplied in rolls of 65meters packed in a box & clearly
marked with item name, quantity & supplied by.
Material should be stored in clean, dry warehouse.
- 120 -
Specimen Label
PROPOSED LABEL
1. Immediate label on the
smallest Packing unit:
(Empty printed carton of the product enclosed)
2. Intermediate Label:
(Enclosed)
3. Packing Insert:
(Enclosed)
- 121 -
10. Stability Testing of the Finished Product
➢ Stability studies report
➢ Methodology of stability studies
STABILITY TEST REPORT
Product
:
Atorvastatin Tablets 10 mg
Shelf-life
:
Atorvastatin Tablets 10 mg, packed in Alu-Alu
strip of 10 X 10 tablets are stable at least 2 years
from the date of manufacture.
Proposed expiry
:
2 years
Storage
:
Store protected from light and temperature not
exceeding 30°.
Stability studies
:
Accelerated stability study at 40°C & Long term
stability study at 30°C are carried out and stability
data are attached.
Type of Packing
:
A pack of 10 x 10 tablets Alu-Alu strip in a carton
STORAGE CONDITIONS:
Accelerated stability studies of the product are kept in humidity chamber
At 400 ± 20C/75% ± 5%RH
For Long term stability studies are kept in control sample room at
At 300 ± 20C/65% ± 5%RH
TESTING INTERVALS:
The stored samples are withdrawn at predetermined intervals the intervals are
as follows:
For Accelerated stability study:
0 month, 1 month, 2 months, 3 months & 6 months
For Long term stability study:
0 month, 3 months, 6 months, 9 months, 12 months, 18 months & 24 months.
- 122 -
TESTING SPECIFICATIONS:
Sr.
No.
1
Test Performed
Specification
Description
2
Identification
White coloured, elongated
shaped, film coated tablet
having a breakline on one side
and plain on other side
Positive for Atorvastatin
3
Average weight
181 mg
4
Uniformity of weight
± 7.5 %
5
Dissolution
Not less than 75 percent of the
stated amount of C66H68 F2N4O10
Complies as per IP
6
7
Related substances
Assay
Each film coated tablet contains:
Atorvastatin calcium
Equivalent to Atorvastatin 10 mg
General Method of Assay:
(Method attached)
Limit:
(NLT 90.0% & NMT 110.0%)
9.0 mg to 11.0 mg
Conditions for normal tests:
At 300 ± 20C/65% ± 5%RH
CONTROLLED BATCHES:
Stability study testing of Atorvastatin Tablets was carried out on 3 batches.
Study No.
B. No.
Mfg. Dt.
Exp. Dt.
A.
MT-1421
04-2014
03-2016
B.
MT-1422
04-2014
03-2016
C.
MT-1423
04-2014
03-2016
Characteristics of the packaging (container /closure interaction with the
product):
A pack of 10 x 10 tablets
Stability study was conducted in the final packing.
- 123 -
➢ A tabulated summary of stability results should be provided.
- 124 -
QUALITY ASSURANCE DEPARTMENT
Long Term Stability Study
Storage conditions: Temperature: 30 + 2°C, Relative Humidity: 65 + 5 %
Product Name
Generic Name
Description
Batch No.
MT-1421
ATORMICK-10 TABLETS
Atorvastatin Tablets IP 10 mg
White coloured, round shaped,biconvex, film coated tablet plain on both side
Batch Size
Mfg. Date
Exp. Date
1.0 Lac
04.2014
03.2016
Storage
Time &
test
Interval
Storage
condition
Temp. %
RH
Product
Description
Up to 24
months
and 6
months
300 ±
20C
Description: White coloured,
round shaped, biconvex, film coated
tablet plain on both side
Identification: positive for
Atorvastatin
Average weight: 181.0 mg
Uniformity of weight: ±7.5%
Dissolution test: NLT 75 %.
Related substances: Complies as per
IP
Assay: NLT 90 % & NMT 110 %
65%
±
5%
Sample Quantity
200 Tablets
Result of Analysis
Initial
Test
Test date:
14/04/14
Complies
After 3
Months
Test date:
13/07/14
Complies
After 6
Months
Test date:
13/10/14
Complies
After 9
Months
Test date:
13/01/15
Complies
After 12
Months
Test date:
13/04/15
Complies
After 18
Months
Test date:
13/10/15
Complies
After 24
Months
Test date:
13/04/16
Complies
Complies
Complies
Complies
Complies
Complies
Complies
Complies
181.4 mg
Complies
92.5 %
Complies
180.6 mg
Complies
92.1 %
Complies
183.5 mg
Complies
91.8 %
Complies
179.8 mg
Complies
91.2 %
Complies
180.2 mg
Complies
90.6 %
Complies
182.6 mg
Complies
89.7 %
Complies
181.8 mg
Complies
88.1 %
Complies
99.76 %
99.44 %
99.13 %
98.54 %
97.90 %
97.40 %
96.53 %
Conclusion: There is no physical and chemical change in the product when stored at 300 ± 20C temperature and 65% ± 5% relative humidity
The product is stable for a period of 24 months
-----------------------------Checked By
----------------------------- Approved By
- 125 -
QUALITY ASSURANCE DEPARTMENT
Long Term Stability Study
Storage conditions: Temperature: 30 + 2°C, Relative Humidity: 65 + 5 %
Product Name
Generic Name
Description
Batch No.
MT-1422
ATORMICK-10 TABLETS
Atorvastatin Tablets IP 10 mg
White coloured, round shaped,biconvex, film coated tablet plain on both side
Batch Size
Mfg. Date
Exp. Date
1.0 Lac
04.2014
03.2016
Storage
Time &
test
Interval
Storage
condition
Temp. %
RH
Product
Description
Up to 24
months
and 6
months
300 ±
20C
Description: White coloured,
round shaped, biconvex, film coated
tablet plain on both side
Identification: positive for
Atorvastatin
Average weight: 181.0 mg
Uniformity of weight: ±7.5%
Dissolution test: NLT 75 %.
Related substances: Complies as per
IP
Assay: NLT 90 % & NMT 110 %
65%
±
5%
Sample Quantity
200 Tablets
Result of Analysis
Initial
Test
Test date:
17/04/14
Complies
After 3
Months
Test date:
16/07/14
Complies
After 6
Months
Test date:
16/10/14
Complies
After 9
Months
Test date:
16/01/15
Complies
After 12
Months
Test date:
16/04/15
Complies
After 18
Months
Test date:
16/10/15
Complies
After 24
Months
Test date:
16/04/16
Complies
Complies
Complies
Complies
Complies
Complies
Complies
Complies
182.2 mg
Complies
92.2 %
Complies
183.4 mg
Complies
92.1 %
Complies
180.5 mg
Complies
91.8 %
Complies
181.8 mg
Complies
91.4 %
Complies
179.2 mg
Complies
90.6 %
Complies
183.2 mg
Complies
90.1 %
Complies
182.4 mg
Complies
89.2 %
Complies
99.77 %
99.52 %
99.19 %
98.58 %
97.90 %
97.34 %
96.41 %
Conclusion: There is no physical and chemical change in the product when stored at 300 ± 20C temperature and 65% ± 5% relative humidity
The product is stable for a period of 24 months
-----------------------------Checked By
----------------------------- Approved By
- 126 -
QUALITY ASSURANCE DEPARTMENT
Long Term Stability Study
Storage conditions: Temperature: 30 + 2°C, Relative Humidity: 65 + 5 %
Product Name
Generic Name
Description
Batch No.
MT-1423
ATORMICK-10 TABLETS
Atorvastatin Tablets IP 10 mg
White coloured, round shaped,biconvex, film coated tablet plain on both side
Batch Size
Mfg. Date
Exp. Date
1.0 Lac
04.2014
03.2016
Storage
Time &
test
Interval
Storage
condition
Temp. %
RH
Product
Description
Up to 24
months
and 6
months
300 ±
20C
Description: White coloured,
round shaped, biconvex, film coated
tablet plain on both side
Identification: positive for
Atorvastatin
Average weight: 181.0 mg
Uniformity of weight: ±7.5%
Dissolution test: NLT 75 %.
Related substances: Complies as per
IP
Assay: NLT 90 % & NMT 110 %
65%
±
5%
Sample Quantity
200 Tablets
Result of Analysis
Initial
Test
Test date:
18/04/14
Complies
After 3
Months
Test date:
17/07/14
Complies
After 6
Months
Test date:
17/10/14
Complies
After 9
Months
Test date:
17/01/15
Complies
After 12
Months
Test date:
17/04/15
Complies
After 18
Months
Test date:
17/10/15
Complies
After 24
Months
Test date:
17/04/16
Complies
Complies
Complies
Complies
Complies
Complies
Complies
Complies
182.4 mg
Complies
92.2 %
Complies
180.6 mg
Complies
92.1 %
Complies
179.5 mg
Complies
91.7 %
Complies
184.3 mg
Complies
91.2 %
Complies
182.0 mg
Complies
90.5 %
Complies
181.6 mg
Complies
89.6 %
Complies
182.6 mg
Complies
88.3 %
Complies
99.76 %
99.42 %
99.16 %
98.60 %
97.84 %
97.43 %
96.34 %
Conclusion: There is no physical and chemical change in the product when stored at 300 ± 20C temperature and 65% ± 5% relative humidity
The product is stable for a period of 24 months
-----------------------------Checked By
----------------------------- Approved By
- 127 -
Real time stability study Report
ATORMICK-10 TABLETS
The stability study were carried out with three batches at temperature 300 ± 20C and RH 65% ± 5% in 10 x 10 Tablets Alu-Alu packing. The same were tested initially and
continued up to 24 months at every 3 & 6 months interval
Observation:
The test result obtained from batches at the above mentioned condition and stability program are as follow:
(a) No change in appearance of tablets
(b) The contents of active ingredients are well with in limit
(c) Identification complies with test of specification
(d) No interaction of the immediate pack with the pharmaceutical dosage form is found during the study, proving that the Alu-Alu packing is suitable for the product
Conclusion:
The product maintains its good appearance, strength and quality, There for the product is accepted to be stable for a period of 24 months storage condition stated in carton is
followed
Compiled by: ______________
Name
Designation
Checked by: ________________
Name
Designation
- 128 -
Approved by: _______________
Name
Designation
QUALITY ASSURANCE DEPARTMENT
Accelerated Stability Study
Storage conditions: Temperature: 40 + 2°C, Relative Humidity: 75 + 5 %
Product Name
Generic Name
Description
Batch No.
MT-1421
Storage
Time &
test
Interval
Up to 6
months
and 1
months
Storage
condition
Temp. %
RH
400 ±
75%
0
2C
±
5%
ATORMICK-10 TABLETS
Atorvastatin Tablets IP 10 mg
White coloured, round shaped,biconvex, film coated tablet plain on both side
Batch Size
Mfg. Date
Exp. Date
Sample Quantity
1.0 Lac
04.2014
03.2016
100 Tablets
Product
Description
Result of Analysis
Description: White coloured, round
shaped,biconvex, film coated tablet
plain on both side
Identification: positive for
Atorvastatin
Average weight: 181.0 mg
Uniformity of weight: ±7.5%
Dissolution test: NLT 75 %.
Related substances: Complies as per
IP
Assay: NLT 90 % & NMT 110 %
Initial Test
Test date: 14/04/14
Complies
After 1 Months
Test date: 13/05/14
Complies
After 2 Months
Test date: 13/06/14
Complies
After 3 Months
Test date: 13/07/14
Complies
After 6 Months
Test date: 13/10/14
Complies
Complies
Complies
Complies
Complies
Complies
181.4 mg
Complies
92.5 %
Complies
179.8 mg
Complies
92.2 %
Complies
182.6 mg
Complies
91.7 %
Complies
181.2 mg
Complies
91.1 %
Complies
182.8 mg
Complies
90.4 %
Complies
99.76 %
99.51 %
98.64 %
98.04 %
97.32 %
Conclusion: There is no physical and chemical change in the product when stored at 400 ± 20C temperature and 75% ± 5% relative humidity
-----------------------------Checked By
----------------------------- Approved By
- 129 -
QUALITY ASSURANCE DEPARTMENT
Accelerated Stability Study
Storage conditions: Temperature: 40 + 2°C, Relative Humidity: 75 + 5 %
Product Name
Generic Name
Description
Batch No.
MT-1422
Storage
Time &
test
Interval
Up to 6
months
and 1
months
Storage
condition
Temp. %
RH
400 ±
75%
0
2C
±
5%
ATORMICK-10 TABLETS
Atorvastatin Tablets IP 10 mg
White coloured, round shaped,biconvex, film coated tablet plain on both side
Batch Size
Mfg. Date
Exp. Date
Sample Quantity
1.0 Lac
04.2014
03.2016
100 Tablets
Product
Description
Result of Analysis
Description: White coloured, round
shaped,biconvex, film coated tablet
plain on both side
Identification: positive for
Atorvastatin
Average weight: 181.0 mg
Uniformity of weight: ±7.5%
Dissolution test: NLT 75 %.
Related substances: Complies as per
IP
Assay: NLT 90 % & NMT 110 %
Initial Test
Test date: 17/04/14
Complies
After 1 Months
Test date: 16/05/14
Complies
After 2 Months
Test date: 16/06/14
Complies
After 3 Months
Test date: 16/07/14
Complies
After 6 Months
Test date: 16/10/14
Complies
Complies
Complies
Complies
Complies
Complies
182.2 mg
Complies
92.2 %
Complies
182.2 mg
Complies
92.0 %
Complies
181.4 mg
Complies
91.6 %
Complies
183.2 mg
Complies
91.0 %
Complies
182.6 mg
Complies
90.2 %
Complies
99.77 %
99.42 %
98.61 %
97.91 %
97.17 %
Conclusion: There is no physical and chemical change in the product when stored at 400 ± 20C temperature and 75% ± 5% relative humidity
-----------------------------Checked By
----------------------------- Approved By
- 130 -
QUALITY ASSURANCE DEPARTMENT
Accelerated Stability Study
Storage conditions: Temperature: 40 + 2°C, Relative Humidity: 75 + 5 %
Product Name
Generic Name
Description
Batch No.
MT-1423
Storage
Time &
test
Interval
Up to 6
months
and 1
months
Storage
condition
Temp. %
RH
400 ±
75%
0
2C
±
5%
ATORMICK-10 TABLETS
Atorvastatin Tablets IP 10 mg
White coloured, round shaped,biconvex, film coated tablet plain on both side
Batch Size
Mfg. Date
Exp. Date
Sample Quantity
1.0 Lac
04.2014
03.2016
100 Tablets
Product
Description
Result of Analysis
Description: White coloured, round
shaped,biconvex, film coated tablet
plain on both side
Identification: positive for
Atorvastatin
Average weight: 181.0 mg
Uniformity of weight: ±7.5%
Dissolution test: NLT 75 %.
Related substances: Complies as per
IP
Assay: NLT 90 % & NMT 110 %
Initial Test
Test date: 18/04/14
Complies
After 1 Months
Test date: 17/05/14
Complies
After 2 Months
Test date: 17/06/14
Complies
After 3 Months
Test date: 17/07/14
Complies
After 6 Months
Test date: 17/10/14
Complies
Complies
Complies
Complies
Complies
Complies
182.4 mg
Complies
92.2 %
Complies
182.4 mg
Complies
92.0 %
Complies
181.2 mg
Complies
91.7 %
Complies
183.4 mg
Complies
91.2 %
Complies
183.0 mg
Complies
90.2 %
Complies
99.76 %
99.40 %
98.56 %
97.81 %
97.11 %
Conclusion: There is no physical and chemical change in the product when stored at 400 ± 20C temperature and 75% ± 5% relative humidity
-----------------------------Checked By
----------------------------- Approved By
- 131 -
Accelerated stability study Report
ATORMICK-10 TABLETS
The stability study were carried out with three batches at temperature 400 ± 20C and RH 75% ± 5% in 10 x 10 Tablets Alu-Alu packing. The same were tested initially and
continued up to 6 months at every 1 & 3 months interval
Observation:
The test result obtained from batches at the above mentioned condition and stability program are as follow:
(a) No change in appearance of tablets
(b) The contents of active ingredients are well with in limit
(c) Identification complies with test of specification
(d) No interaction of the immediate pack with the pharmaceutical dosage form is found during the study, proving that the Alu-Alu packing is suitable for the product
Conclusion:
The product maintains its good appearance, strength and quality, There for the product is accepted to be stable for a period of 24 months storage condition stated in carton is
followed
Compiled by: ______________
Name
Designation
Checked by: ________________
Name
Designation
- 132 -
Approved by: _______________
Name
Designation
11. Other data, if any
SPC (Summary of Product Characteristics)
1. Name of the medicinal product
ATORMICK-10 (Atorvastatin) Tablets
2. Qualitative and quantitative composition
Each Film Coated Tablet Contains:
Atorvastatin calcium IP
Equivalent to Atorvastatin 10 mg
3. Pharmaceutical form
Film-coated tablets for oral administration
4. Clinical particulars
4.1 Therapeutic indications
Hypercholesterolaemia
Atorvastatin is indicated as an adjunct to diet for reduction of elevated total
cholesterol (total-C), LDL-cholesterol (LDL-C), apolipoprotein B, and
triglycerides in adults, adolescents and children aged 10 years or older with
primary hypercholesterolaemia including familial hypercholesterolaemia
(heterozygous variant) or combined (mixed) hyperlipidaemia (Corresponding
to Types IIa and IIb of the Fredrickson classification) when response to diet
and other nonpharmacological measures is inadequate.
