Pharmaceutical Analysis 1 (Quantitative Pharmaceutical
Chemistry)
Pearle Joy Caro,RPh
INTRODUCTION TO QUALITY CONTROL
UNIT 1
Quantitative Pharmaceutical Chemistry
•Application of the procedures of quantitative analytical chemistry
– purity and quality of drugs and chemicals used – chemical constituents found in human body
– medicinal agents and their metabolites
What is Quality?
QUALITY
• It is the combination of attributes or characteristics of a product which when compared to a standard,serves as a basis for measuring the uniformity of the
product and determined its degree of acceptability.
• The totality of features and characteristics of a product or service that bears on its ability to satisfy stated or implied needs.
• degree to which a specific product conforms to a design or specification.
• is a measure of excellence or a state of being free from defects, deficiencies and significant variations.
QUALITY IN DRUGS
•Sum of all factors which contribute directly or indirectly to the safety,effectiveness and reliability of the product.
CONTROL
•Refers to the measure or step that is used to prevent or eliminate drug risk/ hazards to make it safe and effective.
QUALITY ASSURANCE
• The sum total of the organized activities performed with the intent to ensure that all active pharmaceutical ingredients are of the quality required
for their intended use.
• All the planned and systematic activities implemented in a quality system so that quality requirements for a product or service will be fulfilled (American
Society for Quality,ASQ).
• The overall organizational body designed to assure product quality.
• Develop and follows standard operating procedures directed toward assuring the quality,safety,purity and effectiveness of drug products.
QUALITY ASSURANCE
• define and improve the quality related processes and procedures to ensure quality.
• is describe as any systematic process or procedure of determining whether a product or service meets specified requirements
• maintenance of a desired level of quality in a service or product, especially by means of attention to every stage of the process of delivery or production
QA DEPARTMENTAL FUNCTIONS
•Ensures quality policies adopted are followed •Contact with regulatory agency
•Identification and preparation of the policies and Standard Operating Procedures
•Quality monitoring or audit function
QUALITY CONTROL
• A tool that gives the assurance that a product conforms to standards and specifications through a system of inspection,analysis,and action.
• Monitors the finished product
• evaluate the quality,estimate if it meets customer's expectations.
• is a procedure or set of procedures this is designed to ensure that a manufactured product or performed service complies with a defined set of
quality standards or meets the requirements of the end user or customer
• The operational techniques and activities used to fulfill requirements for quality, → To assure safe,pure and effective drug product.
→ Quality is everybody’s business.
Quality Control guarantees that all drug products
• Are safe and free of impurities and contaminations.
• Produces a physically and chemically stable product.
• Contains the exact amount of the active ingredients and even inert materials as stated in the label which conforms to the standards.
• Ensures that the active ingredient will be optimally released upon administration producing a good bioavailability.
QC DEPARTMENTAL FUNCTIONS
•Sampling and analytical testing •In- Process Testing •Environmental monitoring •Tests on finished
dosage form •Monitoring product quality
SAMPLING AND ANALYTICAL TESTING
• Analytical testing of raw materials • Packaging materials
• Labeling
• Selection and qualification of vendors
IN-PROCESS TESTING
•Give in-process alert or action levels
•Provides early warnings of conditions that can lead to out-of- control situations
ENVIRONMENTAL CONDITIONS MONITORING
•Different levels of control are established depending on the intended use of the dosage form
• Air and water systems • Microbial matter
• Levels of particulates
FINAL PRODUCT TESTING •Analytical testing of products before release
3 MAIN AREAS OF QUALITY CONTROL
•Raw Material Quality Control •In-Process Quality Control
•Finished Product Quality Control
QUALITY CONTROL SYSTEM
•is established at the conception of a new product, during production of the batch, and during distribution of the commercial package.
•This system is a combination of those administrative and technical procedures,which must be used to produce and deliver a safe, pure, and
effective product to the end user.
QUALITY CONTROL SYSTEM
•Guarantees that the drug product is: • Free from impurities
• Physically and chemically stable.
• Having the amount of active ingredient as stated on the label.
• Providing an optimal release of active ingredients when the drug product is administered.
QUALITY CONTROL SYSTEM BENEFITS:
• The system minimizes or eliminates the risk of marketing unsafe products
• It guarantees conformance to regulatory requirements
• It guarantees product efficacy
• It reduces operating costs
• It reduces operating losses
• It produces higher employee morale
• It motivates the pharmaceutical/medical professions to sell or prescribe the product
BENCHMARKING
•a process inside an organization with the aim to improve its performance by learning about good practices for primary and/or support processes through
looking at those processes in other, better-performing organizations, building on evaluation of relevant performances in own and other organizations.
TOTAL QUALITY MANAGEMENT (TQM)
• A management approach for an organization, centered on quality, based on the participation of all its members and aiming at long-term success through
customer satisfaction, and benefits to all members of the organization and to society
ELEMENTS OF TQM
Current Good Manufacturing Practice
•provide guidelines to develop systems which ensure that manufacturing facilities and processes are properly designed, monitored and controlled
•covers all aspects of production from the starting materials, premises and equipment to the training and personal hygiene of staff
ACCREDITATION
• quality assessment with an attached judgment that the evaluated unit (programme or organization) is good enough to have the right to exist in a
particular system.
• Often,accreditation is given for a limited period of time (usually between 4 and 10 years) and is repeated in a cyclical process at the end of the period
of validity.
