9th APIC/CEFIC
European Conference on
Active Pharmaceutical Ingredients
Impact of European Legislation
on
Indian API Manufacturers
10th October2006 (09.00-09.45)
Nandkumar Chodankar (Ph D)
Sekhsaria Chemicals Ltd.
Mumbai, India
European Legislation Requirements
Evolution of Indian Pharmaceutical Industry
Historical Background
Journey –DMF-COS- CTD
Current Scenario
Impact of CTD format on document submission
Impact of ICH Q 7 Guidelines
Continuous Improvement
Impact of Customer audits on the API
Manufacturers
Impact of Increase in the audit frequency
Impact due to other factors
Summary
10th
Oct. 2006
Nandkumar Chodankar
2-8
9
10-14
14
15
16
17
18-20
20
22
25
26
2/28
European New Legislation
• The pharmaceutical manufacturer is responsible for
ensuring that the APIs have been manufactured in
accordance with the EU Guidelines to Good
Manufacturing Practice for Active Substances, Volume
4, Part II.
• After 17th December 2005, pharmaceutical
manufacturer’s QP certifies by his or her signature to
the register for release of medicinal products that also
the API has been manufactured in accordance with
GMP
• This means that after that date the signature of the QP
implies a greater responsibility. No separate signature
is required in the register to certify that APIs have
been manufactured in accordance with GMP.
10th Oct. 2006
Nandkumar Chodankar
3/28
Document to substantiate that APIs have been
manufactured in accordance to GMP
• The pharmaceutical manufacturer must have
evidence of appropriate audit being performed
on all its API manufacturers (in respect of
manufacturing, packaging, repackaging,
mixing, labeling, re-labeling, and
supplementary labeling). Audit reports will
become an issue for future inspections at the
premises of pharmaceutical manufacturers.
10th Oct. 2006
Nandkumar Chodankar
4/28
Are third party inspection reports acceptable?
• Most of the EU accepts third party inspections
reports with following conditions, that:
• The auditor is a QP
• The auditor is independent of the company to be audited.
• The auditor is acquainted with the rules of the governing
medicinal products in the European Union, Volume 4,
Part II
• The audit report has been reviewed by the
pharmaceutical manufacturer
• The audit report is adequate .
• Third party audit report must be in detail not just a
summary.
10th Oct. 2006
Nandkumar Chodankar
5/28
Today’s Situation
• From 17th December 2005 onwards the medicinal
products of an API manufacturer who is not
audited are quarantined on inspection until the
API manufacturer has been audited.
• Exception to the rule is there are some medicinal
products that are not comprised by the rules on APIs.
• Medicinal products dispensed by a special
compassionate-use- permit in EU (Denmark)
• Medicinal products prepared in accordance with a
magisterial formula
• Medicinal products for clinical studies for which a
marketing authorization has not been granted
10th
GMP Requirement for API questions & Answers) http;//www.dkma.dk/1024/visUKLSArtikel.asp
Oct. 2006
Nandkumar Chodankar
6/28
Definition of API Manufacturer
• An API manufacturer is defined in Executive
Order No. 1242 of 12 December 2005, which
briefly states that the API manufacturer is:
• The manufacturer of API
• The company in charge of packaging the APIs
• The company in charge of repackaging / unpackaging, mixing the APIs
• The company in charge of labeling or relabeling
or providing supplementary labels for API.
10th Oct. 2006
Nandkumar Chodankar
7/28
Are Regular Inspections in the offing?
• As a general rule, API manufacturers will not be
inspected at regular intervals unless the
manufacture concerned requires an authorization
pursuant to EU Medicinal Act
• API manufacturer who wish to receive GMP
certificate must request an authority inspection.
10th Oct. 2006
Nandkumar Chodankar
8/28
Evolution of Indian Pharmaceutical Industry
Indian Pharma Industry: Historical Background
1950-60 Small Indian Pharmaceutical Industry
Drug product Importation, Repackaging &
Distribution
1960-70 Multinational Companies (MNCs) started
manufacturing drug product with prevailing
GMP with limited API manufacturing (last step)
1970-80 Government of India took initiative to put up
API manufacturing facility for potent antibiotics
& other drugs, vitamins etc.