Atorvastatin is also indicated to reduce total-C and LDL-C in adults with
homozygous familial hypercholesterolaemia as an adjunct to other lipidlowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
Prevention of cardiovascular disease
Prevention of cardiovascular events in adult patients estimated to have a high
risk for a first cardiovascular event (see section 5.1), as an adjunct to correction
of other risk factors.
- 133 -
4.2 Posology and method of administration
Posology
The patient should be placed on a standard cholesterol-lowering diet before
receiving Atorvastatin and should continue on this diet during treatment with
Atorvastatin.
The dose should be individualised according to baseline LDL-C levels, the goal
of therapy, and patient response.
The usual starting dose is 10 mg once a day. Adjustment of dose should be
made at intervals of 4 weeks or more. The maximum dose is 80 mg once a day.
Primary hypercholesterolaemia and combined (mixed) hyperlipidaemia
The majority of patients are controlled with Atorvastatin 10 mg once a day. A
therapeutic response is evident within 2 weeks, and the maximum therapeutic
response is usually achieved within 4 weeks. The response is maintained during
chronic therapy.
Heterozygous familial hypercholesterolaemia
Patients should be started with Atorvastatin 10 mg daily. Doses should be
individualised and adjusted every 4 weeks to 40 mg daily. Thereafter, either the
dose may be increased to a maximum of 80 mg daily or a bile acid sequestrant
may be combined with 40 mg atorvastatin once daily.
Homozygous familial hypercholesterolaemia
Only limited data are available (see section 5.1).
The dose of atorvastatin in patients with homozygous familial
hypercholesterolemia is 10 to 80 mg daily (see section 5.1). Atorvastatin
should be used as an adjunct to other lipid-lowering treatments (e.g. LDL
apheresis) in these patients or if such treatments are unavailable.
Prevention of cardiovascular disease
In the primary prevention trials the dose was 10 mg/day. Higher doses may be
necessary in order to attain (LDL-) cholesterol levels according to current
guidelines.
Patients with renal impairment
No adjustment of dose is required (see section 4.4).
Patients with hepatic impairment
Atorvastatin should be used with caution in patients with hepatic impairment
(see sections 4.4 and 5.2). Atorvastatin is contraindicated in patients with active
liver disease (see section 4.3).
Elderly patients
Efficacy and safety in patients older than 70 using recommended doses are
similar to those seen in the general population.
Paediatric population
Hypercholesterolaemia
- 134 -
Paediatric use should only be carried out by physicians experienced in the
treatment of paediatric hyperlipidaemia and patients should be re-evaluated on
a regular basis to assess progress.
For patients aged 10 years and above, the recommended starting dose of
atorvastatin is 10 mg per day with titration up to 20 mg per day. Titration
should be conducted according to the individual response and tolerability in
paediatric patients. Safety information for paediatric patients treated with doses
above 20 mg, corresponding to about 0.5 mg/kg, is limited.
There is limited experience in children between 6-10 years of age (see section
5.1). Atorvastatin is not indicated in the treatment of patients below the age of
10 years.
Other pharmaceutical forms/strengths may be more appropriate for this
population.
Method of administration
Atorvastatin is for oral administration. Each daily dose of atorvastatin is given
all at once and may be given at any time of day with or without food.
4.3 Contraindications
Atorvastatin is contraindicated in patients:
- with hypersensitivity to the active substance or to any of the excipients listed
in section 6.1
- with active liver disease or unexplained persistent elevations of serum
transaminases exceeding 3 times the upper limit of normal
- during pregnancy, while breast-feeding and in women of child-bearing
potential not using appropriate contraceptive measures (see section 4.6)
4.4 Special warnings and precautions for use
Liver effects
Liver function tests should be performed before the initiation of treatment and
periodically thereafter. Patients who develop any signs or symptoms suggestive
of liver injury should have liver function tests performed. Patients who develop
increased transaminase levels should be monitored until the abnormality(ies)
resolve. Should an increase in transaminases of greater than 3 times the upper
limit of normal (ULN) persist, reduction of dose or withdrawal of Atorvastatin
is recommended (see section 4.8).
Atorvastatin should be used with caution in patients who consume substantial
quantities of alcohol and/or have a history of liver disease.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In a post-hoc analysis of stroke subtypes in patients without coronary heart
disease (CHD) who had a recent stroke or transient ischemic attack (TIA) there
- 135 -
was a higher incidence of hemorrhagic stroke in patients initiated on
atorvastatin 80 mg compared to placebo. The increased risk was particularly
noted in patients with prior hemorrhagic stroke or lacunar infarct at study entry.
For patients with prior hemorrhagic stroke or lacunar infarct, the balance of
risks and benefits of atorvastatin 80 mg is uncertain, and the potential risk of
hemorrhagic stroke should be carefully considered before initiating treatment
(see section 5.1).
Skeletal muscle effects
Atorvastatin, like other HMG-CoA reductase inhibitors, may in rare occasions
affect the skeletal muscle and cause myalgia, myositis, and myopathy that may
progress to rhabdomyolysis, a potentially life-threatening condition
characterised by markedly elevated creatine kinase (CK) levels (> 10 times
ULN), myoglobinaemia and myoglobinuria which may lead to renal failure.
Before the treatment
Atorvastatin should be prescribed with caution in patients with pre-disposing
factors for rhabdomyolysis. A CK level should be measured before starting
statin treatment in the following situations:
- Renal impairment
- Hypothyroidism
- Personal or familial history of hereditary muscular disorders
- Previous history of muscular toxicity with a statin or fibrate
- Previous history of liver disease and/or where substantial quantities of alcohol
are consumed
- In elderly (age > 70 years), the necessity of such measurement should be
considered, according to the presence of other predisposing factors for
rhabdomyolysis
- Situations where an increase in plasma levels may occur, such as interactions
(see section 4.5) and special populations including genetic subpopulations (see
section 5.2)
In such situations, the risk of treatment should be considered in relation to
possible benefit, and clinical monitoring is recommended.
If CK levels are significantly elevated (> 5 times ULN) at baseline, treatment
should not be started.
Creatine kinase measurement
Creatine kinase (CK) should not be measured following strenuous exercise or
in the presence of any plausible alternative cause of CK increase as this makes
value interpretation difficult. If CK levels are significantly elevated at baseline
(> 5 times ULN), levels should be remeasured within 5 to 7 days later to
confirm the results.
Whilst on treatment
- Patients must be asked to promptly report muscle pain, cramps, or weakness
especially if accompanied by malaise or fever.
- If such symptoms occur whilst a patient is receiving treatment with
atorvastatin, their CK levels should be measured. If these levels are found to be
significantly elevated (> 5 times ULN), treatment should be stopped.
- 136 -
- If muscular symptoms are severe and cause daily discomfort, even if the CK
levels are elevated to ≤ 5 x ULN, treatment discontinuation should be
considered.
- If symptoms resolve and CK levels return to normal, then re-introduction of
atorvastatin or introduction of an alternative statin may be considered at the
lowest dose and with close monitoring.
- Atorvastatin must be discontinued if clinically significant elevation of CK
levels (> 10 x ULN) occur, or if rhabdomyolysis is diagnosed or suspected.
Concomitant treatment with other medicinal products
Risk of rhabdomyolysis is increased when atorvastatin is administered
concomitantly with certain medicinal products that may increase the plasma
concentration of atorvastatin such as potent inhibitors of CYP3A4 or transport
proteins (e.g. ciclosporine, telithromycin, clarithromycin, delavirdine,
stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV
protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir,
darunavir, etc). The risk of myopathy may also be increased with the
concomitant use of gemfibrozil and other fibric acid derivates, boceprevir,
erythromycin, niacin, ezetimibe, telaprevir, or the combination of
tipranavir/ritonavir. If possible, alternative (non-interacting) therapies should
be considered instead of these medicinal products.
There have been very rare reports of an immune-mediated necrotizing
myopathy (IMNM) during or after treatment with some statins. IMNM is
clinically characterised by persistent proximal muscle weakness and elevated
serum creatine kinase, which persist despite discontinuation of statin treatment.
In cases where co-administration of these medicinal products with atorvastatin
is necessary, the benefit and the risk of concurrent treatment should be
carefully considered. When patients are receiving medicinal products that
increase the plasma concentration of atorvastatin, a lower maximum dose of
atorvastatin is recommended. In addition, in the case of potent CYP3A4
inhibitors, a lower starting dose of atorvastatin should be considered and
appropriate clinical monitoring of these patients is recommended (see section
4.5).
The concurrent use of atorvastatin and fusidic acid is not recommended,
therefore, temporary suspension of atorvastatin may be considered during
fusidic acid therapy (see section 4.5).
Paediatric population
Developmental safety in the paediatric population has not been established (see
section 4.8).
Interstitial lung disease
Exceptional cases of interstitial lung disease have been reported with some
statins, especially with long term therapy (see section 4.8). Presenting features
can include dyspnoea, non-productive cough and deterioration in general health
- 137 -
(fatigue, weight loss and fever). If it is suspected a patient has developed
interstitial lung disease, statin therapy should be discontinued.
Diabetes Mellitus
Some evidence suggests that statins as a class raise blood glucose and in some
patients, at high risk of future diabetes, may produce a level of hyperglycaemia
where formal diabetes care is appropriate. This risk, however, is outweighed by
the reduction in vascular risk with statins and therefore should not be a reason
for stopping statin treatment. Patients at risk (fasting glucose 5.6 to 6.9
mmol/L, BMI>30kg/m2, raised triglycerides, hypertension) should be
monitored both clinically and biochemically according to national guidelines.
4.5 Interaction with other medicinal products and other forms of
interaction
Effect of co-administered medicinal products on atorvastatin
Atorvastatin is metabolized by cytochrome P450 3A4 (CYP3A4) and is a
substrate to transport proteins e.g. the hepatic uptake transporter OATP1B1.
Concomitant administration of medicinal products that are inhibitors of
CYP3A4 or transport proteins may lead to increased plasma concentrations of
atorvastatin and an increased risk of myopathy. The risk might also be
increased at concomitant administration of atorvastatin with other medicinal
products that have a potential to induce myopathy, such as fibric acid derivates
and ezetimibe (see section 4.4).
CYP3A4 inhibitors
Potent CYP3A4 inhibitors have been shown to lead to markedly increased
concentrations of atorvastatin (see Table 1 and specific information below).
Co-administration of potent CYP3A4 inhibitors (e.g. ciclosporin,
telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole,
voriconazole, itraconazole, posaconazole and HIV protease inhibitors including
ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided if
possible. In cases where co-administration of these medicinal products with
atorvastatin cannot be avoided lower starting and maximum doses of
atorvastatin should be considered and appropriate clinical monitoring of the
patient is recommended (see Table 1).
Moderate CYP3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and
fluconazole) may increase plasma concentrations of atorvastatin (see Table 1)..
An increased risk of myopathy has been observed with the use of erythromycin
in combination with statins. Interaction studies evaluating the effects of
amiodarone or verapamil on atorvastatin have not been conducted. Both
amiodarone and verapamil are known to inhibit CYP3A4 activity and coadministration with atorvastatin may result in increased exposure to
atorvastatin. Therefore, a lower maximum dose of atorvastatin should be
- 138 -
considered and appropriate clinical monitoring of the patient is recommended
when concomitantly used with moderate CYP3A4 inhibitors. Appropriate
clinical monitoring is recommended after initiation or following dose
adjustments of the inhibitor.
CYP3A4 inducers
Concomitant administration of atorvastatin with inducers of cytochrome P450
3A (e.g. efavirenz, rifampin, St. John's Wort) can lead to variable reductions in
plasma concentrations of atorvastatin. Due to the dual interaction mechanism
of rifampin, (cytochrome P450 3A induction and inhibition of hepatocyte
uptake transporter OATP1B1), simultaneous co-administration of atorvastatin
with rifampin is recommended, as delayed administration of atorvastatin after
administration of rifampin has been associated with a significant reduction in
atorvastatin plasma concentrations. The effect of rifampin on atorvastatin
concentrations in hepatocytes is, however, unknown and if concomitant
administration cannot be avoided, patients should be carefully monitored for
efficacy.
Transport protein inhibitors
Inhibitors of transport proteins (e.g. ciclosporin) can increase the systemic
exposure of atorvastatin (see Table 1). The effect of inhibition of hepatic
uptake transporters on atorvastatin concentrations in hepatocytes is unknown. If
concomitant administration cannot be avoided, a dose reduction and clinical
monitoring for efficacy is recommended (see Table 1).
Gemfibrozil / fibric acid derivatives
The use of fibrates alone is occasionally associated with muscle related events,
including rhabdomyolysis. The risk of these events may be increased with the
concomitant use of fibric acid derivatives and atorvastatin. If concomitant
administration cannot be avoided, the lowest dose of atorvastatin to achieve the
therapeutic objective should be used and the patients should be appropriately
monitored (see section 4.4).
Ezetimibe
The use of ezetimibe alone is associated with muscle related events, including
rhabdomyolysis. The risk of these events may therefore be increased with
concomitant use of ezetimibe and atorvastatin. Appropriate clinical monitoring
of these patients is recommended.
Colestipol
Plasma concentrations of atorvastatin and its active metabolites were lower (by
approx. 25%) when colestipol was co-administered with Atorvastatin.
However, lipid effects were greater when Atorvastatin and colestipol were coadministered than when either medicinal product was given alone.
Fusidic acid
Interaction studies with atorvastatin and fusidic acid have not been conducted.
As with other statins, muscle related events, including rhabdomyolysis, have
been reported in post-marketing experience with atorvastatin and fusidic acid
given concurrently. The mechanism of this interaction is not known. Patients
should be closely monitored and temporary suspension of atorvastatin
treatment may be appropriate.
- 139 -
Colchicine
Although interaction studies with atorvastatin and colchicine have not been
conducted, cases of myopathy have been reported with atorvastatin coadministered with colchicine, and caution should be exercised when
prescribing atorvastatin with colchicine.
Effect of atorvastatin on co-administered medicinal products
Digoxin
When multiple doses of digoxin and 10 mg atorvastatin were co-administered,
steady-state digoxin concentrations increased slightly. Patients taking digoxin
should be monitored appropriately.
Oral contraceptives
Co-administration of Atorvastatin with an oral contraceptive produced
increases in plasma concentrations of norethindrone and ethinyl oestradiol.
Warfarin
In a clinical study in patients receiving chronic warfarin therapy,
coadministration of atorvastatin 80 mg daily with warfarin caused a small
decrease of about 1.7 seconds in prothrombin time during the first 4 days of
dosing which returned to normal within 15 days of atorvastatin treatment.
Although only very rare cases of clinically significant anticoagulant
interactions have been reported, prothrombin time should be determined before
starting atorvastatin in patients taking coumarin anticoagulants and frequently
enough during early therapy to ensure that no significant alteration of
prothrombin time occurs. Once a stable prothrombin time has been
documented, prothrombin times can be monitored at the intervals usually
recommended for patients on coumarin anticoagulants. If the dose of
atorvastatin is changed or discontinued, the same procedure should be repeated.