ISO
• Popular name for International Organization For Standardization (IOS)
• A voluntary, non-treaty federation of standards setting bodies of some 130 countries.Founded in 1946-47 in Geneva as a UN agency, it promotes
development of standardization and related activities to facilitate international trade in goods and services, and cooperation on
economic,intellectual,scientific,and technological aspects.
• ISO 9001 – quality management
• Quality refers to all those features of a product (or service) which are required by the customer.
• Quality management means what the organization does to ensure that its products or services satisfy the customer’s quality requirements and
comply with any regulations applicable to those products or services.
• ISO 14001 – environmentalmanagement system
• This means what the organization does to minimize harmful effects on the environment caused by its activities,to conform to applicable regulatory
requirements, and to achieve continual improvement of its environmental performance
INDUSTRIAL PHARMACY
•is defined as a discipline which includes manufacturing, development, marketing and distribution of drug products including quality
assurance and quality control of these activities
ORGANIZATION OF QUALITY CONTROL
•Part of a manufacturing firm is a defined organization.
•functions and responsibilities •effective coordination
•all activities are performed towards the production of a product of the highest standard and at the lowest cost.
•The following are the basic divisions or departments in a manufacturing firm:
A. Finance or accounting division B. Production
C. Quality Control
D. Research and development E. Marketing and sales F.Administrative
A. FINANCE DIVISION
•Responsibilities: – Money out
– Money in – Payroll
– Reporting
– Financial Controls
• May be composed of the following personnel: a) Chief Financial Officer (or CFO
b) Financial Controller c) Treasury Manager
d) Accounting Manager e) Chief Accounting
f) Accounting Supervisor g) Accountant
h) Bookkeepers
B. PRODUCT DIVISION
• The production department is responsible for converting raw materials and other inputs into finished goods or services.
• Responsibilities:
– Identifying Inputs
– Scheduling Production
– Minimizing Production Costs – Ensuring Product Quality
– Improve Existing Products
PERSONNELS:
• Capsule filling machine operators
• Ampule and
vial fillers
• Ampule and
vial inspectors
• Granulator machine operators • Coaters
• Fermenter operators
C. QUALITY CONTROL DIVISION
•focuses on testing substances for compliance to standards and requirements.
– Raw Materials Analyst – In Process Analyst
– Finished Product testing
Responsibilities:
– prepares and test samples from all phases of a manufacturing or other handling process,
– prepare technical documents that report the results of their lab work
– minor equipment troubleshooting, calibration and repair
Personnel:
– QC Analysts
– In Process Analysts
– QC Chemists
– Raw Materials Analysts
– Quality Controllers
– Finished Product Analyst – QC Specialists – Analytical Chemists
– QC Support
– In Process Chemists
Organizational Structure of Pharmaceutical Industrial Quality Control Department
QUA
LITY
CON
TRO
L
DEP
ART
MEN
T
Materials Inspection
Department
Analytical Laboratory
Department
Specifications and
analytical development
Quality Coordination
Office
Biological Testing
Laboratory Department
Materials Inspection Department
• Scope of responsibilities:
1.To sample and examine all raw materials received.
2.To sample and conduct physical tests on: a.all shipments of packaging materials
b. all manufacturing, filling and packaging operations.
3.To maintain periodic examination on the quality of inventories throughout all phases of storage, shipping, and distribution.
4.To perform an audit which is independent of the work done by production personnel
Analytical Laboratory Department
•Scope of responsibility:
1. Performs physical and chemical analysis checking whether these parameters conforms to the standards.
Biological Testing Laboratory Department
•Scope of responsibilities:
1.To perform and evaluate microbiological and pharmacological assays, as well as sterility, pyrogen tests and acute toxicity tests.
2.To conduct environmental monitoring and assessment.
Specifications and Analytical Development
1. Coordinates with research,product development, production, sales and management towards improvement of a product.
2. Establish specifications for raw and packaging materials. 3.Validates existing and tentative procedures for testing. 4.
Establish specifications based on validated procedures. 5. Develops new assay methods for in-house use.
6. Develops and improves specifications for quality characteristics of the final product being manufactured
Quality Coordination Office
1.This department is responsible in storing and maintainingrecords of a certain batch from start to finish.
2.They provide data that aids in analyzingthe product’s performance in the market
3.They usually relates to the customers regarding complaints,and product inquiry these data will be reported to the technical sales committee.
4.They also coordinate with the development group for product improvement.
5.Helps develop Standard Operating Procedures (SOP)
6. Helps to provide data that gives scientific and legal status.
D. RESEARCH AND DEVELOPMENT
•responsible in discovering and developing new pharmaceutical compounds “Candidates” bioactive molecule compounds suspected to possess
pharmacological activity are being selected using computerized tool and are being tested by its pharmacokinetics and pharmacodynamics
property and its interaction with a desired pathology.
E. MARKETING AND SALES DEPARTMENT
• Functions: advertising the products,product promotion,customer service, and even sales
•Scope of responsibilities: 1.Sales goal setting
2.Pricing and distribution planning of the product 3.Customer service and sales
4.Product promotions and marketing
F. ADMINISTRATIVE DEPARTMENT
•backbone of an organization •headed by an administrator
• ensures the smooth flow of information from one part to another
CONTROL FUNCTIONS
CONTROL FUNCTIONS
• may appear varied and never quite identical in any two companies by basically, these functions can be classified into four categories:
• Analytical Function • Monitor Function
• Record Review and Release Function • Audit Function.