Indian entrepreneurs were encouraged to start
API & drug product manufacturing to meet the
domestic demand & to save foreign exchange
10th Oct. 2006
Nandkumar Chodankar
10/28
Indian Pharma Industry: Historical Background
1980-1990
The Indian Industry dominated.
Took part in Trade Exhibitions.
Exports of APIs to Hamburg and Italy and Drug
products to non-regulated countries (neutral pack)
European and American Generic Manufacturers
started taking interest
DMF for API submission to various Authorities
Inspections from Health Authorities started
MNC’s market share reversed (70:30 to 30:70)
Many more Small & Medium scale Drug Product
manufacturing industry started
10th Oct. 2006
Nandkumar Chodankar
11/28
Indian Pharma Industry: Historical Background
1990-2000
Started Research & Development & entered into
Biotechnology field.
Inspections from US FDA, MHRA, EDQM & other
Regulators increased many folds.
Latest drug products become easily available at
substantially low prices
Inspections of Formulation plants from MHRA, US
FDA, IMBA, WHO and other Authorities opened the
door for the Global Pharma Market
Continuous Improvement in the application of GMP
and Quality Management
10th Oct. 2006
Nandkumar Chodankar
12/28
Indian Historical Background
Approximately 11,000 registered units, engaged in the
manufacture of drug substances and drug products.
Among these around 300 are Large scale
More than 300 units have approval from International
Agencies
All units licensed for export (300) are inspected by
domestic Regulatory (Central & State) team, for
WHO certification
150- have received Approvals from: MHRA, TGA, etc.
65 are US FDA Inspected & accepted.
10th Oct. 2006
Nandkumar Chodankar
13/28
Journey: DMF to EDMF- COS –CTD Formats
UK companies took the lead and their Quality
Assurance personnel started investing their time
in Indian companies.
Grabbing of opportunity: Indians were quick to
learn and grab the opportunity.
Introduction of COS and its declaration that the
APIs are manufactured under GMP,
Introduction of ICH Guidelines and their
implementation:.
The CTD format for DMF submission.
10th Oct. 2006
Nandkumar Chodankar
14/28
Current scenario: DMFs, COSs, Dossiers and
ANDAs
DMF Filing by Indians: Largest number of
DMFs & COSs from Indian Companies
About 132 ANDA in Partnerships have been
submitted with US Generic companies.
Similarly Dossiers have been submitted
A few have signed partnerships.
The acquisitions of pharmaceutical industries
by Indians and vice versa.
Indian Generic Products available at Indian cost
with
International standard for all Regulated Markets
10th Oct. 2006
Nandkumar Chodankar
15/28
The impact of CTD Formats for Document submission
• The new legislation such as improved
documentation/CTD is a positive move for all
involved as it is moving to one common
standard of documents and ultimately
material and pharmacopoeia standards
which has a very positive impact on the
ability of companies to produce good
documentation and quality product. Indians
have taken a lead in this field.
10th Oct. 2006
Nandkumar Chodankar
16/28
The Impact: ICH Q 7 requirements for GMP
Manufacturing
 Implementation of ICH Q7 A guideline for
manufacturing API and Intermediates.
 Training of the staff to understand and to follow the
requirements of the ICH guidelines
 Realigning of the facilities to meet GMP &
environmental requirements
 Separation of the Final API purification step from
the other synthetic steps, and manufacture it with
precisely as per the ICH Q7 Requirements
 Product isolation at each stage of manufacturing in a
controlled environment.
 Critical unit operations like Drying, Milling,
Packaging, Labeling, etc., in controlled environment.
10th Oct. 2006
Nandkumar Chodankar
17/28
Continuous Improvement (At What Cost?)
Quality Management
Personnel selection and their education, apparels, etc.
Equipment design, finishes
Documentation & Records
Material Management & Sampling
Production & Process control, Contamination control,
Blending to make large batch size & blending of
Tailings
Laboratory Control
Stability monitoring & Storage conditions
Expiry and Retest Period (Reprocessed Material?)
10th Oct. 2006
Nandkumar Chodankar
18/28
Continuous Improvement (At What Cost?)
Qualification (URS, DQ, IQ, OQ, PQ)
Calibrations
Validations
 Process Validation (Prospective, retrospective,
concurrent)
 Analytical method validation,
 Cleaning process and analytical method validations
OOS, OOT,
Change Control,
Annual reports,
Reprocessing, Recovery, Reworking
Returns and Complaint handling, etc.