Atorvastatin therapy has not been associated with bleeding or with changes in
prothrombin time in patients not taking anticoagulants.
Paediatric population
Drug-drug interaction studies have only been performed in adults. The extent
of interactions in the paediatric population is not known. The above mentioned
interactions for adults and the warnings in section 4.4 should be taken into
account for the paediatric population.
Table 1: Effect of co-administered medicinal products on the pharmacokinetics
of atorvastatin
Co-administered medicinal Atorvastatin
product and dosing regimen Dose (mg)
Clinical Recommendation#
Tipranavir 500 mg BID/
Ritonavir 200 mg BID, 8
days (days 14 to 21)
Telaprevir 750 mg q8h, 10
In cases where
coadministration with
atorvastatin is necessary, do
not exceed 10 mg
Change in
AUC&
40 mg on day 1, 10 mg ↑ 9.4 fold
on day 20
↑ 7.9 fold
20 mg, SD
- 140 -
days
Ciclosporin 5.2 mg/kg/day, 10 mg OD for 28 days
stable dose
Lopinavir 400 mg BID/
20 mg OD for 4 days
Ritonavir 100 mg BID, 14
days
Clarithromycin 500 mg BID, 80 mg OD for 8 days
9 days
↑ 8.7 fold
↑ 5.9 fold
↑ 4.4 fold
atorvastatin daily. Clinical
monitoring of these patients
is recommended
In cases where coadministration with
atorvastatin is necessary,
lower maintenance doses of
atorvastatin are
recommended. At
atorvastatin doses exceeding
20 mg, clinical monitoring
of these patients is
recommended.
In cases where coadministration with
atorvastatin is necessary,
lower maintenance doses of
atorvastatin are
recommended. At
atorvastatin doses exceeding
40 mg, clinical monitoring
of these patients is
recommended.
Saquinavir 400 mg BID/
Ritonavir (300 mg BID from
days 5-7, increased to 400
mg BID on day 8), days 418, 30 min after atorvastatin
dosing
Darunavir 300 mg BID/
Ritonavir 100 mg BID, 9
days
Itraconazole 200 mg OD, 4
days
Fosamprenavir 700 mg BID/
Ritonavir 100 mg BID, 14
days
Fosamprenavir 1400 mg
BID, 14 days
Nelfinavir 1250 mg BID, 14
days
Grapefruit Juice, 240 mL
OD *
40 mg OD for 4 days
↑ 3.9 fold
10 mg OD for 4 days
↑ 3.3 fold
40 mg SD
↑ 3.3 fold
10 mg OD for 4 days
↑ 2.5 fold
10 mg OD for 4 days
↑ 2.3 fold
10 mg OD for 28 days
↑ 1.7 fold^
No specific recommendation
40 mg, SD
↑ 37%
Diltiazem 240 mg OD, 28
days
40 mg, SD
↑ 51%
Concomitant intake of large
quantities of grapefruit juice
and atorvastatin is not
recommended.
After initiation or following
dose adjustments of
diltiazem, appropriate
clinical monitoring of these
patients is recommended.
Lower maximum dose and
clinical monitoring of these
patients is recommended.
↑ 33%^
Erythromycin 500 mg QID, 10 mg, SD
7 days
- 141 -
Amlodipine 10 mg, single
dose
Cimetidine 300 mg QID, 2
weeks
Antacid suspension of
magnesium and aluminium
hydroxides, 30 mL QID, 2
weeks
Efavirenz 600 mg OD, 14
days
Rifampin 600 mg OD, 7
days (co-administered)
Rifampin 600 mg OD, 5
days (doses separated)
↑ 18%
80 mg, SD
10 mg OD for 2 weeks ↓ less than
1%^
10 mg OD for 4 weeks ↓ 35%^
↓ 41%
10 mg for 3 days
No specific
recommendation.
No specific
recommendation.
No specific
recommendation.
No specific
recommendation.
40 mg SD
↑ 30%
If co-administration cannot
be avoided, simultaneous coadministration of
40 mg SD
↓ 80%
atorvastatin with rifampin is
recommended, with clinical
monitoring.
Gemfibrozil 600 mg BID, 7 40mg SD
↑ 35%
Lower starting dose and
days
clinical monitoring of these
patients is recommended.
Fenofibrate 160 mg OD, 7 40mg SD
↑ 3%
Lower starting dose and
days
clinical monitoring of these
patients is recommended.
Boceprevir 800 mg TID, 7 40mg SD
↑ 2.3 fold
Lower starting dose and
days
clinical monitoring of these
patients is recommended.
The dose of atorvastatin
should not exceed a daily
dose of 20 mg during coadministration with
boceprevir.
&
Data given as x-fold change represent a simple ratio between coadministration and atorvastatin alone (i.e., 1-fold = no change). Data given as
% change represent % difference relative to atorvastatin alone (i.e., 0% = no
change).
#
See sections 4.4 and 4.5 for clinical significance.
* Contains one or more components that inhibit CYP3A4 and can increase
plasma concentrations of medicinal products metabolized by CYP3A4. Intake
of one 240 ml glass of grapefruit juice also resulted in a decreased AUC of
20.4% for the active orthohydroxy metabolite. Large quantities of grapefruit
juice (over 1.2 l daily for 5 days) increased AUC of atorvastatin 2.5 fold and
AUC of active (atorvastatin and metabolites) HMG-CoA reductase inhibitors
1.3 fold.
^ Total atorvastatin equivalent activity
Increase is indicated as “↑”, decrease as “↓”
- 142 -
OD = once daily; SD = single dose; BID = twice daily; TID = three times daily;
QID = four times daily
Table 2: Effect of atorvastatin on the pharmacokinetics of co-administered
medicinal products
Atorvastatin and dosing Co-administered medicinal product
regimen
Medicinal product/Dose
Change in
(mg)
AUC&
80 mg OD for 10 days Digoxin 0.25 mg OD, 20
↑ 15%
days
40 mg OD for 22 days
Clinical Recommendation
Patients taking digoxin
should be monitored
appropriately.
No specific
recommendation.
Oral contraceptive OD, 2
months
↑ 28%
- norethindrone 1 mg
↑ 19%
-ethinyl estradiol 35 µg
80 mg OD for 15 days * Phenazone, 600 mg SD
↑ 3%
No specific recommendation
10 mg, SD
Tipranavir 500 mg
No change
No specific recommendation
BID/ritonavir 200 mg BID, 7
days
10 mg, OD for 4 days Fosamprenavir 1400 mg
↓ 27%
No specific recommendation
BID, 14 days
10 mg OD for 4 days
Fosamprenavir 700 mg
No change
No specific recommendation
BID/ritonavir 100 mg BID,
14 days
&
Data given as % change represent % difference relative to atorvastatin alone
(i.e., 0% = no change)
* Co-administration of multiple doses of atorvastatin and phenazone showed
little or no detectable effect in the clearance of phenazone.
Increase is indicated as “↑”, decrease as “↓”
OD = once daily; SD = single dose
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of child-bearing potential should use appropriate contraceptive
measures during treatment (see section 4.3).
Pregnancy
Atorvastatin is contraindicated during pregnancy (see section 4.3). Safety in
pregnant women has not been established. No controlled clinical trials with
atorvastatin have been conducted in pregnant women. Rare reports of
congenital anomalies following intrauterine exposure to HMG-CoA reductase
- 143 -
inhibitors have been received. Animal studies have shown toxicity to
reproduction (see section 5.3).
Maternal treatment with atorvastatin may reduce the fetal levels of mevalonate
which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic
process, and ordinarily discontinuation of lipid-lowering medicinal products
during pregnancy should have little impact on the long-term risk associated
with primary hypercholesterolaemia.
For these reasons, Atorvastatin should not be used in women who are pregnant,
trying to become pregnant or suspect they are pregnant. Treatment with
Atorvastatin should be suspended for the duration of pregnancy or until it has
been determined that the woman is not pregnant (see section 4.3.)
Breast-feeding
It is not known whether atorvastatin or its metabolites are excreted in human
milk. In rats, plasma concentrations of atorvastatin and its active metabolites
are similar to those in milk (see section 5.3). Because of the potential for
serious adverse reactions, women taking Atorvastatin should not breast-feed
their infants (see section 4.3). Atorvastatin is contraindicated during
breastfeeding (see section 4.3).
Fertility
In animal studies atorvastatin had no effect on male or female fertility (see
section 5.3).
4.7 Effects on ability to drive and use machines
Atorvastatin has negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
In the atorvastatin placebo-controlled clinical trial database of 16,066 (8755
Lipitor vs. 7311 placebo) patients treated for a mean period of 53 weeks, 5.2%
of patients on atorvastatin discontinued due to adverse reactions compared to
4.0% of the patients on placebo.
Based on data from clinical studies and extensive post-marketing experience,
the following table presents the adverse reaction profile for Atorvastatin.
Estimated frequencies of reactions are ranked according to the following
convention: common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare
(≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be
estimated from the available data).
Infections and infestations
Common: nasopharyngitis.
- 144 -
Blood and lymphatic system disorders
Rare: thrombocytopenia.
Immune system disorders
Common: allergic reactions.
Very rare: anaphylaxis.
Metabolism and nutrition disorders
Common: hyperglycaemia.
Uncommon: hypoglycaemia, weight gain, anorexia
Psychiatric disorders
Uncommon: nightmare, insomnia.
Nervous system disorders
Common: headache.
Uncommon: dizziness, paraesthesia, hypoesthesia, dysgeusia, amnesia.
Rare: peripheral neuropathy.
Eye disorders
Uncommon: vision blurred.
Rare: visual disturbance.
Ear and labyrinth disorders
Uncommon: tinnitus
Very rare: hearing loss.
Respiratory, thoracic and mediastinal disorders
Common: pharyngolaryngeal pain, epistaxis.
Gastrointestinal disorders
Common: constipation, flatulence, dyspepsia, nausea, diarrhoea.
Uncommon: vomiting, abdominal pain upper and lower, eructation,
pancreatitis.
Hepatobiliary disorders
Uncommon: hepatitis.
Rare: cholestasis.
Very rare: hepatic failure.
Skin and subcutaneous tissue disorders
Uncommon: urticaria, skin rash, pruritus, alopecia.
Rare: angioneurotic oedema, dermatitis bullous including erythema
multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders
- 145 -
Common: myalgia, arthralgia, pain in extremity, muscle spasms, joint swelling,
back pain.
Uncommon: neck pain, muscle fatigue.
Rare: myopathy, myositis, rhabdomyolysis, tendonopathy, sometimes
complicated by rupture.
Not known: immune-mediated necrotizing myopathy (see section 4.4).
Reproductive system and breast disorders
Very rare: gynecomastia.
General disorders and administration site conditions
Uncommon: malaise, asthenia, chest pain, peripheral oedema, fatigue, pyrexia.
Investigations
Common: liver function test abnormal, blood creatine kinase increased.
Uncommon: white blood cells urine positive.
As with other HMG-CoA reductase inhibitors elevated serum transaminases
have been reported in patients receiving Atorvastatin. These changes were
usually mild, transient, and did not require interruption of treatment. Clinically
important (> 3 times upper normal limit) elevations in serum transaminases
occurred in 0.8% patients on Atorvastatin. These elevations were dose related
and were reversible in all patients.
Elevated serum creatine kinase (CK) levels greater than 3 times upper limit of
normal occurred in 2.5% of patients on Atorvastatin, similar to other HMGCoA reductase inhibitors in clinical trials. Levels above 10 times the normal
upper range occurred in 0.4% Atorvastatin treated patients (see section 4.4).
Paediatric Population
The clinical safety database includes safety data for 249 paediatric patients who
received atorvastatin, among which 7 patients were < 6 years old, 14 patients
were in the age range of 6 to 9, and 228 patients were in the age range of 10 to
17.
Nervous system disorders
Common: Headache
Gastrointestinal disorders
Common: Abdominal pain
Investigations
Common: Alanine aminotransferase increased, blood creatine phosphokinase
increased
Based on the data available, frequency, type and severity of adverse reactions
in children are expected to be the same as in adults. There is currently limited
experience with respect to long-term safety in the paediatric population.
The following adverse events have been reported with some statins:
• Sexual dysfunction.
• Depression.
- 146 -
• Exceptional cases of interstitial lung disease, especially with long term
therapy (see section 4.4).
• Diabetes Mellitus: Frequency will depend on the presence or absence of risk
factors (fasting blood glucose ≥ 5.6 mmol/L, BMI>30kg/m2, raised
triglycerides, history of hypertension).
4.9 Overdose
Specific treatment is not available for Atorvastatin overdose. Should an
overdose occur, the patient should be treated symptomatically and supportive
measures instituted, as required. Liver function tests should be performed and
serum CK levels should be monitored. Due to extensive atorvastatin binding to
plasma proteins, haemodialysis is not expected to significantly enhance
atorvastatin clearance.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Lipid modifying agents, HMG-CoA-reductase
inhibitors, ATC code: C10AA05
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the
rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including
cholesterol. Triglycerides and cholesterol in the liver are incorporated into very
low-density lipoproteins (VLDL) and released into the plasma for delivery to
peripheral tissues. Low-density lipoprotein (LDL) is formed from VLDL and is
catabolized primarily through the receptor with high affinity to LDL (LDL
receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by
inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in
the liver and increases the number of hepatic LDL receptors on the cell surface
for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles.
Atorvastatin produces a profound and sustained increase in LDL receptor
activity coupled with a beneficial change in the quality of circulating LDL
particles. Atorvastatin is effective in reducing LDL-C in patients with
homozygous familial hypercholesterolaemia, a population that has not usually
responded to lipid-lowering medicinal products.
Atorvastatin has been shown to reduce concentrations of total-C (30% - 46%),
LDL-C (41% - 61%), apolipoprotein B (34% - 50%), and triglycerides (14% 33%) while producing variable increases in HDL-C and apolipoprotein A1 in a
- 147 -
dose response study. These results are consistent in patients with heterozygous
familial hypercholesterolaemia, nonfamilial forms of hypercholesterolaemia,
and mixed hyperlipidaemia, including patients with noninsulin-dependent
diabetes mellitus.
Reductions in total-C, LDL-C, and apolipoprotein B have been proven to
reduce risk for cardiovascular events and cardiovascular mortality.
Homozygous familial hypercholesterolaemia
In a multicenter 8 week open-label compassionate-use study with an optional
extension phase of variable length, 335 patients were enrolled, 89 of which
were identified as homozygous familial hypercholesterolaemia patients. From
these 89 patients, the mean percent reduction in LDL-C was approximately
20%. Atorvastatin was administered at doses up to 80 mg/day.
Atherosclerosis
In the Reversing Atherosclerosis with Aggressive Lipid- Lowering Study
(REVERSAL), the effect of intensive lipid lowering with atorvastatin 80 mg
and standard degree of lipid lowering with pravastatin 40 mg on coronary
atherosclerosis was assessed by intravascular ultrasound (IVUS), during
angiography, in patients with coronary heart disease. In this randomised,
double- blind, multicenter, controlled clinical trial, IVUS was performed at
baseline and at 18 months in 502 patients. In the atorvastatin group (n=253),
there was no progression of atherosclerosis.
The median percent change, from baseline, in total atheroma volume (the
primary study criteria) was -0.4% (p=0.98) in the atorvastatin group and +2.7%
(p=0.001) in the pravastatin group (n=249). When compared to pravastatin the
effects of atorvastatin were statistically significant (p=0.02). The effect of
intensive lipid lowering on cardiovascular endpoints (e. g. need for
revascularisation, non fatal myocardial infarction, coronary death) was not
investigated in this study.
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L ± 0.8
(78.9 mg/dl ± 30) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 28) and in the
pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L ± 0.7 (110
mg/dl ± 26) from baseline 3.89 mmol/L ± 0.7 (150 mg/dl ± 26) (p<0.0001).
Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: 18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009), and
mean apolipoprotein B by 39.1% (pravastatin: -22.0%, p<0.0001). Atorvastatin
increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a
36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2%
reduction in the pravastatin group (p<0.0001).
Study results were obtained with the 80 mg dose strength. Therefore, they
cannot be extrapolated to the lower dose strengths.
The safety and tolerability profiles of the two treatment groups were
comparable.
The effect of intensive lipid lowering on major cardiovascular endpoints was
not investigated in this study. Therefore, the clinical significance of these
- 148 -
imaging results with regard to the primary and secondary prevention of
cardiovascular events is unknown.