A. ANALYTICAL FUNCTIONS
•This control function plays an important role in conducting tests and assays on raw materials, packaging materials, bulk or volume product
and packaging of product prior to release.
•This also covers the end user distribution of the products and even confirmation of the expiration date.
B. MONITOR FUNCTIONS
•does not depend solely to a certain personnel responsibility.
•This test includes determining microbial content in the air and determining whether the levels of these particulates are within limits.
C. RECORD, REVIEW AND RELEASE FUNCTIONS
•This function covers the carefully review of batch records for a certain period of time of production.
D. AUDIT FUNCTIONS
•The audit function detects if there is a non-compliance from these procedures and takes steps to inform the upper management to take corrective
measures.
OTHER AREAS IN MANUFACTURING FIRM THAT A PHARMACIST CAN WORK
•Marketing
•Production
•Medical Affairs
•Research and
•Legal or Regulatory •Medical Liaisons
•Administration Development
Affairs
END OF UNIT 1
STANDARDS AND SPECIFICATIONS
Unit 2
STANDARDS AND SPECIFICATIONS
• Quality Characteristics are interpreted by descriptive words and measurements.
• Characteristics are subject to variation. • Depends on the quality of the product.
• Quality variation which is not confined within a specific range, tolerance or limit, will grow to uncontrolled magnitude and will encourage the proliferation
of errors; thus, producing a defective product.
• To avoid producing a defective product, standards and specifications are developed to serve as a basis for accepting or rejecting a product. In a
product,these must cover the following points:
1. FORMULA - This is concise and precise statement of the ingredientsthat comprise the product,together with the percentage and/or weight of each.
2. RAW MATERIAL SPECIFICATION - This should enumerate the characteristics of all the materials that go into the product and the permissible range
of purity of each ingredient.Deviation beyond this range may be expected to cause failure of the product to function as planned or,at least,result in
an undesirable lack of uniformity.Standard compendia like the USP,NF,BP,BPC, Merck Index,etc.,provide this valuable information.
3.STANDARD OPERATING PROCEDURE - This is a step-by-step method on how to go about a job. It must spell out all information and
instructions that assure that variations in production from day to day and week to week will be held to within acceptable established ranges.
4.FINISHED PRODUCT SPECIFICATION - This should cover all characteristics that affect the proper performance, purity, safety and stability of the
product.Tolerances may be minimum, maximum,or both, depending on the nature of the situation.
• Boxed, Labeled,Ready for Shipping
5.PACKAGING MATERIAL STANDARD -This should be set for everything that goes around the product, i.e.,bottles,cans,aluminum foil,cellophane,
jars,caps, cap liners,labels,printed inserts, cartons,wrapping papers,and shipping cases.Packaging must be considered with the following points in mind:
• The units may have to run on a high-speed line. • They may involve a complicated
assembly
• The package may be functional
• The package must be completely compatible with the product • The package must protect the product and assure its
stability. • The package must ship well.
6. TESTING METHODS - These are indispensable in assuring conformity to standards. Since they play such a vital role, testing procedures must be
standardized so that they yield results of comparable precision and accuracy in the hands of different operators and laboratories.The tests must be
validated to ensure precision and accuracy on application.
SPECIFICATIONS
• Exact statement of the particular needs to be satisfied or essential characteristics that a customer requires (in a good, material, method, process,
service, system, or work) and which a vendor must deliver.
• Written usually in a manner that enables both parties (and/or an independent certifier) to measure the degree of conformance
• A description of starting material, intermediate, bulk or finished product in terms of its chemical, physical and microbiological characteristics, if any.
• A specification shall include descriptive and or numerical clauses stating standards and tolerated deviations, whenever applicable
• Lists of detailed requirements with which the products or materials used or obtained during manufacture have to conform, they serve as a basis for
quality evaluation
Specifications are divided generally into two main categories:
(1) PERFORMANCE SPECIFICATIONS- conform known customer requirements such as keeping the temperature within a specified range
(2) TECHNICALSPECIFICATIONS express the level of performance of the individual units
• a.INDIVIDUAL UNIT SPECIFICATIONS which state boundaries or parameters of the unit performance consisting of a nominal value and
tolerance
• b.ACCEPTABLE QUALITYLEVEL which states limits that are to be satisfied by most of the units,but a certain percentage of the units is
allowed to exceed those limits
• c.DISTRIBUTION SPECIFICATIONS which define an acceptable statistical distribution for each unit and are used by a producer to monitor
its production processes
Example of Specifications for Finished Products
REFERENCES
OFFICIAL REFERENCES
• USP = United States Pharmacopeia and (NF) National Formulary
• JP = Japan Pharmacopeia • BP = British Pharmacopeia • European
Pharmacopeia
• International Pharmacopeia
UNOFFICIAL REFERENCE:
• China Pharmacopeia
• India Pharmacopeia
• Philippine Pharmacopeia
PHARMACOPOEIAS
• Greek, “pharmakon”, meaning “drug”, and “poiein”, meaning “make”
• Indicates any
recipe or formula or other standards required to make or prepare a drug.
• is a legally binding collection, prepared by a national or regional authority of standards and quality specifications for medicines used in that country
or region.