Agents, brokers, traders, distributors, re-packers & re-labelers
10th Oct. 2006
Nandkumar Chodankar
19/28
Impact of Increase in the audit frequency
Positive Impact
Other side of the impact
Number of
Audit
frequency has
increased
The overall cost and time required has
increased.
Requirement of the number of QA &
other staff personnel has increased
Time spent from personnel with the
auditors to explain the systems,
processes, from individual department
has increased, at the cost of routine work
Different auditors have different views
and interpretation of the ICH guidelines
leading to confusion (Comparison)
10th Oct. 2006
Nandkumar Chodankar
20/28
Impact of Increase in the audit frequency
Positive Impact
Audits have increased the
awareness of GMP
requirement among the
staffs (Training)
Observation, lead to
discussions & debates
during and after audits for
finding solutions. This is
Good as a training aid.
Preparation of audit
minutes for management
awareness, Review of the
audit reports.
10th Oct. 2006
Other side of the impact
Though this is good way of
training, is not recorded as
training in the training
documentation
These kind of discussions
lead to confusion and the end
result is sometime negative
Need to Edit the Observation
Increase in the time required
for these activities, the paper
work and documentation (to
prepare suitable answers) etc.
Nandkumar Chodankar
21/28
Impact of Increase in the audit frequency
Positive Impact
Preparation of the answers
and implementing
corrective measures for
every audit. (Continuous
improvement)
Changes suggested in
SOPs during audits to
meet ICH guidelines
Overall commitment for
corrective measures
(Continuous Compliance
preparedness)
10th Oct. 2006
Other side of the impact
Time required for review
and approval of corrective
action from the higher
management has increased.
Sometimes such changes are
not practical and may not be
possible to implement.
May not be possible to
implement as planned due to
circumstances and thus
creates a bad impression in
the mind of the staff
Nandkumar Chodankar
22/28
Impact of Increase in the audit frequency
Positive Impact
Audit reports are received
after long time, sometimes
after two months. (Auditors
have too many Audits to
conduct and prepare
reports, sometimes may
miss vital details or context
provided )
10th Oct. 2006
Other side of the impact
This delay indirectly
reduces the importance of
the auditors concern. The
audit observation should be
made available immediately
to have greater effect.
Nandkumar Chodankar
23/28
Impact due to other factors
• Overall documentation / Expectation and
Paper work has increased.
• Analytical work has increased, especially
Validation of every method that is used.
• QC, QA, Documentation staff has increased
almost by two folds
• Customer request for impurity reference
standards has increased.
10th Oct. 2006
Nandkumar Chodankar
25/28
Summary
• European Legislation is showing a positive effect on the
Indian API manufacturers with long term benefits to the end
customer
• Among 11,000 Registered units (India), only 300 are large and
medium scale Manufacturing units and have almost 70%
market share
• EDQM and US FDA inspections have brought in a change in
the “Mind Set”
• European customers have started Auditing the API
Manufacturing Plants, which is leading to up-gradation of the
facilities, documentation and Quality Assurance Systems
• Domestic CGPM Guidelines “Schedule M” (almost equivalent
to ICH Q7A) are being enforced on all manufacturing plants.
• To meet CGMP New API Manufacturing plants are being
installed using ISPE & ICH Guidelines.
10th Oct. 2006
Nandkumar Chodankar
26/28
• I will like to thank the following individuals
for making this presentation possible;
• Laurie Cook
• Lalit Sharma
10th Oct. 2006
Nandkumar Chodankar
27/28
Impact of European Legislation on Indian API manufacturers
To Vacuum
Crystallization Reactor
U
T
I
L
I
T
Y
Dissolution
Reactor
To Recovery
U
T
I
L
I
T
Y
Sifter
Sifter
U
T
I
L
I
T
Y
Multi
Mill
Blender
S
E
S
K
E
H
K
S
H
A
S
R
A
S
I
R
E
A
I
K
A
H
Receiver
Pump
Dryer
S
A
R
I
A
Mill
Packaging
Mother Liquor
Tank
10th Oct. 2006
Nandkumar Chodankar
28/28