Acute coronary syndrome
In the MIRACL study, atorvastatin 80 mg has been evaluated in 3,086 patients
(atorvastatin n=1,538; placebo n=1,548) with an acute coronary syndrome (non
Q-wave MI or unstable angina). Treatment was initiated during the acute phase
after hospital admission and lasted for a period of 16 weeks. Treatment with
atorvastatin 80 mg/day increased the time to occurrence of the combined
primary endpoint, defined as death from any cause, nonfatal MI, resuscitated
cardiac arrest, or angina pectoris with evidence of myocardial ischaemia
requiring hospitalization, indicating a risk reduction by 16% (p=0.048). This
was mainly due to a 26% reduction in re-hospitalisation for angina pectoris
with evidence of myocardial ischaemia (p=0.018). The other secondary
endpoints did not reach statistical significance on their own (overall: Placebo:
22.2%, Atorvastatin: 22.4%).
The safety profile of atorvastatin in the MIRACL study was consistent with
what is described in section 4.8.
Prevention of cardiovascular disease
The effect of atorvastatin on fatal and non-fatal coronary heart disease was
assessed in a randomized, double-blind, placebo-controlled study, the AngloScandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA).
Patients were hypertensive, 40-79 years of age, with no previous myocardial
infarction or treatment for angina, and with TC levels ≤6.5 mmol/L (251
mg/dl). All patients had at least 3 of the pre-defined cardiovascular risk factors:
male gender, age ≥55 years, smoking, diabetes, history of CHD in a firstdegree relative, TC:HDL-C >6, peripheral vascular disease, left ventricular
hypertrophy, prior cerebrovascular event, specific ECG abnormality,
proteinuria/albuminuria. Not all included patients were estimated to have a
high risk for a first cardiovascular event.
Patients were treated with anti-hypertensive therapy (either amlodipine or
atenolol-based regimen) and either atorvastatin 10 mg daily (n=5,168) or
placebo (n=5,137).
The absolute and relative risk reduction effect of atorvastatin was as follows:
Event
Fatal CHD plus non-fatal MI
Total cardiovascular events and
revascularization procedures
Total coronary events
Relative No. of
Absolute Risk
Risk
Events
Reduction1(%)
Reduction (Atorvastatin
(%)
vs Placebo)
pvalue
36%
100 vs. 154 1.1%
0.0005
20%
389 vs. 483 1.9%
0.0008
29%
178 vs 247 1.4%
0.0006
- 149 -
1
Based on difference in crude events rates occurring over a median follow-up
of 3.3 years.
CHD = coronary heart disease; MI = myocardial infarction.
Total mortality and cardiovascular mortality were not significantly reduced
(185 vs. 212 events, p=0.17 and 74 vs. 82 events, p=0.51). In the subgroup
analyses by gender (81% males, 19% females), a beneficial effect of
atorvastatin was seen in males but could not be established in females possibly
due to the low event rate in the female subgroup. Overall and cardiovascular
mortality were numerically higher in the female patients (38 vs. 30 and 17 vs.
12), but this was not statistically significant. There was significant treatment
interaction by antihypertensive baseline therapy. The primary endpoint (fatal
CHD plus non-fatal MI) was significantly reduced by atorvastatin in patients
treated with amlodipine (HR 0.47 (0.32-0.69), p=0.00008), but not in those
treated with atenolol (HR 0.83 (0.59-1.17), p=0.287).
The effect of atorvastatin on fatal and non-fatal cardiovascular disease was also
assessed in a randomized, double-blind, multicenter, placebo-controlled trial,
the Collaborative Atorvastatin Diabetes Study (CARDS) in patients with type 2
diabetes, 40-75 years of age, without prior history of cardiovascular disease,
and with LDL-C ≤4.14 mmol/L (160 mg/dl) and TG ≤6.78 mmol/L (600
mg/dl). All patients had at least 1 of the following risk factors: hypertension,
current smoking, retinopathy, microalbuminuria or macroalbuminuria.
Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo
(n=1,410) for a median follow-up of 3.9 years.
The absolute and relative risk reduction effect of atorvastatin was as follows:
Relative No. of
Absolute Risk
Risk
Events
Reduction1(%)
Reduction (Atorvastatin
(%)
vs Placebo)
p-value
37%
83 vs. 127 3.2%
0.0010
Event
Major cardiovascular events
(fatal and non-fatal AMI, silent
MI, acute CHD death, unstable
angina, CABG, PTCA,
42%
38 vs 64
1.9%
0.0070
revascularization, stroke)
48%
21 vs. 39
1.3%
0.0163
MI (fatal and non-fatal AMI,
silent MI)
Strokes (Fatal and non-fatal)
1
Based on difference in crude events rates occurring over a median follow-up
of 3.9 years.
AMI = acute myocardial infarction; CABG = coronary artery bypass graft;
CHD = coronary heart disease; MI = myocardial infarction; PTCA =
percutaneous transluminal coronary angioplasty.
There was no evidence of a difference in the treatment effect by patient's
gender, age, or baseline LDL-C level. A favourable trend was observed
regarding the mortality rate (82 deaths in the placebo group vs. 61 deaths in the
atorvastatin group, p=0.0592).
- 150 -
Recurrent stroke
In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels
(SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke
was evaluated in 4731 patients who had a stroke or transient ischemic attack
(TIA) within the preceding 6 months and no history of coronary heart disease
(CHD). Patients were 60% male, 21-92 years of age (average age 63 years),
and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDLC was 73 mg/dL (1.9 mmol/L) during treatment with atorvastatin and 129
mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9
years.
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or nonfatal stroke by 15% (HR 0.85; 95% CI, 0.72-1.00; p=0.05 or 0.84; 95% CI,
0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo.
All cause mortality was 9.1% (216/2365) for atorvastatin versus 8.9%
(211/2366) for placebo.
In a post-hoc analysis, atorvastatin 80 mg reduced the incidence of ischemic
stroke (218/2365, 9.2% vs. 274/2366, 11.6%, p=0.01) and increased the
incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%, p=0.02)
compared to placebo.
• The risk of hemorrhagic stroke was increased in patients who entered the
study with prior hemorrhagic stroke (7/45 for atorvastatin versus 2/48 for
placebo; HR 4.06; 95% CI, 0.84-19.57), and the risk of ischemic stroke was
similar between groups (3/45 for atorvastatin versus 2/48 for placebo; HR 1.64;
95% CI, 0.27-9.82).
• The risk of hemorrhagic stroke was increased in patients who entered the
study with prior lacunar infarct (20/708 for atorvastatin versus 4/701 for
placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was
also decreased in these patients (79/708 for atorvastatin versus 102/701 for
placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke
is increased in patients with prior lacunar infarct who receive atorvastatin 80
mg/day.
All cause mortality was 15.6% (7/45) for atorvastatin versus 10.4% (5/48) in
the subgroup of patients with prior hemorrhagic stroke. All cause mortality was
10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the
subgroup of patients with prior lacunar infarct.
Paediatric Population
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 617 years old
An 8-week, open-label study to evaluate pharmacokinetics,
pharmacodynamics, and safety and tolerability of atorvastatin was conducted in
children and adolescents with genetically confirmed heterozygous familial
hypercholesterolemia and baseline LDL-C ≥4 mmol/L. A total of 39 children
and adolescents, 6 to 17 years of age, were enrolled. Cohort A included 15
children, 6 to 12 years of age and at Tanner Stage 1. Cohort B included 24
children, 10 to 17 years of age and at Tanner Stage ≥2.
- 151 -
The initial dose of atorvastatin was 5 mg daily of a chewable tablet in Cohort A
and 10 mg daily of a tablet formulation in Cohort B. The atorvastatin dose was
permitted to be doubled if a subject had not attained target LDL-C of <3.35
mmol/L at Week 4 and if atorvastatin was well tolerated.
Mean values for LDL-C, TC, VLDL-C, and Apo B decreased by Week 2
among all subjects. For subjects whose dose was doubled, additional decreases
were observed as early as 2 weeks, at the first assessment, after dose escalation.
The mean percent decreases in lipid parameters were similar for both cohorts,
regardless of whether subjects remained at their initial dose or doubled their
initial dose. At Week 8, on average, the percent change from baseline in LDLC and TC was approximately 40% and 30%, respectively, over the range of
exposures.
Heterozygous Familial Hypercholesterolaemia in Paediatric Patients aged 1017 years old
In a double-blind, placebo controlled study followed by an open-label phase,
187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years)
with heterozygous familial hypercholesterolaemia (FH) or severe
hypercholesterolaemia were randomised to atorvastatin (n=140) or placebo
(n=47) for 26 weeks and then all received atorvastatin for 26 weeks. The
dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was >3.36 mmol/L. Atorvastatin
significantly decreased plasma levels of total-C, LDL-C, triglycerides, and
apolipoprotein B during the 26 week double-blind phase. The mean achieved
LDL-C value was 3.38 mmol/L (range: 1.81-6.26 mmol/L) in the atorvastatin
group compared to 5.91 mmol/L (range: 3.93-9.96 mmol/L) in the placebo
group during the 26-week double-blind phase.
An additional paediatric study of atorvastatin versus colestipol in patients with
hypercholesterolaemia aged 10-18 years demonstrated that atorvastatin (N=25)
caused a significant reduction in LDL-C at week 26 (p<0.05) compared with
colestipol (N=31).
A compassionate use study in patients with severe hypercholesterolaemia
(including homozygous hypercholesterolaemia) included 46 paediatric patients
treated with atorvastatin titrated according to response (some subjects received
80 mg atorvastatin per day). The study lasted 3 years: LDL-cholesterol was
lowered by 36%.
The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity
and mortality in adulthood has not been established.
The European Medicines Agency has waived the obligation to submit the
results of studies with atorvastatin in children aged 0 to less than 6 years in the
treatment of heterozygous hypercholesterolaemia and in children aged 0 to less
than 18 years in the treatment of homozygous familial hypercholesterolaemia,
combined (mixed) hypercholesterolaemia, primary hypercholesterolaemia and
in the prevention of cardiovascular events (see section 4.2 for information on
paediatric use).
- 152 -
5.2 Pharmacokinetic properties
Absorption
Atorvastatin is rapidly absorbed after oral administration; maximum plasma
concentrations (Cmax) occur within 1 to 2 hours. Extent of absorption increases
in proportion to atorvastatin dose. After oral administration, atorvastatin filmcoated tablets are 95% to 99% bioavailable compared to the oral solution. The
absolute bioavailability of atorvastatin is approximately 12% and the systemic
availability of HMG-CoA reductase inhibitory activity is approximately 30%.
The low systemic availability is attributed to presystemic clearance in
gastrointestinal mucosa and/or hepatic first-pass metabolism
Distribution
Mean volume of distribution of atorvastatin is approximately 381 l.
Atorvastatin is ≥ 98% bound to plasma proteins.
Biotransformation
Atorvastatin is metabolized by cytochrome P450 3A4 to ortho- and
parahydroxylated derivatives and various beta-oxidation products. Apart from
other pathways these products are further metabolized via glucuronidation. In
vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated
metabolites is equivalent to that of atorvastatin. Approximately 70% of
circulating inhibitory activity for HMG-CoA reductase is attributed to active
metabolites.
Elimination
Atorvastatin is eliminated primarily in bile following hepatic and/or
extrahepatic metabolism. However, atorvastatin does not appear to undergo
significant enterohepatic recirculation. Mean plasma elimination half-life of
atorvastatin in humans is approximately 14 hours. The half-life of inhibitory
activity for HMG-CoA reductase is approximately 20 to 30 hours due to the
contribution of active metabolites.
Special populations
Elderly patients
Plasma concentrations of atorvastatin and its active metabolites are higher in
healthy elderly subjects than in young adults while the lipid effects were
comparable to those seen in younger patient populations.
Paediatric population
In an open-label, 8-week study, Tanner Stage 1 (N=15) and Tanner Stage ≥2
(N=24) paediatric patients (ages 6-17 years) with heterozygous familial
hypercholesterolemia and baseline LDL-C ≥4 mmol/L were treated with 5 or
10 mg of chewable or 10 or 20 mg of film-coated atorvastatin tablets once
daily, respectively. Body weight was the only significant covariate in
atorvastatin population PK model. Apparent oral clearance of atorvastatin in
- 153 -
paediatric subjects appeared similar to adults when scaled allometrically by
body weight. Consistent decreases in LDL-C and TC were observed over the
range of atorvastatin and o-hydroxyatorvastatin exposures.
Gender
Concentrations of atorvastatin and its active metabolites in women differ from
those in men (Women: approx. 20% higher for Cmax and approx. 10% lower for
AUC). These differences were of no clinical significance, resulting in no
clinically significant differences in lipid effects among men and women.
Renal impairment
Renal disease has no influence on the plasma concentrations or lipid effects of
atorvastatin and its active metabolites.
Hepatic impairment
Plasma concentrations of atorvastatin and its active metabolites are markedly
increased (approx. 16-fold in Cmax and approx. 11-fold in AUC) in patients with
chronic alcoholic liver disease (Child-Pugh B).
SLOC1B1 polymorphism
Hepatic uptake of all HMG-CoA reductase inhibitors including atorvastatin,
involves the OATP1B1 transporter. In patients with SLCO1B1 polymorphism
there is a risk of increased exposure of atorvastatin, which may lead to an
increased risk of rhabdomyolysis (see section 4.4). Polymorphism in the gene
encoding OATP1B1 (SLCO1B1 c.521CC) is associated with a 2.4-fold higher
atorvastatin exposure (AUC) than in individuals without this genotype variant
(c.521TT). A genetically impaired hepatic uptake of atorvastatin is also
possible in these patients. Possible consequences for the efficacy are unknown.
5.3 Preclinical safety data
Atorvastatin was negative for mutagenic and clastogenic potential in a battery
of 4 in vitro tests and 1 in vivo assay. Atorvastatin was not found to be
carcinogenic in rats, but high doses in mice (resulting in 6-11 fold the AUC024h reached in humans at the highest recommended dose) showed
hepatocellular adenomas in males and hepatocellular carcinomas in females.
There is evidence from animal experimental studies that HMG-CoA reductase
inhibitors may affect the development of embryos or fetuses. In rats, rabbits
and dogs atorvastatin had no effect on fertility and was not teratogenic,
however, at maternally toxic doses fetal toxicity was observed in rats and
rabbits. The development of the rat offspring was delayed and post-natal
survival reduced during exposure of the dams to high doses of atorvastatin. In
rats, there is evidence of placental transfer. In rats, plasma concentrations of
atorvastatin are similar to those in milk. It is not known whether atorvastatin or
its metabolites are excreted in human milk.
6. Pharmaceutical particulars
- 154 -
6.1 List of excipients
Maize Starch
Microcrystalline cellulose
Purified Talc
Sodium Starch Glycollate
Colloidal Anhydrous Silica
Titanium Dioxide
Hydoxypropyl methylcellulose
Povidone
Methylene Chloride
Isopropyl alcohol
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years (24 months)
6.4 Special precautions for storage
Do not store above 30°C.
Keep in the original container.
6.5 Nature and contents of container
Alu-Alu of 10 tablets and 10 x 10 carton pack
6.6 Special precautions for disposal and other handling
None
7. Marketing authorisation holder
- 155 -
Niramaya Pharmaceuticals (P) Ltd.
Village Juddi Khurd Barotiwala Road,
Baddi, Distt. Solan, Himachal Pradesh, INDIA
8. Marketing authorisation number(s)
--------------------9. Date of first authorisation/renewal of the authorisation
---------------------10. Date of revision of the text
November 2020
- 156 -
PUBLISHED REPORTS ON CLINICAL TRIALS
Clinical studies
Prevention of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of
atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed
in 10,305 hypertensive patients 40-80 years of age (mean of 63 years), without
a previous myocardial infarction and with TC levels ≤251 mg/dl (6.5 mmol/l).
Additionally all patients had at least 3 of the following cardiovascular risk
factors: male gender (81.1%), age >55 years (84.5%), smoking (33.2%),
diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6
(14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy
(14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality
(14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebocontrolled study patients were treated with anti-hypertensive therapy (Goal BP
<140/90 mm Hg for non-diabetic patients, <130/80 mm Hg for diabetic
patients) and allocated to either atorvastatin 10 mg daily (n=5168) or placebo
(n=5137), using a covariate adaptive method which took into account the
distribution of nine baseline characteristics of patients already enrolled and
minimized the imbalance of those characteristics across the groups. Patients
were followed for a median duration of 3.3 years.