OVERVIEW OF USP/NF
• The first American pharmacopeia was so called “Lititz Pharmacopeia,” published in 1778 at Lititz, Pennsylvania, for use by the Military Hospital of
the United States Army.
• On January 6, 1817, D r. Lyman Spalding, a physician from New York City, submitted a plan to the Medical Society of the Country of New York for
creation pharmacopeia of national
• Dr. Spalding’s effort were later to result in his being recognized as the “Father of United States Pharmacopeia.”
• January 1, 1820 conducted the first United States Pharmacopeia Convention assembled in Washington, D.C.
• December 15, 1820, the first United States Pharmacopeia was published in English and Latin.
MONOGRAPHS AND GENERAL CHAPTERS
• Monographs set forth the article's name, definition, specification, and other requirements related to packaging, storage, and labelling.
• The specification consists of tests, procedures, and acceptance criteria that help ensure the identity, strength, quality and purity of the article.
*An official article is an article that is recognized in USP or NF.
COMPONENTS OF MONOGRAPH
1. Molecular Formula
3. Description and
4. Identification 5.Assay
Substances
6. Impurities and Foreign 2.Added Substances
7. Performance Tests Solubility 8. USP Reference Standards
GENERAL NOTICES SECTION
• presents the basic assumptions, definitions, and default conditions for the interpretation and application of the USP- NF
• Requirements stated apply to all articles recognized in the USP and NF and to all general chapters unless specifically stated otherwise.
GENERAL NOTICES: TOPICS
• Monographs and General chapters • Monograph components
• Testing practices and procedures • Test results
• Terms and definitions
• Prescribing and dispensing
• Preservation, packaging, storage and labeling
GENERAL
CHAPTERS
➢ 711 – DISSOLUTION
➢ 701 – DISINTEGRATION
➢ 905 – UNIFORMITY OF DOSAGE UNITS ➢ 85 – BET
➢ 788 – PARTICULATE CONTAMINATION ➢ 281 – RESIDUE ON
IGNITION
➢ 71 – STERILITYTEST
➢ 786 – PARTICLE SIZE DIST. ESTIMATION
➢ 616 – BULK DENSITYAND TAPPED
DENSITY
➢ 1174 – POWDER FLOW ➢ 1216 –
TABLET FRIABILITY ➢ 811 – POWDER
FINENESS
➢ 621 – CHROMATOGRAPHY
CERTIFICATE OF ANALYSIS •A document containing the results of all test
conducted on a specific material or product to show compliance or non-compliance with established standards or specifications by responsible
personnel.
DEFECTS AND QUALITY VARIATION
DEFECT
• an undesirable characteristic of a product • a failure to conform to specifications
• A unit product which may contain one or more defect is called defective.
• Defects can be classified as follows: • According to measurability
• According to seriousness or gravity • According to nature
According to measurability:
•Variable defect
• can be measured directly by instruments
•Attribute defect
• cannot be measured directly by instruments
• it shows mainly the conformance or non-conformance of the material to specifications
According to seriousness or gravity
• Critical defect (resulted to death)
• renders the item unusable or poses risk of harm to the end consumer
• Major defect (affects the function)
• adversely affects performance of the product or is otherwise likely cause a customer to return the product
• Minor defect (Not endanger)
• is usually an insignificant issue,often related to the product’s appearance, that doesn’t affect the item’s function or form
According to nature
•Ocular defect • visible
•Internal defect
• not seen although present
•Performance defect • function
PRODUCT RECALL
• RECALL – is the method of withdrawing or correcting unsafe or hazardous health products from the distribution chain that may present a health
hazard to the consumer or user.
• It is an action taken by establishments involved in the supply chain (e.g., manufacturers, distributors, or retailers) as
➢ Part of their responsibility to protect the public health and well-being
➢ Compliance to the appropriate good practices (eg.,good manufacturing, distribution,or storage practices),and
➢ Compliance to existing standards and regulations.
• Always check for FDAregarding product recall (drugs withdraw from market)
CLASSIFICATION OF PRODUCT RECALL
CLASS I RECALL(Resulted to death):
➢ a situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health
consequences or death.
CLASS II RECALL(Serious adverse effect – Blindness):
➢ a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where
the probability of serious adverse health consequences is remote.
CLASS III RECALL(Not very serious adverse effect):
➢ a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences
VARIATION
•Inevitable change in the output or result of a system (process) because all systems vary over time.
•Two major types of variations:
• Common, which is inherent in a system
• Special,which is caused by changes in the circumstances or environment
END OF UNIT 2
MATERIAL CONTROL AND MANUFACTURING CONTROL
UNIT 3
MATERIALS CONTROL
MATERIALS CONTROL
• Raw material
• Packaging material
• Each container of raw materials is examined visually for damage or contamination in transit, including breakage of seals when indicated.
• Receiving number - assigned to each batch received from the supplier. • A receiving number – distinct
• RTR (Receiving Tally Report) is completed upon receipt of material.
RECEIVING TALLY REPORT (RTR)
• A document used to record the amount and type of finished goods or raw materials when a shipment has been accepted
• Completed upon receipt of material
• The receiving tally report is checked by a QC inspector for accuracy.
• The materials receive a status of.
• The RTR should be distributed to all groups concerned: ✓ Quality control
✓ Warehouse ✓
Purchasing
✓ Accounting department
RTR Information includes:
• I. PRE-PRINTED DATA 1 Name of report
2 Name of drug/cosmetic company 3 Address
4 Receiving number
5 Name of the department receiving a copy
• II. INFORMATION TO BE SUPPLIED BY:
• AWAREHOUSE
1 Name of the material 2 Item code
number
3 Label claim
4 Purchase order number 5 Invoice number
6 Vendor (supplier/distributor)
7 Unit of measure
8 Number of containers received
• 1 Inspector’s report a Quantity of
sample b Comments, if any
c Name of inspector d Date
inspected
• 2 Analysis
a Analytical reference number b Name of
analyst
c Date of analysis
3 Disposition
• 9 Weight/volume/pieces contained in each container
a. Reason if Rejected
10 Date the report was prepared 11 Date the
shipment was received
12 Name of the warehouse personnel receiving the shipment
b. If approved (Re-assay date, Release Number)
• B QUALITY CONTROL
4. Name of the person responsible for receiving the report
• 5 Date of review
RAW MATERIALS
• Are the ingredients intended for use in the manufacture of drugs and cosmetics,including those that may not appear in the final product.
• The control of raw materials is set into different stages:
• Reception
• QC inspector will check the RTR.
• Each container is visually examined carefully for damages.
• Adequate number of samples are taken from representative containers.
• Quarantine
• The inspector checks the raw material container has a “hold” or quarantine sticker pasted by a warehouse personnel to indicate if the material is
subjected for acceptance or rejection.
• Samples are submitted to the laboratory for testing.
• The sample is subjected to tests such as: • physical and organoleptic examination
• identification tests • limits of impurities •
potency or assay
• microbiological test
• If the raw materials meet with monograph specifications it is “approved” for used. Otherwise,it is rejected.
• Decision stickers (approved or reject) are issued by the QC department.The decision sticker is placed on the top of the quarantine sticker.
• Materials will then be sending to either rejected or approved areas.
DECISION STICKERS
• If the test results indicate that the raw material meets monograph specifications, the material is approved for use; otherwise, it is rejected.
• Decision stickers are then issued by quality control.
1.No two stickers of different dispositions must be present on the same container.
2.The decision stickers are either placed on top of the quarantine sticker or the quarantine sticker is first removed before the decision sticker is
pasted.
3.At this stage,the raw material is transferred to either the rejected or approved materials area.
REJECTED – RED STICKER
•Held at a rejected materials area to prevent the possibility of use in any manufacturing or processing procedure
•Returned to the supplier
APPROVED – GREEN STICKER
• Approved materials are brought to the approved materials area.
• Approved materials are subject for re-assay
• Approved raw materials are audited to assure that they are rotated in such a manner that the oldest stock is used first.
• This is known as the FIFO (first in, first out) policy.
• A policy based on the materials’ shelf life is FEFO
RE-ASSAY DATE
• Periodic testing is done to revalidate the material.
• The date of retest ,given in terms of month and year, determined from the last assay date.
• The finished product can only be as good as the raw materials used in its manufacture.
○ monitoring of the quality of the raw materials during the storage.
• Based on the stability of raw materials, the re-assay dates assigned are:
• Monthly or prior to use – highly unstable materials • 6 months – vitamins, flavors
• 12 months – active ingredients, dyes • 24 months – excipients
PRINTED, PACKAGING AND LABELING CONTROL
Aspects considered in packaging
• the functions of packaging
• the selection of a packaging material • the testing of the material selected
• filling and assembling • sterilization
• labeling
• storage and stability
TYPES OF PACKAGING MATERIAL
• Primary packaging components – packaging materials which come in direct contact with the product itself.
• bottles, tubes,ampuls,vials,carpules,caps,stoppers,plungers, stripping materials jar,fillers,and seals.
• Secondary packaging components – packaging material which do not come in direct contact with the product and serve as accessory to the
primary packaging component
• labels,inserts,unit cartons,brochures,packer boxes and shippers.
PACKAGING CONTROL
• The auditing of packaging and labeling operation falls on the inspector. These operations are controlled for the following reasons:
• To assure that only those products that have met the standards and specifications established in the master formula records shall be
distributed to the market.
• To prevent mix-ups
• To assure correct labelling and labelling materials.
• To assure that the finished product is properly identified with appropriate control.
• Mix ups and errors are prevented by the following measures:
• Facilities are cleared out of package finished products and packaging materials
• Products which has a similar appearance,containers or labels are not processed simultaneously on adjacent or nearby lines
• Proper reconciliation is done after the packaging is completed
LABEL (FDA)
• Means any display of written, printed, or graphic matter on the immediate container of any article, or any such matter affixed to any consumer commodity
or affixed to or appearing upon a package containing any consumer commodity.
Labeling (FDA)
• Includes all written, printed, or graphic matter accompanying an article at any time while such article is in interstate commerce or held for sale after
shipment or delivery in interstate commerce.
• These are subjected to inspections by an experienced proofreader for
• graphical errors
• compliance with specifications as to type and grade of stock printing quality
• dimensional tolerance.
• Criteria for acceptance of printed materials: • Text
• Color • Size
• Thickness
• Grain direction • Sealability
• Cleanliness
• Surface finish
• Adequate paste • Shape
CONTAINERS
•Article which holds or is intended to contain and protect a drug and is or may be in direct contact with it
•Physical and chemical evaluation of containers like those made of glass, plastic, and metal have been extensive.