The effect of 10 mg/day of Atorvastatin on lipid levels was similar to that seen
in previous clinical trials.
Atorvastatin significantly reduced the rate of coronary events [either fatal
coronary heart disease (46 events in the placebo group vs. 40 events in the
Atorvastatin group) or nonfatal MI (108 events in the placebo group vs. 60
events in the atorvastatin group)] with a relative risk reduction of 36% [(based
on incidences of 1.9% for atorvastatin vs. 3.0% for placebo), p=0.0005 (see
Figure 1)]. The risk reduction was consistent regardless of age, smoking status,
obesity or presence of renal dysfunction. The effect of atorvastatin was seen
regardless of baseline LDL levels. Due to the small number of events, results
for women were inconclusive.
Figure 1: Effect of Atorvastatin 10 mg/day on Cumulative Incidence of
Nonfatal
Myocardial Infarction or Coronary Heart Disease Death (in ASCOT-LLA)
- 157 -
Atorvastatin also significantly decreased the relative risk for revascularization
procedures by 42%. Although the reduction of fatal and non-fatal strokes did
not reach a pre-defined significance level (p=0.01), a favorable trend was
observed with a 26% relative risk reduction (incidences of 1.7% for
atorvastatin and 2.3% for placebo). There was no significant difference
between the treatment groups for death due to cardiovascular causes (p=0.51)
or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of
Atorvastatin on cardiovascular disease (CVD) endpoints was assessed in 2838
subjects (94% White, 68% male), ages 40-75 with type 2 diabetes based on
WHO criteria, without prior history of cardiovascular disease and with LDL
≤160 mg/dL and TG ≤600 mg/dL. In addition to diabetes, subjects had 1 or
more of the following risk factors: current smoking (23%), hypertension (80%),
retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No
subjects on hemodialysis were enrolled in the study. In this multicenter,
placebo-controlled, double-blind clinical trial, subjects were randomly
allocated to either atorvastatin 10 mg daily (1429) or placebo (1411) in a 1:1
ratio and were followed for a median duration of 3.9 years. The primary
endpoint was the occurrence of any of the major cardiovascular events:
myocardial infarction, acute CHD death, unstable angina, coronary
revascularization, or stroke. The primary analysis was the time to first
occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA1c
7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG 151
mg/dL; median HDL-C 52mg/dL.
The effect of atorvastatin 10 mg/ day on lipid levels was similar to that seen in
previous clinical trials.
Atorvastatin significantly reduced the rate of major cardiovascular events
(primary endpoint events) (83 events in the atorvastatin group vs. 127 events in
the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI
(0.48,0.83) (p=0.001) (see Figure 2). An effect of atorvastatin was seen
regardless of age, sex, or baseline lipid levels.
- 158 -
Figure 2. Effect of atorvastatin 10 mg/day on Time to Occurrence of
Major Cardiovascular Event (myocardial infarction, acute CHD death,
unstable angina, coronary revascularization, or stroke) in CARDS.
Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the
atorvastatin group vs 39 events in the placebo group), HR 0.52, 95% CI
(0.31,0.89) (p=0.016) and reduced the risk of MI by 42% (38 events in the
atorvastatin group vs 64 events in the placebo group), HR 0.58, 95.1% CI
(0.39, 0.86) (p=0.007). There was no significant difference between the
treatment groups for angina, revascularization procedures, and acute CHD
death.
There were 61 deaths in the atorvastatin group vs 82 deaths in the placebo
group, (HR 0.73, p=0.059).
In the Treating to New Targets Study (TNT), the effect of atorvastatin 80
mg/day vs. atorvastatin 10 mg/day on the reduction in cardiovascular events
was assessed in 10,001 subjects (94% white, 81% male, 38% ≥65 years) with
clinically evident coronary heart disease who had achieved a target LDL-C
level <130 mg/dL after completing an 8-week, open-label, run-in period with
atorvastatin 10 mg/day. Subjects were randomly assigned to either 10 mg/day
or 80 mg/day of atorvastatin and followed for a median duration of 4.9 years.
The primary endpoint was the time-to-first occurrence of any of the following
major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial
infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean
LDL-C, TC, TG, non-HDL and HDL cholesterol levels at 12 weeks were 73,
145, 128, 98 and 47 mg/dL during treatment with 80 mg of atorvastatin and 99,
177, 152, 129 and 48 mg/dL during treatment with 10 mg of atorvastatin.
- 159 -
Treatment with atorvastatin 80 mg/day significantly reduced the rate of MCVE
(434 events in the 80mg/day group vs 548 events in the 10 mg/day group) with
a relative risk reduction of 22%, HR 0.78, 95% CI (0.69,0.89), p=0.0002 (see
Figure 3 and Table 1). The overall risk reduction was consistent regardless of
age (<65, ≥65) or gender.
Figure 3. Effect of atorvastatin 80 mg/day vs.10 mg/day on Time to
Occurrence of Major Cardiovascular Events (TNT)
TABLE 1. Overview of Efficacy Results in TNT
Endpoint
Atorvastatin Atorvastatin
HRa
10mg
80mg
(95%CI)
(N=5006)
(N=4995)
PRIMARY
n
(%)
n
(%)
ENDPOINT
First major
cardiovascular
548 (10.9) 434 (8.7)
endpoint
Components of the Primary Endpoint
CHD death
127 (2.5)
101 (2.0)
Nonfatal, nonprocedure related MI
308 (6.2)
243 (4.9)
Resuscitated cardiac
arrest
26
25
Stroke (fatal and non-
155 (3.1)
(0.5)
- 160 -
(0.5)
117 (2.3)
0.78
(0.69,
0.89)
0.80
(0.61,
1.03)
0.78
(0.66,
0.93)
0.96
(0.56,
1.67)
0.75
fatal)
(0.59,
0.96)
SECONDARY ENDPOINTS*
First CHF with
hospitalization
164 (3.3)
122 (2.4)
First PVD endpoint
282 (5.6)
275 (5.5)
First CABG or other
coronary
revascularization
procedureb
904 (18.1)
667 (13.4)
First documented
angina endpointb
615 (12.3)
545 (10.9)
All cause mortality
282 (5.6)
284 (5.7)
0.74
(0.59,
0.94)
0.97
(0.83,
1.15)
0.72
(0.65,
0.80)
0.88
(0.79,
0.99)
1.01
(0.85,
1.19)
Components of all cause mortality
Cardiovascular death
155 (3.1)
126 (2.5)
Noncardiovascular
death
127 (2.5)
158 (3.2)
Cancer death
75
(1.5)
85
(1.7)
Other non-CV death
43
(0.9)
58
(1.2)
0.81
(0.64,
1.03)
1.25
(0.99,
1.57)
1.13
(0.83,
1.55)
1.35
(0.91,
2.00)
1.67
(0.73,
3.82)
Suicide, homicide and
other traumatic non9
(0.2)
15 (0.3)
CV death
a Atorvastatin 80 mg: atorvastatin 10 mg
b component of other secondary endpoints
* secondary endpoints not included in primary endpoint
HR=hazard ratio; CHD=coronary heart disease; CI=confidence
interval; MI=myocardial infarction; CHF=congestive heart
failure;
CV=cardiovascular; PVD=peripheral vascular disease;
CABG=coronary artery bypass graft Confidence intervals for
the Secondary Endpoints were not adjusted for multiple
comparisons
- 161 -
Of the events that comprised the primary efficacy endpoint, treatment with
atorvastatin 80 mg/day significantly reduced the rate of nonfatal, nonprocedure related MI and fatal and non-fatal stroke, but not CHD death or
resuscitated cardiac arrest (Table 1). Of the predefined secondary endpoints,
treatment with atorvastatin 80 mg/day significantly reduced the rate of
coronary revascularization, angina and hospitalization for heart failure, but not
peripheral vascular disease. The reduction in the rate of CHF with
hospitalization was only observed in the 8% of patients with a prior history of
CHF.
There was no significant difference between the treatment groups for all-cause
mortality (Table 1). The proportions of subjects who experienced
cardiovascular death, including the components of CHD death and fatal stroke
were numerically smaller in the atorvastatin 80 mg group than in the
atorvastatin 10 mg treatment group. The proportions of subjects who
experienced noncardiovascular death were numerically larger in the
atorvastatin 80 mg group than in the atorvastatin 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering
Study (IDEAL), treatment with atorvastatin 80 mg/day was compared to
treatment with simvastatin 20-40 mg/day in 8,888 subjects up to 80 years of
age with a history of CHD to assess whether reduction in CV risk could be
achieved. Patients were mainly male (81%), white (99%) with an average age
of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76%
were on statin therapy. In this prospective, randomized, open-label, blinded
endpoint (PROBE) trial with no run-in period, subjects were followed for a
median duration of 4.8 years. The mean LDL-C, TC, TG, HDL and non-HDL
cholesterol levels at Week 12 were 78, 145, 115, 45 and 100 mg/dL during
treatment with 80 mg of atorvastatin and 105, 179, 142, 47 and 132 mg/dL
during treatment with 20-40 mg of simvastatin.
There was no significant difference between the treatment groups for the
primary endpoint, the rate of first major coronary event (fatal CHD, nonfatal
MI and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin 80 mg/day
group vs. 463 (10.4%) in the simvastatin 20-40 mg/day group, HR 0.89, 95%
CI ( 0.78,1.01), p=0.07.
There were no significant differences between the treatment groups for allcause mortality: 366 (8.2%) in the atorvastatin 80 mg/day group vs. 374 (8.4%)
in the simvastatin 20-40 mg/day group. The proportions of subjects who
experienced CV or non-CV death were similar for the atorvastatin 80 mg group
and the simvastatin 20-40 mg group.
Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed
Dyslipidemia (Fredrickson Types IIa and IIb)
- 162 -
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases
HDL-C in patients with hypercholesterolemia and mixed dyslipidemia.
Therapeutic response is seen within 2 weeks, and maximum response is usually
achieved within 4 weeks and maintained during chronic therapy.
Atorvastatin is effective in a wide variety of patient populations with
hypercholesterolemia, with and without hypertriglyceridemia, in men and
women, and in the elderly. Experience in pediatric patients has been limited to
patients with homozygous FH. In two multicenter, placebo-controlled, doseresponse studies in patients with hypercholesterolemia, atorvastatin given as a
single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG
(Pooled results are provided in Table 1).
TABLE 2. Dose-Response in Patients With Primary Hypercholesterolemia
(Adjusted Mean % Change From Baseline)a
LDL- Apo
HDL- Non-HDLTG
C
B
C
C/HDL-C
Placebo 21
4
4
3
10
-3
7
10
22
-29 -39 -32 -19 6
-34
20
20
-33 -43 -35 -26 9
-41
40
21
-37 -50 -42 -29 6
-45
80
23
-45 -60 -50 -37 5
-53
a Results are pooled from 2 dose-response studies.
Dose
N
TC
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled
from 24 controlled trials, the median (25th and 75th percentile) percent changes
from baseline in HDL-C for atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4,
14), 8.7(0, 17), 7.8(0, 16), and 5.1 (-2.7, 15), respectively. Additionally,
analysis of the pooled data demonstrated consistent and significant decreases in
total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients with
hypercholesterolemia, atorvastatin was compared to other HMG-CoA reductase
inhibitors. After randomization, patients were treated for 16 weeks with either
atorvastatin 10 mg per day or a fixed dose of the comparative agent (Table 3).
TABLE 3. Mean Percent Change From Baseline at Endpoint
(Double-Blind, Randomized, Active-Controlled Trials)
Treatment
(Daily Dose)
N
Total-C LDL-C Apo B TG
HDLC
Non-HDLC/HDL-C
+7
-37a
Study 1
Atorvastatin 10 707 -27a
-36a
-28a
- 163 -
-17a
mg
Lovastatin 20
mg
191 -19
95% CI for
Diff1
-9.2, 6.5
-27
-20
-6
+7
-28
-10.7, - -10.0, - -15.2, - -1.7,
7.1
6.5
7.1
2.0
-11.1, -7.1
Atorvastatin 10
222 -25b
mg
-35b
-27b
-17b
+6
-36b
Pravastatin 20
mg
-23
-17
-9
+8
-28
Study 2
77
95% CI for
Diff1
-17
-10.8, - -14.5, - -13.4, - -14.1, - -4.9,
6.1
8.2
7.4
0.7
1.6
-11.5, -4.1
Study 3
Atorvastatin 10
132 -29c
mg
-37c
-34c
-23c
+7
-39c
Simvastatin 10
45
mg
-24
-30
-30
-15
+7
-33
95% CI for
Diff1
-8.7, 2.7
-10.1, - -8.0, - -15.1, - -4.3,
2.6
1.1
0.7
3.9
-9.6, -1.9
1
A negative value for the 95% CI for the difference between treatments favors
atorvastatin for all except HDL-C, for which a positive value favors
atorvastatin. If the range does not include 0, this indicates a statistically
significant difference.
a
Significantly different from lovastatin, ANCOVA, p≤0.05
b
Significantly different from pravastatin, ANCOVA, p≤0.05
c
Significantly different from simvastatin, ANCOVA, p≤0.05
The impact on clinical outcomes of the differences in lipid-altering effects
between treatments shown in Table 3 is not known. Table 3 does not contain
data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin,
pravastatin, and simvastatin. The drugs compared in the studies summarized in
the table are not necessarily interchangeable.
Hypertriglyceridemia (Fredrickson Type IV)
The response to atorvastatin in 64 patients with isolated hypertriglyceridemia
treated across several clinical trials is shown in the table below. For the
atorvastatin-treated patients, median (min, max) baseline TG level was 565
(267-1502).
- 164 -
TABLE 4. Combined Patients With Isolated Elevated TG:
Median (min, max) Percent Changes From Baseline
Placebo
(N=12)
Atorvastatin 10 Atorvastatin 20 Atorvastatin 80
mg
mg
mg
(N=37)
(N=13)
(N=14)
Triglycerides
-12.4 (-36.6, -41.0 (-76.2,
82.7)
49.4)
-38.7 (-62.7,
29.5)
-51.8 (-82.8,
41.3)
Total-C
-2.3 (-15.5,
24.4)
-28.2 (-44.9, 6.8)
-34.9 (-49.6, 15.2)
-44.4 (-63.5, 3.8)
LDL-C
3.6 (-31.3,
31.6)
-26.5 (-57.7,
9.8)
-30.4 (-53.9,
0.3)
-40.5 (-60.6, 13.8)
HDL-C
3.8 (-18.6,
13.4)
13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2)
VLDL-C
-1.0 (-31.9,
53.2)
-48.8 (-85.8,
57.3)
-44.6 (-62.2, 10.8)
-62.0 (-88.2,
37.6)
non-HDL-C
-2.8 (-17.6,
30.0)
-33.0 (-52.1, 13.3)
-42.7 (-53.7, 17.4)
-51.5 (-72.9, 4.3)
Dysbetalipoproteinemia (Fredrickson Type III)
The results of an open-label crossover study of 16 patients (genotypes: 14 apo
E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson Type III)
are shown in the table below.
TABLE 5. Open-Label Crossover Study of 16 Patients
With Dysbetalipoproteinemia (Fredrickson Type III)
Median % Change (min,
max)
Median (min,
max) at
Baseline
(mg/dL)
Total-C
Triglycerides
Atorvastatin Atorvastatin
10 mg
80 mg
-58 (-90, 31)
-53 (-95, 678 (273, 5990) -39 (-92, -8)
30)
442 (225, 1320) -37 (-85, 17)
IDL-C +
VLDL-C
215 (111, 613)
-32 (-76, 9)
-63 (-90, -8)
non-HDL-C
411 (218, 1272)
-43 (-87, 19)
-64 (-92, 36)
- 165 -
Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29 patients ages 6 to 37 years
with homozygous FH received maximum daily doses of 20 to 80 mg of
atorvastatin. The mean LDL-C reduction in this study was 18%. Twenty-five
patients with a reduction in LDL-C had a mean response of 20% (range of 7%
to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in
LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2
patients also had a portacaval shunt and had no significant reduction in LDL-C.