CLASSES
• Material –Glass,plastics,metal
• Plastics
• Polyethylene (LDPE and HDPE) for dry oral dosage forms
• Polyethylene terephthalate (PET, PETG) for oral liquid dosage form • Polypropylene (PP) – either for dry solid or oral liquids
• Polyvinyl Chloride – for blister packs
• Capacity – Single Unit,Multiple unit,Single dose,multiple dose • Ability to protect – well-closed,tight,herm
ACCORDING TO CAPACITY
• Single unit container- designed to hold a quantity of drug intended for single administration as a single dose or dose of the medication
• Multiple unit containers- contain more than a single unit or dose of the medication.
• Single dose container – in which the quantity of the sterile drug contained is intended as single dose and which cannot be resealed once opened.
• Multiple-dose container – a hermetic container which permits withdrawal of successive portions of the contents without changing the strength or
endangering the quality or purity of the remaining portions
ACCORDING TO PROTECTION
GLASS
• Chemical Resistance Test • Types I,II, III and NP
• Uses autoclave @121deg C, hardened steel mortar and pestle (crushing 6/more containers), titration set-up, 0.02 N H2SO4
• 5 drops Methyl Red Solution
◉ Powdered GlassTest – I,III and IV ◉ Water Attack Test - II
• Specifications: refer to Table 2, General Chapter - Container
GLASS TYPES AND TEST LIMITS
Light Transmission Test (Light Resistant)
• Transparent and opaque containers
• Uses Spectrophotometer (290 – 450nm) • Limits depend on type of containers
Containers Permeation
• Vapor Transmission
• 12 containers,2 as controls
• Filled with desiccant,glass beads • Weighed and stored under
• ○ 23 +/-2 °C and RH 75 +/-3% (35 g of NaCl in 100 ml of water) • Well closed orTight container based on % moisture permeation
• Test is run for 14 days
• Specifications: General Chapter – Container Permeation
MANUFACTURING CONTROL
PRODUCTION CONTROL
• is the activity of monitoring and controlling any particular production or operation
• is one of the key functions of operations management
Four important documents used in production control:
•Manufacturing monographs •Quality control monographs •Batch records
•Standard operating procedures
• MANUFACTURING MONOGRAPH
• master formula and batch production records are based
• QUALITY CONTROL MONOGRAPH
• Contains the quality of each component used in manufacturing and assuring that they had been tested and met the specifications
in accordance with the standards.
• STANDARD OPERATING PROCEDURES
• Are generated to explain in detail the reason behind a procedure and proper sequence of steps to be done,and how an equipment is operated.
• BATCH PRODUCTION RECORD
• An accurate reproduction of the master formula record.
• It permits the reconstruction of the history of the product,manufacturing procedures,production records,packaging records,raw material
record.
CONTROL TESTING
• required to assure product safety, identity, purity, quality and strength.
• Different control testing is conducted for the following: • solid preparation
• Liquid preparation
• semi-solid preparation
• lyophilized preparations • aerosols preparations
• Master Formula
• used as key in the production of the products. • it is kept in a secured documentation room
• Batch
• A specific amount produced in a unit time or according to a single manufacturing order during the same cycle of manufacture
• Lot
• A batch,a portion of a batch or a combination of batches
• Batch number
• Any distinctive combination of marking, letters, or numbers by which a history of the manufacture and control of a batch of product can be
determined
PROCESS CONTROL SYSTEMS
• Compliance,traceability, consistency, and reliability of measurement data are primary concerns for the pharmaceutical industry.
• The control system(s) in place need to verify the product quality through measuring, counting, inspection and testing of the manufacturing process
•Process control systems are being observed which encompass the six major systems in an industrial pharmacy which includes:
• Quality
• Production • Laboratory •
Materials
• Facilities &Equipment • Packaging & Labeling
PRODUCTION SYSTEM
• Includes measures and activities to control the manufacture of in-process materials and drug products including:
• batch compounding
• dosage form production
• in-process sampling and testing and • process validation
• establishing,following,and documenting
• performance of approved manufacturing procedures
PRODUCTION AND PROCESS CONTROLS SYSTEMS (PPC)
• Written procedures; deviations
• assure that the drug products have the identity,strength,quality,and purity they purport or represent to possess.
• Any deviation from the written procedures shall be recorded and justified
• Charge-in of components
• The batch shall be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient
• Components for drug product manufacturingshall be weighed,measured, or subdivided as appropriate.
• Calculation of yield
• Requires determination of actual yields and % theoretical yield
• Equipment identification
• Requires proper identification (ID) of all equipment at all times during production
• Requires identification and recording of a major equipment by a distinctive ID number or code in the batch production record
• Sampling and testing of in-process materials and drug products
• Requires establishing and following written procedures
• Requires establishing valid in-process specifications for such characteristics
• Requires testing of in-process materials for identity,strength, quality,and purity as appropriate
• Time limitations on production
• Requires establishing time limits for the completion of each phase of production when appropriate.
•Control of microbiological contamination •Reprocessing
• shall not be performed without the review and approval of the quality control unit
RAW MATERIAL QUALITY CONTROL (RMQC)
RMQC
• Identification Test
• Assay
• Limit Tests
• Physical Test
• Special Test
IDENTIFICATION TEST
ASSAY
•1. Chemical Assay
• Titrimetry – burette
• Instrumental Methods
•2. Biological Assay – uses intact animals, microorganisms or isolated living tissue cells.
• Animal Assays
• Microorganisms/Microbial Assays
BIOLOGICAL ASSAY – ANIMAL ASSAY
• Digoxin – pigeon
• Parathyroid hormone – Dog
• Insulin – rabbit
• Heparin – Sheep
• Tubocurarine – rabbit
• Protamine - Sheep
• Glucagon – cat
• Corticotropin inj.– rat
• Cod Liver Oil – rat
• Chorionic Gonadotropin – female rat
• Vasopressin – male rats
• Oxytocin – Chicken
BIOLOGICAL ASSAY – MICROBIAL ASSAY
• Methods:
• I. Cylinder Plate/Plate Assay – Based on diameter of the zone of inhibition.
• II.Turbidimetric Method/Tube Assay – based on measurement of turbidity/transmittance • Ex.
1.Antibiotics – Potency Pen.G – S.
aureus
Bacitracin – Micrococcus luteus Streptomycin –
Klebsiella pneumoniae Chloramphenicol – E.coli
Vancomycin – Bacillus subtilis 2.Vitamins
Niacin, Pantothenate – Lactobacillus plantarum Cyanocobalamin –
Lactobacillus leichmanii
LIMIT TEST
• Impurities
• Gross impurities – presence of insoluble matter/dirt
• Biological impurities – spoilage / presence of microorganism
• Chemical impurities:
• Ex.
• Heavy metals – H2S TS
Common Sulfides – Black
ZnS – white
Arsenic – Ag diethyl-dithiocarbamate (red color)
Chloride – AgNO3 (White ppt of AgCl)
MgS – Pink
Sulfates – BaCl2 (White ppt of BaSO4)
CdS- yellow
Iron – NH4SCN – (blood red of Fe)
SbS - Orange
PHYSICAL TEST
• Specific Gravity
• Refractive Index
• Optical Activity
• Solubility
• Melting point/Boiling Point
• Loss on Drying
• Water Content Determination
WATER CONTENT DETERMINATION
• Method I – Karl Fisher Titrimetry
• Method II – Azeotropic Distillation (USP) – Xylene Method (NF)
• Method III – Gravimetry – Recommended for natural products/crude drugs.
SPECIAL
• Example:
• Paracetamol/Acetaminophen
Test for p. chloroacetanilide
Test for p. aminophenol
• Quinine
Test for dihydroquinone sulfate
IN-PROCESS QUALITY CONTROL (IPQC)
IPQC
• In-process quality control (IPQC) tests are performed to determine if the product meets specifications throughout the entire processing period and
particularly during critical stages of manufacturing.
• The audit also fulfills the primary objective of the IPQC which is to monitor all features of a product
• A. IPQC for Powders and Granules
• B IPQC for Tablets
IPQC of POWDERS and GRANULES
• 1. Initial Moisture Content
• For those processed by wet granulation • underwet/overwet (to
avoid)
Methods:
• Gravimetry – initial amount – oven – weight • Ohaus Moisture
Balance Analyzer (OMBA)
• 2.Adequacy of wetness
• 3. Particle Size Distribution • Optical Microscopy
• Sieve Analysis
SIEVE ANALYSIS
• Limitations:
• A.NLT25g (large sample size is needed) • B.Not for Oily or
Cohesive Materials
• Equipment: Set of sieves with Varying sieves no. • Methods:
1. Mechanical Sieving/Agitation Dry Sieving
2.Air Entrainment Airjet sieving
Sonic Sifter Sieving
DENSITY
• A. Bulk Density – ratio of mass of an untapped sample. Its volume including the interparticulate void volume.
• Formula: 𝜌𝑏𝑢𝑙𝑘= 𝑚𝑎𝑠𝑠/(𝑢𝑛𝑡𝑎𝑝𝑝𝑒𝑑 𝑣𝑜𝑙𝑢𝑚𝑒)
• Methods:
I. Graduated cylinder method
II.Volumeter
III.Vessel
POWDER FLOW
• Methods:
• Angle of Repose – the constant, 3-dimensional angle w/c is relative to the horizontal base assumed by a cone-like pile of material.
• Apparatus:
• Fixed funnel • TiltingBox
• Revolving cylinder
• HAUSNER RATIO & CARR’S INDEX COMPRESSIBILITY INDEX • Measures of a powder’s ability to
settle.
• Method:
• 1.Graduated Cylinder (same with bulk & tapped density determination)
• C. Flow through orifice – measured as mass of a powder/substance per time flowing from any type of container. (funnel, cylinder, hopper)
• D. Shear cell method
IPQC FOR TABLETS
• 1.Tablet Hardness/Breaking force • Hardness Testers:
• Stoke’s Monsanto • Strong
cobb
• Pfizer
• Erweka
• Schleuniger
• 2.Tablet Thickness
• Apparatus: Vernier Caliper
• 3.Tablet Weight Variation/ Content Uniformity
END OF UNIT 3
STATISTICAL QUALITY CONTROL
UNIT 4
STATISTICAL PROCESS CONTROL (SPC)
• defined as the use of statistical techniques to control a process or production method.