The remaining 3 receptor-negative patients had a mean LDL-C reduction of
22%.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
In a double-blind, placebo-controlled study followed by an open-label phase,
187 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years)
with heterozygous familial hypercholesterolemia (FH) or severe
hypercholesterolemia were randomized to atorvastatin (n=140) or placebo
(n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion
in the study required 1) a baseline LDL-C level ≤190 mg/dL or 2) a baseline
LDL-C ≤160 mg/dL and positive family history of FH or documented
premature cardiovascular disease in a first- or second-degree relative. The
mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in
the atorvastatin group compared to 230.0 mg/dL (range: 160.0-324.5 mg/dL) in
the placebo group. The dosage of atorvastatin (once daily) was 10 mg for the
first 4 weeks and up-titrated to 20 mg if the LDL-C level was > 130 mg/dL.
The number of atorvastatin-treated patients who required up-titration to 20 mg
after Week 4 during the double-blind phase was 80 (57.1%).
atorvastatin significantly decreased plasma levels of total-C, LDL-C,
triglycerides, and apolipoprotein B during the 26 week double-blind phase (see
Table 6).
TABLE 6
Lipid-altering Effects of atorvastatin in Adolescent Boys and Girls with
Heterozygous Familial Hypercholesterolemia or Severe
Hypercholesterolemia
(Mean Percent Change from Baseline at Endpoint in Intention-to-Treat
Population)
DOSAGE N
Placebo
47
atorvastatin 140
Total- LDL- HDLApolipoprotein
TG
C
C
C
B
-1.5 -0.4 -1.9 1.0 0.7
-31.4 -39.6 2.8
-34.0
12.0
- 166 -
The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL)
in the atorvastatin group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL)
in the placebo group during the 26 week double-blind phase.
The safety and efficacy of doses above 20 mg have not been studied in
controlled trials in children. The long-term efficacy of atorvastatin therapy in
childhood to reduce morbidity and mortality in adulthood has not been
established.
- 167 -
References:
1.
J Atheroscler Thromb. 2004;11(6):341-7.
Atorvastatin and pravastatin elevated pre-heparin lipoprotein lipase mass
of type 2 diabetes with hypercholesterolemia.
Endo K, Miyashita Y, Saiki A, Oyama T, Koide N, Ozaki H, Otsuka M, Ito Y,
Shirai
K.
To clarify whether 3-hydroxy-3-methylglutaryl coenzyme A reductase
inhibitors (statin) increases lipoprotein lipase mass in preheparin plasma
(preheparin LPL mass), we observed the change in preheparin LPL mass
during administration of atorvastatin and pravastatin to type 2 diabetes mellitus
patients with hypercholesterolemia. The subjects were randomly divided into
two groups. One group was 24 patients given atorvastatin (10 mg/day), and the
other was 23 patients given pravastatin (20 mg/day) for 4 months. After 4
months of administration, no significant change of HbA1c was observed. TC
significantly decreased in the atorvastatin group compared to the pravastatin
group. TG significantly decreased in the atorvastatin group. Low density
lipoprotein cholesterol level significantly decreased in both groups (- 36.3%, p
< 0.01 in atorvastatin, - 24.3%, p < 0.01 in pravastatin). Preheparin LPL mass
slightly increased in both groups after 4 months of administration. Especially in
patients who showed low preheparin LPL mass (less than 50 ng/ml) before
statin administration, preheparin LPL mass significantly increased in both
groups (+ 25.8% in the atorvastatin group, + 24.39% in the pravastatin group).
These results suggested that administration of atorvastatin and pravastatin to
type 2 diabetic patients with hypercholesterolemia increased serum preheparin
LPL mass concentration. Especially, its effect was remarkable in patients who
showed low preheparin LPL mass.
2.
Pharmacol Res. 2005 Jan;51(1):31-6.
Effect of atorvastatin on non-cholesterol sterols in patients with type 2
diabetes mellitus and cardiovascular disease.
Smahelova A, Hyspler R, Haas T, Ticha A, Blaha V, Zadak Z.
An increased risk of cardiovascular morbidity and mortality in diabetes
- 168 -
mellitus type 2 has been associated with disturbances of lipid homeostasis.
Recently, decreased intestinal absorption of cholesterol and increased liver
cholesterol production have been reported. To investigate the influence of
cholesterol lowering therapy using statin on cholesterol turnover in diabetes
mellitus type 2, the levels of non-cholesterol based sterols were studied. One
hundred and thirty five patients with type 2 diabetes and non-diabetic controls
with cardiovascular diseases were studied. Both groups were divided into two
subgroups: treated with atorvastatin and without statin therapy. The diabetics
showed significantly higher levels of lathosterol (6.97micromol l(-1) versus
5.11micromol l(-1), p = 0.012) and lower levels of sitosterol (5.03micromol l(1) versus 8.98micromol l(-1), p < 0.001) and campesterol (6.35micromol l(-1)
versus 9.80micromol l(-1), p < 0.001). Non-diabetics showed no significant
differences in non-cholesterol based sterols in relation to atorvastatin therapy.
A significantly lower level of lathosterol as well as a decrease in
lathosterol/cholesterol ratio in the statin treated groups was found in diabetics
(4.11micromol l(-1) versus 7.83micromol l(-1), p < 0.001). The results based
on ANOVA analysis show that the effect of atorvastatin on the lathosterol level
is more pronounced in diabetics. Regression analysis showed the relationship
between increased triglycerides levels and the increase in cholesterol synthesis.
The calculated regression model for loglathosterol in diabetics has the
following form: log(lathosterol) = 2.76 - 0.52.statin + 0.22.cholesterol
(ANOVA, p < 0.001, R(2) = 34%, p = 0.005 for statin, p < 0.001 for
cholesterol). We conclude that in spite the total cholesterol level in diabetics
type 2 is not increased, its endogenous synthesis is enhanced. Our results show
that the diabetics type 2 with increased serum lathosterol and expressed
metabolic syndrome (mild increase of triglycerides) might represent a suitable
group for intensive treatment with statins.
3.
Clin Nephrol. 2004 Oct;62(4):287-94.
Lipid and apoprotein changes during atorvastatin up-titration in
hemodialysis patients with hypercholesterolemia: a placebo-controlled
study.
Lins RL, Matthys KE, Billiouw JM, Dratwa M, Dupont P, Lameire NH,
Peeters PC, Stolear JC, Tielemans C, Maes B, Verpooten GA, Ducobu J,
Carpentier YA.
BACKGROUND: Patients with end-stage renal disease commonly present with
an atherogenic lipid profile characterized by the accumulation of triglyceriderich, apoprotein B-containing "remnant" lipoproteins, small dense low-density
lipoprotein, and low levels of high-density lipoprotein. They are at increased
- 169 -
cardiovascular risk and may benefit from drastic lipid-lowering treatment with
atorvastatin, a potent, broadacting lipid regulator. This study aims to assess the
effects of atorvastatin on the lipid profile in hemodialysis patients, to determine
wether atorvastatin is also effective at lowering lipid levels in this particular
high-risk subgroup. METHODS: In this randomized, placebo-controlled,
double-blind study in hemodialysis patients with hypercholesterolemia (n = 42,
mean total cholesterol 243 +/- 33 mg/dl (6.3 +/- 0.8 mmol/l)), the efficacy of 4weekly increasing doses of atorvastatin (10 - 40 mg daily) was investigated.
Lipids and apoproteins were measured in plasma and isolated lipoprotein
fractions. RESULTS: Mean total cholesterol and low-density lipoprotein
cholesterol progressively decreased with increasing doses of atorvastatin (total
cholesterol -33%, low-density lipoprotein cholesterol -43% after 12 weeks),
while high-density lipoprotein cholesterol remained unchanged. Plasma levels
of apoprotein B and apoprotein E were also significantly reduced by
atorvastatin 10 mg, while up-titration to 20 and 40 mg daily provided
additional benefits by lowering triglycerides and apoprotein C-III. At week 12,
the fraction of small dense low-density lipoprotein was significantly reduced
from 23% - 18%, and apoprotein B-containing intermediate-density
lipoproteins were no longer detectable. CONCLUSION: In conclusion,
atorvastatin not only treated hypercholesterolemia but also favorably affected
the uremic lipid profile in patients on hemodialysis. Atorvastatin 4-weekly dose
escalation up to 40 mg daily was well-tolerated. Further prospective studies are
needed to evaluate the impact of this improved lipid profile on morbidity and
mortality.
4.
Rom J Intern Med. 2002;40(1-4):61-73.
Effects of Atorvastatin on some inflammatory parameters in severe
primary
hypercholesterolemia.
Dobreanu M, Galateanu C, Simionescu A, Deac R.
Recent publications have reanimated the point of view that there exist links
between atherosclerosis--inflammation and hypercholesterolemia. The aim of
our study was to investigate the possible influence of statins on some
inflammatory parameters in persons with severe primary hypercholesterolemia
(PHC). The effects of the HMG CoA reductase inhibitor--Atorvastatin--on
serum lipids, apoproteins, C reactive protein (CRP), soluble Intercellular
Adhesion Molecule (sICAM), lipid peroxides, antibodies to oxidized LDL (Ab
oxLDL) and homocystein were evaluated in 21 persons (52.9 +/- 8.38 years
old) with severe PHC, 12 of these having significant coronary-artery stenosis
(diameter stenosis > or = 70%), in at least one major coronary artery branch.
- 170 -
Ab oxLDL, sICAM, TBARS, CRP and homocystein were significantly
increased (p < 0.05) in patients with coronary-artery stenosis. Following a 4
weeks hypolipemiant free baseline period, all persons were treated with
Atorvastatin 40 mg once daily for 8 weeks. Atorvastatin 40 mg resulted in a
reduction of LDL-C with 57.8% (baseline 259.6 +/- 71.39 mg%) p < 0.001,
total Cholesterol with 44.08% (baseline 343.1 +/- 71.72 mg%) p < 0.001, Apo
B with 50.6% (baseline 194.7 +/- 48.71 mg%) p < 0.001, TG with 12.02%
(baseline 177.4 +/- 83.63 mg%) and HDL-C was increased with 6.84%
(baseline 48.0 +/- 7.86 mg%). In coronary heart disease patients, Atorvastatin
reduced homocystein concentrations with 19.41% (baseline 17.7 +/- 11.16
microM/l) (p < 0.01), and CRP with 21.9% (baseline 4.8 +/- 4.19 mg/l) p <
0.01 and TBARS with 52% (baseline 0.87 +/- 0.89 nM/ml) p < 0.001, but did
not influence sICAM and Ab oxLDL. Thus atherogenic concentrations of
LDL-C have to be closely modulated by minimal changes in LDL oxidative
state. The effects of Atorvastatin on inflammatory parameters may crucially
contribute to the clinical benefit of statins, independent of cholesterol lowering.
Plaque stabilization may be a paradigm for antiinflammatory mechanism of
action by this class of drugs.
5.
J Urol. 2004 Dec;172(6 Pt 1):2456-9.
Atorvastatin ameliorates renal tissue damage in unilateral ureteral
obstruction.
Mizuguchi Y, Miyajima A, Kosaka T, Asano T, Asano T, Hayakawa M.
PURPOSE:: The current study was done to determine whether atorvastatin, the
HMGCoA (3-hydroxy-3-methylglutaryl CoA) reductase inhibitor, could
decrease renal transforming growth factor-beta (TGF-beta) levels in unilateral
ureteral obstruction (UUO) and concomitantly affect renal tissue damage in
UUO. MATERIALS AND METHODS:: Atorvastatin (20 mg/kg) was
administered to rats 1 day prior to UUO and every day thereafter. Kidneys were
harvested at day 14 after UUO. Tissue TGF-beta was measured by bioassay
using mink lung epithelial cells. Renal tubular proliferation and apoptosis were
detected by immunostaining proliferating cell nuclear antigen and polyclonal
antisingle strand DNA antibody, respectively. Fibrosis was assessed by
measuring collagen deposition with trichrome stained slides. Interstitial
leukocyte was detected by immunostaining CD45. RESULTS:: TGF-beta
bioassay showed that the obstructed kidney in the control group contained
significantly higher TGF-beta than the unobstructed kidney in the control group
(mean +/- SD 79.1 +/- 48.5 vs 28.7 +/- 13.7 pg/mg tissue) and atorvastatin
- 171 -
significantly decrease tissue TGF-beta in the obstructed kidney (53.4 +/- 37.0
pg/mg tissue). Immunostaining polyclonal antisingle strand DNA antibody
demonstrated that the obstructed kidney in the control group has significantly
more tubular apoptosis than the unobstructed counterpart (4.8 +/- 2.8 vs 2.1 +/1.2 nuclei per high power field) and atorvastatin significantly decreased renal
tubular apoptosis in the obstructed kidney (1.1 +/- 0.7 nuclei per high power
field). In addition, immunostaining proliferating cell nuclear antigen showed
that the obstructed kidney in the atorvastatin group had significantly more renal
tubular proliferation than the obstructed kidney in the control group (48.7 +/20.8 vs 17.3 +/- 10.6 per high power field). Control obstructed kidney showed
significantly more fibrosis, which was also blunted by atorvastatin.
CONCLUSIONS:: Atorvastatin significantly decreases tissue TGF-beta,
resulting in a decrease in tubular damage and interstitial fibrosis. This suggests
that atorvastatin is a promising agent for preventing renal tubular damage in
UUO.
6.
Acta Trop. 2005 Jan;93(1):1-9.
Antischistosomal action of atorvastatin alone and concurrently with
medroxyprogesterone acetate on Schistosoma haematobium harboured in
hamster: surface ultrastructure and parasitological study.
Soliman MF, Ibrahim MM.
Aiming to study the influence of long-term administration of lipid lowering
agents (atorvastatin; AV), and to study the action of combined treatment with
injectable contraceptive (medroxyprogesterone acetate; MPA) on tegumental
ultrastrucutre and survival of Schistosoma worms, this study was established.
AV (0.9 mg kg-1) was administered orally for 49 successive days to
Schistosoma heamatobium-infected hamster starting from day 35 post-infection
(pi). Another group of infected hamster was administrated MPA
intramuscularly (0.1 ml kg-1) at days 7 and 35 pi followed by AV treatment
regimen. Both treatment regimens significantly affected the surface
ultrastructure of the male worms more pronouncedly than the female ones.
Combined treatment was more severe in action compared to single one. The
combined treatment was characterized by losing of spines and damaging of
tubercles throughout the tegument, severe erosion and peeling and appearance
of deep crakes in different parts of the tegument. Moreover, mild to sever
destruction to the oral suckers of both female and male worms was noticed. On
the other hand, both treatment regimens significantly reduced numbers of
recovered S. haematobium worms and tissue egg load. Oogram pattern was
affected only in case of combined treatment with high percentage of dead eggs.
- 172 -
In conclusion, AV, if given continuously for long time, has a pronounced
antischistosomal action especially when accompanied with contraceptive
intake. These promising results may encourage further investigation with the
intention of their possible application on treatment of schistosomiasis as a
complement strategy to praziquantel chemotherapy.
7.
Clin Ther. 2004 Nov;26(11):1821-33.
Twelve-week, multicenter, randomized, open-label comparison of the
effects of rosuvastatin 10 mg/d and atorvastatin 10 mg/d in high-risk
adults: a DISCOVERY study.
Strandberg TE, Feely J, Sigurdsson EL; DISCOVERY study group.
BACKGROUND: Guidelines for the prevention of coronary heart disease
(CHD) advocate reductions in low-density lipoprotein cholesterol (LDL-C) and
total cholesterol (TC) levels as the primary goals. However, approximately
50% to 60% of patients fail to reach recommended cholesterol goals.
OBJECTIVES: The primary objective of this Direct Statin Comparison of
LDL-C Values: An Evaluation of Rosuvastatin Therapy Compared with
Atorvastatin (DISCOVERY) trial was to compare the efficacy of the 3hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors rosuvastatin
calcium and atorvastatin calcium in achieving the 1998 Second Joint Task
Force (JTF) of European and Other Societies on Coronary Prevention target for
LDL-C. Secondary objectives included comparing the efficacy of rosuvastatin
and atorvastatin in achieving the 1998 JTF-recommended goal for TC and
modifying other lipid levels, and to compare the tolerability of the 2 statins.
METHODS: This 12-week, randomized, open-label, 2-arm, parallel-group trial
was conducted at 210 centers in Finland, Iceland, and Ireland. Patients aged >
or =18 years with a high risk for CHD and primary hypercholesterolemia
(LDL-C >3.5 mmol/L [>135 mg/dL]) were randomized (2:1) to receive
rosuvastatin 10 mg or atorvastatin 10 mg PO OD for 12 weeks. Before
randomization, statin-naive patients underwent 6 weeks of dietary counseling,
whereas patients receiving treatment with a starting dose of another lipidlowering therapy but with an LDL-C level >3.1 mmol/L (>120 mg/dL) were
switched to study drug immediately after they were determined eligible for the
study Patients were assessed for fasting lipid levels at weeks 0 and 12, and the
proportions of patients attaining 1998 and 2003 JTF lipid goals (1998: LDL-C,
<3.0 mmol/L [<116 mg/dL]; TC, <5.0 mmol/L [<193 mg/dL]; 2003: LDL-C,
<2.5 mmol/L [<97 mg/dL]; TC, <4.5 mmol/L [<174 mg/dL]) were calculated.
Tolerability was monitored for the 12-week study and for an additional 36week optional extension period. RESULTS: One thousand twenty-four patients
were randomized to treatment (568 men, 456 women; mean age, 60.7 years).
Patient demographic characteristics were similar between the 2 treatment
- 173 -
groups. The efficacy analysis consisted of 911 patients (504 men, 407 women;
mean age, 60.7 years; mean body weight, 82.4 kg); 627 received rosuvastatin
and 284 received atorvastatin.
Compared with atorvastatin, rosuvastatin was associated with significantly
greater reductions in LDL-C and TC (both, P < 0.05), and with a significantly
greater increase in high-density lipoprotein cholesterol level (P < (105). A
greater proportion of patients in the rosuvastatin group compared with the
atorvastatin group reached the 1998 goals for LDL-C (83.4% vs 683%; P <
0.001) and TC (76.4% vs 59.5%; P < 0.001). Also, compared with the
atorvastatin group, greater proportions of patients in the rosuvastatin group
achieved the 2003 JTF goals for LDL-C and TC (both, P < 0.001). Both agents
were well tolerated: serious drug-related events were observed in < or =3.0% of
patients in each group, and no clinically significant differences were found
between the 2 treatment groups. CONCLUSIONS: In this study of selected
patients at high risk for CHD and with primary hypercholesterolemia,
rosuvastatin 10 mg/d for 12 weeks was associated with significantly greater
reductions in LDL-C and TC levels compared with atorvastatin 10 mg/d.
Furthermore, significantly more patients receiving rosuvastatin achieved the
1998 and 2003 JTF-recommended lipid targets compared with those receiving
atorvastatin. Both agents were well tolerated.
8.
Drugs Today (Barc). 2004 Jul;40(7):621-31.
Recent developments in lipid-lowering therapy. Highlights from the
Atorvastatin Landmark Program: Global Investigators Meeting III. June
1-3,
2004.
Toronto,
Canada.
Bandyopadhyay P.
The Atorvastatin Landmark Program: Global Investigators Meeting III was
held June 1-3, in Toronto, Canada. The purpose of the meeting was to update
investigators on the current status of the clinical trials that encompass the
Atorvastatin Landmark Program. The main objectives were the following: 1.
To review the range of studies that comprise the Atorvastatin Landmark
Program. 2. To communicate recently completed study results and discuss the
current and future impact of the findings, both individually and collectively, on
clinical practice and guideline recommendations. 3. To discuss how the
program is anticipated to evolve, highlighting new therapeutic modalities.
9.
- 174 -
Clin Ther. 2004 Sep;26(9):1388-99.
Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on
non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios
in patients with hypercholesterolemia: additional results from the
STELLAR trial.
Jones PH, Hunninghake DB, Ferdinand KC, Stein EA, Gold A, Caplan RJ,
Blasetto JW; Statin Therapies for Elevated Lipid Levels Compared Across
Doses to Rosuvastatin Study Group.
BACKGROUND: Non-high-density lipoprotein cholesterol (HDL-C),
apolipoprotein (apo) B, and lipid and apolipoprotein ratios that include both
atherogenic and antiatherogenic lipid components have been found to be strong
predictors of coronary heart disease risk. OBJECTIVE: The goal of this study
was to examine prospectively the effects of rosuvastatin, atorvastatin,
simvastatin, and pravastatin across dose ranges on non-HDL-C, apo B, apo A-I,
and total cholesterol (TC):HDL-C, low-density lipoprotein cholesterol (LDLC):HDL-C, non-HDL-C:HDL-C, and apo B:apo A-I ratios in patients with
hypercholesterolemia (LDL-C > or =160 mg/dL and <250 mg/dL and
triglycerides <400 mg/dL) in the Statin Therapies for Elevated Lipid Levels
compared Across doses to Rosuvastatin (STELLAR) trial. METHODS: In this
randomized, Multicenter, parallel-group, open-label trial (4522IL/0065),
patients > or =18 years of age received rosuvastatin 10, 20, 40, or 80 mg;
atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or
pravastatin 10, 20, or 40 mg for 6 weeks. Pairwise comparisons were
prospectively planned and performed between rosuvastatin 10, 20, and 40 mg
and milligram-equivalent or higher doses of comparators. RESULTS: A total
of 2268 patients were randomized to the rosuvastatin 10- to 40-mg,
atorvastatin, simvastatin, and pravastatin groups. Fifty-one percent of patients
were women, the mean (SD) age was 57 (12) years, and 19% had a
documented history of atherosclerotic disease. Over 6 weeks, rosuvastatin
significantly reduced non-HDL-C, apo B, and all lipid and apolipoprotein ratios
assessed, compared with milligram-equivalent doses of atorvastatin and
milligram-equivalent or higher doses of simvastatin and pravastatin (all, P <
0.002). Rosuvastatin reduced non-HDL-C by 42.0% to 50.9% compared with
34.4% to 48.1% with atorvastatin, 26.0% to 41.8% with simvastatin, and 18.6%
to 27.4% with pravastatin. Rosuvastatin reduced apo B by 36.7% to 45.3%
compared with 29.4% to 42.9% with atorvastatin, 22.2% to 34.7% with
simvastatin, and 14.7% to 23.0% with pravastatin. The highest increase in apo
A-I (8.8%) was observed in the rosuvastatin 20-mg group, and this increase
was significantly greater than in the atorvastatin 40-mg and 80-mg groups
(both, P < 0.002).
CONCLUSION: Rosuvastatin 10 to 40 mg was more efficacious in improving
the lipid profile of patients with hypercholesterolemia than milligram-
- 175 -
equivalent doses of atorvastatin and milligram-equivalent or higher doses of
simvastatin and pravastatin.
10.
Pharm Res. 2004 Sep;21(9):1686-91.
Interactions of human P-glycoprotein with simvastatin, simvastatin acid,
and
atorvastatin.
Hochman JH, Pudvah N, Qiu J, Yamazaki M, Tang C, Lin JH, Prueksaritanont
T.
PURPOSE: In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin
(SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp
by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug
interactions. METHODS: P-gp mediated efflux of SV, SVA, and AVA was
determined by directional transport across monolayers of LLC-PK1 cells and
LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was
evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp
overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50
microM. RESULTS: Directional transport studies showed insignificant P-gp
mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher
Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA,
respectively. Inhibition studies did not show the same trend as the transport
studies with SV and AVA inhibiting P-gp (IC50 -25-50 microM) but SVA not
showing any inhibition of P-gp. CONCLUSIONS: The moderate level of P-gp
mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition
compared to systemic drug levels suggest that drug interactions due to
competition for P-gp transport is unlikely to be a significant factor in adverse
drug interactions. Moreover, the inconsistencies between P-gp inhibition
studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition
studies are not a valid means to identify statins as Pgp substrates.
11.
Pharmacology. 2005 Feb;73(2):102-5. Epub 2004 Oct 19.
Atorvastatin and simvastatin decrease the uptake of acetylated low-density
lipoprotein by human monocytes.
Tavridou A, Manolopoulos VG.
- 176 -
Several lines of evidence indicate that HMG-CoA reductase inhibitors, calcium
channel blockers, and angiotensin-converting enzyme inhibitors exert antiatherogenic effects in vitro and in vivo. In the present study, we determined the
effect of members of the above classes of drugs on the uptake of modified lowdensity lipoprotein (LDL) by U937 cells (human monocytic cell line), a key
event in the progression of atherosclerosis. U937 cells were treated with drugs
and subsequently the uptake of fluorescent acetylated LDL was assessed by
flow cytometry. The HMG-CoA reductase inhibitors, atorvastatin and
simvastatin (1-30 mumol/l), but not calcium channel blockers or angiotensinconverting enzyme inhibitors, inhibited the uptake of modified LDL by
monocytes. Therefore, atorvastatin and simvastatin may slow down the
progression of atherosclerosis by inhibiting the formation of foam cells.
12.
Int J Clin Pharmacol Ther. 2004 Nov;42(11):589-93.
Effect of monthly atorvastatin treatment on hemostasis.
Okopien B, Krysiak R, Herman ZS.
Apart from lowering lipid levels, 3-hydroxy-3-methylglutaryl coenzyme A
reductase inhibitors (statins) produce many other favorable effects that
contribute to their clinical efficacy in the primary and secondary prevention of
cardiovascular diseases. The aim of this study was to assess the effect of 30day atorvastatin treatment on major hemostatic risk factors (fibrinogen, PAI-1
levels, factor VII coagulant activity) in patients with primary
hypercholesterolemia. We studied 18 hypercholesterolemic patients and 12
matched control subjects. Compared to the control subjects,
hypercholesterolemic patients exhibited increased plasma PAI-1 levels and
factor VII activity. Atorvastatin (20 mg/d) not only decreased total cholesterol,
LDL cholesterol and oxidized LDL, but also reduced PAI-1 levels and factor
VII activity and tended to decrease fibrinogen levels. The hemostatic effects of
atorvastatin did not correlate with its lipid-lowering potential. Our study is the
first to show that atorvastatin may exhibit a quick, beneficial and
multidirectional nonlipid-related effect on hemostasis.
13.
J Spinal Cord Med. 2004;27(5):484-7.
Combined hyperlipidemia in a single subject with tetraplegia: ineffective
risk reduction after atorvastatin monotherapy.
- 177 -
Nash MS, Johnson BM, Jacobs PL.
BACKGROUND/OBJECTIVE: Effects of atorvastatin (Lipitor) drug
monotherapy (10 mg daily) on fasting blood lipid profiles and cardiovascular
disease (CVD) risks were examined for a single subject with C5-C6 tetraplegia.
Routine fasting lipid profiles were analyzed by standard biochemistry
techniques for total cholesterol (TC), triglycerides (TG), low-density
lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol
(HDL-C). Lipid profiles were analyzed on 3 occasions before drug therapy was
initiated and 3 months after therapy commenced. The TC:HDL and LDL:HDL
ratios were computed for all sampling times and used to assess pretreatment
and post-treatment CVD risk. RESULTS: Fasting TC, TG, and LDL-C were all
significantly reduced by therapy. The pretreatment HDL-C of 35 mg/dL was
lowered to 21 mg/dL. As a result, the TC:HDL risk ratio was only marginally
reduced from 6.6 to 6.4, whereas the LDL:HDL risk ratio remained unchanged
by treatment. CONCLUSIONS: In this man with tetraplegia, atorvastatin drug
monotherapy rapidly lowered TC, TG, LDL-C, and HDL-C. However, the
TC:HDL ratio, considered the best predictor of CVD risk, was unchanged.
14.
Am J Cardiol. 2005 Jan 15;95(2):249-53.
Reaching recommended lipid and blood pressure targets with
amlodipine/atorvastatin combination in patients with coronary heart
disease.
Dorval JF, Anderson T, Buithieu J, Chan S, Hutchison S, Huynh T, Jobin J,
Lonn E, Poirier P, Title L, Walling A, Tran T, Boudreau G, Charbonneau F,
Genest J.
The effects of combined atorvastatin and amlodipine on blood pressure (BP)
and low-density lipoprotein (LDL) cholesterol levels were investigated in 134
patients with documented coronary heart disease treated for 1 year. BP at
baseline was 128 +/- 15/79 +/- 9 mm Hg and was controlled by the treating
physician; no calcium channel blockers were allowed. Baseline means for
plasma cholesterol were 6.4 +/- 1.1 mmol/L (147 +/- 39 mg/dl), triglycerides
2.0 +/- 0.9 mmol/L (177 +/- 88 mg/dl), LDL cholesterol 4.4 +/- 1.0 mmol/L
(170 +/- 39 mg/dl), and high-density lipoprotein cholesterol 1.2 +/- 0.3 mmol/L
(46 +/- 12 mg/dl).
Patients were all given atorvastatin 10 mg, then increased to 80 mg if the LDL
cholesterol was <2.5 mmol/L (100 mg/dl). At 3 months, patients were
randomized to amlodipine 10 mg or placebo. Plasma LDL cholesterol was
decreased by 50%, and the LDL cholesterol target of <2.5 mmol/L was
achieved in 81% of the patients. BP targets were achieved in 69% of the
- 178 -
atorvastatin + placebo group, versus 96% in the atorvastatin + amlodipine
group (p = 0.0002). With use of combination atorvastatin + amlodipine at doses
ranging from 10 to 80 mg and 5 to 10 mg, respectively, recommended
therapeutic goals were reached in most select subjects with coronary artery
disease who were concomitantly receiving aspirin and antihypertensive
therapy.
15.
JOP. 2004 Nov 10;5(6):502-4.
Recurrent acute pancreatitis possibly induced by atorvastatin and
rosuvastatin. Is statin induced pancreatitis a class effect?
Singh S, Nautiyal A, Dolan JG.
CONTEXT: Few data exist about the incidence of drug-induced pancreatitis in
the general population. Drugs are related to the etiology of pancreatitis in about
1.4-2% of cases. While statins are generally well tolerated they have been
known to be associated with pancreatitis. Acute pancreatitis has been reported
in a few cases treated with atorvastatin, fluvastatin, lovastatin, simvastatin and
pravastatin. CASE REPORT: We report the case of a 77-year-old patient who
developed acute pancreatitis after treatment with rosuvastatin, which resolved
on withdrawal of the medication. She had a similar episode of pancreatitis a
year ago precipitated by atorvastatin, which resolved on withdrawal. Extensive
workup on both occasions failed to reveal any other etiology for the
pancreatitis. CONCLUSION: To our knowledge this is the first report of
rosuvastatin-induced pancreatitis. The occurrence of pancreatitis with two
different statins in our patient argues that statins induced pancreatitis may be a
class-effect of statins. With statin prescriptions on the rise clinicians need to be
aware of this complication of statin treatment and remember that the newest
statin, rosuvastatin is not dissimilar to the other statins in causing pancreatitis.
16.
Eur Heart J. 2004 Nov;25(21):1898-902.
Antiplatelet effects of a 600 mg loading dose of clopidogrel are not
attenuated in patients receiving atorvastatin or simvastatin for at least 4
weeks prior to coronary artery stenting.
Gorchakova O, von Beckerath N, Gawaz M, Mocz A, Joost A, Schomig A,
Kastrati A.
AIMS: To test prospectively whether the antiplatelet effect of a 600 mg loading
- 179 -
dose of clopidogrel is attenuated in patients receiving atorvastatin and
simvastatin for at least 4 weeks prior to coronary artery stenting. METHODS
AND RESULTS: Blood samples were obtained at least 2 h after receiving 100
mg aspirin and 600 mg clopidogrel and prior to coronary stenting from 90
patients without statin therapy and 90 patients with statin (atorvastatin and
simvastatin) therapy for at least 4 weeks. Maximal and residual platelet
aggregation was evaluated with optical aggregometry in response to ADP (5
and 20 micromol/l). Surface expression of IIb/IIIa (CD61) and P-selectin
(CD62) was assessed with whole blood flow-cytometry at baseline and
following stimulation (5 and 20 micromol/l ADP). Inhibition of ADP-induced
platelet aggregation was not impaired in the presence of concomitant statin
therapy. Moreover, patients with and without statin therapy did not differ in
respect to all flow-cytometric parameters obtained. CONCLUSION: The
antiplatelet effect of a high, 600 mg loading dose of clopidogrel is not
diminished in patients receiving atorvastatin and simvastatin for at least 4
weeks prior to coronary stenting.