• helps in monitoring the process behavior, discover issues in internal systems,and find solutions for production issues
Control charts attempt to distinguish between two types of process variation:
1. Common cause variation
• which is intrinsic to the process and will always be present
2. Special cause variation
• which stems from external sources and indicates that the process is out of statistical control
7 Quality Control (7-QC) Tools
• Dr.Kaoru Ishikawa - 1974
• Cause-and-effect diagram (also called Ishikawa diagram or fishbone diagram)
• Check sheet • Control chart •
Histogram
• Pareto chart
• Scatter diagram • Stratification
Supplemental (7-SUPP) Tools
• Data stratification • Defect maps
• Events logs
• Process flowcharts • Progress centres
• Randomization
• Sample size determination
INSPECTION
•formal organized evaluation process which compares a certain attributes, and dimensions of a product against the standards and specifications this in
turn evaluates these variables if they are within the prescribed limits or parameters.
•The following are the general process of inspection: • Interpretation of the specification
• measurement of the product
• Comparison of the product with specification • Judgment as to conformance
• Disposition of the product
• Recording of the data obtained
•Sampling
• is a process of securing a unit that will represent a bulk quantity of materials or population (total of actual items).
•Sample
• is a smaller,manageable version of a larger group.
• It is a subset containing the characteristics of a larger population.
SAMPLING PLAN
•is a detailed outline of which measurements will be taken at what times, on which material, in what manner, and by whom.
•working rule regarding size and frequency of sample and the basis for acceptance or rejection
The steps involved in developing a sampling plan are:
• Identify the parameters to be measured,the range of possible values, and the required resolution
• Design a sampling scheme that details how and when samples will be taken
• Select sample sizes
• Design data storage formats
• Assign roles and responsibilities
The basic symbols used in sampling plans are:
• (N) which represents the lot or batch from which the sample will be taken or withdrawn
• (n) represents the random sample size drawn from a lot or a batch.
• (c) represents the criteria value or acceptance number.
TYPES OF SAMPLIN PLAN
• Single sampling Plan
• type of sampling method in which the decision is obtained based after conducting a single sampling procedure
• The procedure is to take a random sample of size (n) and inspect each item. If the number of defects does not exceed a specified
acceptance number (c),the consumer accepts the entire lot.
• Double sampling Plan
• type of sampling method in which decisions can only be made after a second sampling procedure
• specifies two sample sizes and two acceptance numbers
• Sequential-Sampling Plan
• consumer randomly selects items from the lot and inspects them one by one
• Each time an item is inspected,a decision is made to (1) reject the lot (2) accept the lot,or (3) continue sampling,based on the cumulative results
•Square root sampling plan
•to determine the number of units to inspect. Each unit is tested individually.The lot on zero defectives is accepted, or,in the case of continuous
measurements, the lot is accepted if the average falls within given specifications.
•Military standard sampling plan
Validation
• process of establishing and securing documented evidence that will provide high degree of assurance that a certain specific procedure,process or
protocol will persistently produce an end product that meets the pre-determined specifications,standards and quality attributes
• Validation methods
– are made to ensure the accuracy, specificity,reproducibility and ruggednes comparable to given specified range that the example or analyte
will be analyzed
• Accuracy
• closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value,and the
value found
• Precision
• expresses the closeness of agreement (degree of scatter)
between a series of measurements obtained from multiple sampling of the homogeneous sample under the prescribed conditions.
•Specificity
• is the ability to assess unequivocally the target pathogen or analyte in the presence of components which might be expected to be
present
•Ruggedness
• is the reproducibility of the assay under a variety of normal,but variable,test conditions.
• different machines,operators,and reagent
•Robustness
• measure of the assay capacity to remain unaffected by small but deliberate changes in test conditions
•Limits of Quantitation
• lowest and highest concentrations of an analyte in a sample that can be quantitatively determined with suitable precision and accuracy
• Limit of Detection
• lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.
• Linearity
• ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample
• Range
• interval between the upper and lower concentration (amounts) of analyte in the sample for which it has been demonstrated
that the analytical procedure has a suitable level of precision, accuracy and linearity
• Repeatability
• expresses the precision under the same operating conditions over a short interval of time
• Reproducibility
• expresses the precision between laboratories
Process Validation
• Stage 1 Process Design:
• Lab,pilot,small scale and commercial scale studies to establish process
• Stage 2 Process Performance Qualification (PPQ): • Facility,utilities and equipment
• Performance Qualification
• Stage 3 Continued Process Verification (CPV):
• Monitor,collect information,assess during commercialization • Maintenance,continuous verification,process
improvement
• Requires Statistical Quality Control criteria for appropriate acceptance or rejection levels
Stage 1 Process Design:
• The goal of this stage is to design a process:
• Suitable for routine commercial manufacturing that can consistently deliver a product that meets its critical quality attributes
• Important to understand the degree to which models represent the commercial process
• Control of the process through operational limits and in-process monitoring is essential
Stage 2 Process Performance Qualification (PPQ)
• Two elements:
• Design of the facility and qualification of the equipment and utilities
• Process Performance Qualification confirming the commercial process design
– Products manufactured during this stage,if acceptable,can be released under certain situations.
Stage 3 Continued Process Verification (CPV)
•Goal: is to continually assure that the process remains in a state of control (the validated state) during commercial manufacture
•Calibration
• process of comparing the unknown with a reference standard and adjusting the instrument response as close to the values shown by
reference standards and reporting the results
•Verification
• is the comparison of results against specifications
END OF UNIT 4