17.
Med Clin (Barc). 2004 Oct 23;123(14):535-7.
[Atorvastatin lowers C-reactive protein in dislipemic patients with type 2
diabetes mellitus]
Illan Gomez F, Alcaraz Tafalla MS, Pascual Diaz M, Carrillo Alcaraz A.
BACKGROUND AND OBJECTIVE: Type 2 diabetes mellitus is associated
with an augmented risk for cardiovascular disease. The levels of C-reactive
protein (CRP), the prototypic marker of inflammation, are associated with an
increased risk for cardiovascular events. The statins have direct antiinflammatory effects. Thus, we tested the effects of atorvastatin on levels of
CRP on patients with type 2 diabetes.
PATIENTS AND METHOD: We evaluated CRP in baseline and 6 months
after onset of 20 mg daily atorvastatin therapy of 30 patients with type 2
diabetes with hyperlipidemia. Clinical and biochemical data were obtained.
RESULTS: CRP-levels were significantly decreased after treatment with
atorvastatin compared with baseline (median change: -4,99 mg/l; p < 0.001).
We observed an correlation between CRP baseline with body mass index (r =
0.429; p = 0.018), serum fibrinogen (r = 0.607; p = 0.001) and
microalbuminuria (r = 0.470; p = 0.01). Conversely, there was no significant
correlation between CRP baseline with LDL cholesterol. The CRP reduction
was significantly correlated with fasting glucose (r = -0.457; p = 0.019) and
glycosylated hemoglobin at 6 months (r = -0.421; p = 0.03). CONCLUSIONS:
- 180 -
These results confirm findings from previous studies that atorvastatin reduce
CRP levels in a largely LDL cholesterol independent manner.
18.
Ann Rheum Dis. 2004 Dec;63(12):1571-5.
Atorvastatin reduces arterial stiffness in patients with rheumatoid
arthritis.
Van Doornum S, McColl G, Wicks IP.
BACKGROUND: Chronic systemic inflammation may contribute to
accelerated atherosclerosis and increased arterial stiffness in patients with
rheumatoid arthritis (RA). In addition to lowering cholesterol, statins have
immunomodulatory effects which may be especially beneficial in patients with
RA who have systemic immune activation. OBJECTIVE: To investigate the
effect of atorvastatin on the augmentation index (AIx: a measure of arterial
stiffness) and systemic inflammation in RA. METHODS: 29 patients with RA
(mean (SD) age 55 (13) years) with moderately active disease of long duration
were studied. AIx, lipid levels, serum inflammatory markers, and disease
activity score were measured before and after 12 weeks of atorvastatin 20 mg
daily. RESULTS: AIx improved significantly from 34.1 (11.6)% to 29.9 (11)%
(p = 0.0002), with the greatest improvements in AIx occurring in those subjects
with the highest disease activity scores (r = -0.5, p = 0.007). Total and LDL
cholesterol were reduced from 5.5 (0.9) to 3.9 (0.7) mmol/l and 3.3 (0.8) to 1.9
(0.6) mmol/l, respectively (p = 0.0001). Serum inflammatory markers remained
unchanged during the study. CONCLUSIONS: Atorvastatin significantly
reduced arterial stiffness in patients with RA. The greatest improvements were
seen in patients with more active disease, suggesting that, in addition to the
beneficial effects of cholesterol reduction, immune modulation may contribute
to the cardioprotective effect of statins.
19.
J Clin Endocrinol Metab. 2004 Oct;89(10):5021-9.
Effects of atorvastatin on fasting plasma and marginated apolipoproteins
B48 and B100 in large, triglyceride-rich lipoproteins in familial combined
hyperlipidemia.
- 181 -
Verseyden C, Meijssen S, Cabezas MC.
Large triglyceride (TG)-rich lipoproteins (TRLs) circulate in the blood, but
they may also be present in a marginated pool, probably attached to the
endothelium. It is unknown whether statins can influence this marginated pool
in vivo in humans. Intravenous fat tests were performed in familial combined
hyperlipidemia (FCHL) subjects before and after atorvastatin treatment and in
controls to investigate whether acute increases in apoB in TRL fractions would
occur, potentially reflecting the release of this TRL from a marginated pool.
After a 12-h fast, a bolus injection of 10% Intralipid was given to 12 FCHL
patients before and after 16-wk treatment with atorvastatin. Twelve carefully
matched controls were included. For 60 min postinjection, apoB48, apoB100,
and lipids were measured in TRLs. Fasting apoB100 in all TRL fractions were
2- to 3-fold higher in untreated FCHL compared with controls. ApoB48
concentrations in chylomicron fractions increased significantly within 10 min
in FCHL before and after treatment, but not in controls. ApoB100 increased
significantly in the chylomicron fractions in untreated FCHL and in controls,
but not in FCHL after treatment. In very low density lipoprotein 1, apoB100
increased only in untreated FCHL. In very low density lipoprotein 2, apoB100
did not change in any group. These data show that increasing the number of
circulating TRLs by chylomicron-like particles, results in increased plasma
apoB-TRLs, probably by acute release from a marginated pool. This is a
physiological process occurring in FCHL and in healthy normolipidemic
subjects, but it is more pronounced in the former. Decreased marginated TRL
particles in FCHL is a novel antiatherogenic property of atorvastatin.
20.
Am Heart J. 2005 Jan;149(1):e1.
Comparison of the efficacy and safety of atorvastatin initiated at different
starting doses in patients with dyslipidemia.
Jones PH, McKenney JM, Karalis DG, Downey J.
BACKGROUND: The NASDAC study was designed to evaluate the safety and
efficacy of atorvastatin at starting doses of 10, 20, 40, and 80 mg. METHODS:
After an 8-week placebo washout period, 919 patients who were candidates for
lipid-lowering therapy according to the National Cholesterol Education
Program's Adult Treatment Panel III guidelines were randomized to 1 of 4
atorvastatin treatment groups: 10 mg (n = 229), 20 mg (n = 228), 40 mg (n =
231), and 80 mg (n = 231). RESULTS: Atorvastatin reduced low-density
lipoprotein cholesterol (LDL-C) levels dose dependently across the 10- to 80mg-dose range (35.7%-52.2%). Each of the 20-, 40-, and 80-mg doses provided
- 182 -
significantly greater decreases in LDL-C than all lower doses (P < .01). All
doses also reduced total cholesterol, the LDL-C/high-density lipoprotein
cholesterol ratio, apolipoprotein B, and triglycerides from baseline. An increase
in high-density lipoprotein cholesterol was observed in all dose groups. Most
participants, regardless of their level of coronary heart disease risk, attained
their National Cholesterol Education Program's Adult Treatment Panel III
LDL-C goal by the end of the study. Patients in all risk groups were more
likely to achieve the NCEP LDL-C goal at higher starting doses. Atorvastatin
was well tolerated at all dose levels. CONCLUSIONS: Atorvastatin initiated at
doses of 10, 20, 40, and 80 mg is effective and safe for the treatment of patients
with dyslipidemia. Depending on the percentage reduction needed to achieve
an LDL-C goal, patients with or at risk of coronary heart disease may benefit
from starting therapy at a higher dose of atorvastatin.
21.
Eur J Clin Pharmacol. 2004 Dec;60(10):685-91. Epub 2004 Oct 14.
Atorvastatin effect on high-density lipoprotein-associated paraoxonase
activity and oxidative DNA damage.
Harangi M, Seres I, Varga Z, Emri G, Szilvassy Z, Paragh G, Remenyik E.
OBJECTIVE: High-density lipoprotein (HDL)-associated antioxidant
paraoxonase (PON) may reduce low-density lipoprotein (LDL) oxidation and
prevent atherosclerosis. The aim of this present study was to investigate the
effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
inhibitor atorvastatin on hydrogen-peroxide-induced DNA damage by comet
assay and the correlation between oxidative DNA damage and antioxidant PON
activity. METHODS: Thirteen type-II/a hyperlipidemic patients were enrolled
in the study. We examined the effect of 10 mg/day atorvastatin treatment on
lipid levels and the degree of DNA damage in lymphocytes separated from
hyperlipidemic patients, nitric oxide (NO), thiobarbituric acid-reactive
substances (TBARS), PON levels and activity. RESULTS: After 6 months,
atorvastatin treatment significantly decreased serum cholesterol and LDLcholesterol levels. The triglyceride level did not change, and there was no
significant change in the HDL cholesterol level. The visual score characteristic
to the degree of DNA damage in comet assay was significantly decreased, as
well as the TBARS level, while the level of NO was non-significantly
increased. PON activity and the PON/HDL ratio were significantly increased
after atorvastatin treatment. There was a negative correlation between DNA
damage and PON activity, as well as between DNA damage and the PON/HDL
ratio before and after atorvastatin treatment. CONCLUSION: These findings
show that atorvastatin treatment favorably affected the lipid profile, increasing
the activity of HDL-associated PON and decreasing the cytotoxic effect of
oxidative stress.
- 183 -
Toxicity And Terratogenecity
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100
mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one,
there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This
dose represents a plasma AUC (0-24) value of approximately 16 times the
mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day
resulted in a significant increase in liver adenomas in high-dose males and liver
carcinomas in high-dose females. These findings occurred at a plasma AUC (024) values of approximately 6 times the mean human plasma drug exposure
after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests
with and without metabolic activation: the Ames test with Salmonella
typhimurium and Escherichia coli, the HGPRT forward mutation assay in
Chinese hamster lung cells, and the chromosomal aberration assay in Chinese
hamster lung cells. Atorvastatin was negative in the in vivo mouse
micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human
exposure) produced no changes in fertility. There was aplasia and aspermia in
the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3
months (16 times the human AUC at the 80 mg dose); testis weights were
significantly lower at 30 and 100 mg/kg and epididymal weight was lower at
100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had
decreased sperm motility, spermatid head concentration, and increased
abnormal sperm. Atorvastatin caused no adverse effects on semen parameters,
or reproductive organ histopathology in dogs given doses of 10, 40, or 120
mg/kg for two years.
- 184 -
References:
1.
Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):161-7. Epub 2004 Oct 28.
Effect of low dose atorvastatin versus diet-induced cholesterol lowering on
atherosclerotic lesion progression and inflammation in apolipoprotein
E*3-Leiden transgenic mice.
Verschuren L, Kleemann R, Offerman EH, Szalai AJ, Emeis SJ, Princen HM,
Kooistra T.
OBJECTIVE: To evaluate whether low-dose atorvastatin suppresses
atherosclerotic lesion progression and inflammation in apolipoprotein E*3
(apoE*3)-Leiden mice beyond its cholesterol-lowering effect. METHODS
AND RESULTS: ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet
until mild atherosclerotic lesions had formed. Subsequently, HC diet feeding
was continued or mice received HC supplemented with 0.002% (w/w)
atorvastatin (HC+A), resulting in 19% plasma cholesterol lowering, or mice
received a low-cholesterol (LC) diet to establish a plasma cholesterol level
similar to that achieved in the HC+A group. HC+A and LC diet reduced,
significantly and to the same extent, lesion progression and complication in the
aortic root, as assessed by measuring total atherosclerotic lesion area, lesion
severity, and macrophage and smooth muscle cell area. In the aortic arch,
HC+A but not LC blocked lesion progression. HC+A and LC reduced vascular
inflammation (ie, expression of macrophage migration inhibitory factor ,
plasminogen activator inhibitor- 1, matrix metalloproteinase-9), but HC+A
additionally suppressed vascular cell adhesion molecule-1 expression and, in
parallel, monocyte adhesion. In contrast, low-dose atorvastatin showed no
antiinflammatory action toward hepatic inflammation markers (serum amyloid
A, C-reactive protein [CRP]) in apoE*3-Leiden mice and human CRP
transgenic mice. CONCLUSIONS: Low-dose atorvastatin cholesteroldependently reduces lesion progression in the aortic root but shows
antiinflammatory vascular activity and tends to retard atherogenesis in the
aortic arch beyond its cholesterol-lowering effect.
2.
J Immunol. 2004 Dec 15;173(12):7641-6.
Atorvastatin inhibits autoreactive B cell activation and delays lupus
development in New Zealand black/white F1 mice.
- 185 -
Lawman S, Mauri C, Jury EC, Cook HT, Ehrenstein MR.
Systemic lupus erythematosus is a multisystem autoimmune disease
characterized by a wide range of immunological abnormalities that underlie the
loss of tolerance. In this study we show that administration of atorvastatin to
lupus-prone NZB/W F(1) mice resulted in a significant reduction in serum IgG
anti-dsDNA Abs and decreased proteinuria. Histologically, the treatment was
associated with reduced glomerular Ig deposition and less glomerular injury.
Disease improvement was paralleled by decreased expression of MHC class II
on monocytes and B lymphocytes and reduced expression of CD80 and CD86
on B lymphocytes. Consequent upon this inhibition of Ag presentation, T cell
proliferation was strongly impaired by atorvastatin in vitro and in vivo. A
significant decrease in MHC class II expression was also observed in the target
organ of lupus disease (i.e., the glomerulus). Serum cholesterol in atorvastatintreated lupus mice fell to the level found in young NZB/W mice before disease
onset. This is the first demonstration that atorvastatin can delay the progression
of a spontaneous autoimmune disease and may specifically benefit patients
with systemic lupus erythematosus.
3.
J Neurosurg. 2004 Nov;101(5):813-21.
Atorvastatin reduction of intravascular thrombosis, increase in cerebral
microvascular patency and integrity, and enhancement of spatial learning
in rats subjected to traumatic brain injury.
Lu D, Mahmood A, Goussev A, Schallert T, Qu C, Zhang ZG, Li Y, Lu M,
Chopp
M.
OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A
reductase inhibitor, has pleiotropic effects, such as promoting angiogenesis,
increasing fibrinolysis, and reducing inflammatory responses, and has shown
promise in enhancing recovery in animals with traumatic brain injury (TBI)
and stroke. The authors tested the effect of atorvastatin on vascular changes
after TBI. METHODS: Male Wistar rats subjected to controlled cortical impact
injury were perfused at different time points with fluorescein isothiocyanate
(FITC)--conjugated dextran 1 minute before being killed.
Spatial memory function had been measured using a Morris Water Maze test at
various points before and after TBI. The temporal profile of intravascular
thrombosis and vascular changes was measured on brain tissue sections by
using a microcomputer imaging device and a laser confocal microscopy. The
study revealed the following results. 1) Vessels in the lesion boundary zone and
hippocampal CA3 region showed a variety of damage, morphological
alterations, reduced perfusion, and intraluminal microthrombin formation. 2)
- 186 -
Atorvastatin enhanced FITC-dextran perfusion of vessels and reduced
intravascular coagulation. 3) Atorvastatin promoted the restoration of spatial
memory function. CONCLUSIONS. These results indicated that atorvastatin
warrants investigation as a potential therapeutic drug for TBI.
4.
J Neurosurg. 2004 Nov;101(5):822-5.
Atorvastatin reduction of intracranial hematoma volume in rats subjected
to controlled cortical impact.
Lu D, Mahmood A, Qu C, Goussev A, Lu M, Chopp M.
OBJECT: Atorvastatin, a beta-hydroxy-beta-methylglutaryl coenzyme A
reductase inhibitor, has pleiotropic effects such as improving thrombogenic
profile, promoting angiogenesis, and reducing inflammatory responses and has
shown promise in enhancing neurological functional improvement and
promoting neuroplasticity in animal models of traumatic brain injury (TBI),
stroke, and intracranial hemorrhage. The authors tested the effect of
atorvastatin on intracranial hematoma after TBI. METHODS: Male Wistar rats
were subjected to controlled cortical impact, and atorvastatin (1 mg/kg) was
orally administered 1 day after TBI and daily for 7 days thereafter. Rats were
killed at 1, 8, and 15 days post-TBI. The temporal profile of intraparenchymal
hematoma was measured on brain tissue sections by using a MicroComputer
Imaging Device and light microscopy. CONCLUSIONS: Data in this study
showed that intraparenchymal and intraventricular hemorrhages are present 1
day after TBI and are absorbed at 15 days after TBI. Furthermore, atorvastatin
reduces the volume of intracranial hematoma 8 days after TBI.
- 187 -