Impact of European Legislation on Indian Industries

workkinkajouBiotechnology

Dec 5, 2012 (4 years and 6 months ago)

147 views

Nandkumar Chodankar (Ph D)

Sekhsaria Chemicals Ltd.

Mumbai, India



Impact of European Legislation

on

Indian API Manufacturers

9
th

APIC/CEFIC

European Conference on

Active Pharmaceutical Ingredients

10
th

October2006 (09.00
-
09.45)

10
th

Oct. 2006

Nandkumar Chodankar

2
/28

European Legislation Requirements

2
-
8

Evolution of Indian Pharmaceutical Industry

9

Historical Background

10
-
14

Journey

DMF
-
COS
-

CTD

14

Current Scenario

15

Impact of CTD format on document submission

16

Impact of ICH Q 7 Guidelines

17

Continuous Improvement

18
-
20

Impact of Customer audits on the API
Manufacturers

20

Impact of Increase in the audit frequency

22

Impact due to other factors

25

Summary

26

10
th

Oct. 2006

Nandkumar Chodankar

3
/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 17
th

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.

10
th

Oct. 2006

Nandkumar Chodankar

4
/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.

10
th

Oct. 2006

Nandkumar Chodankar

5
/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.


10
th

Oct. 2006

Nandkumar Chodankar

6
/28

Today’s Situation


From 17
th

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


GMP Requirement for API questions & Answers) http;//www.dkma.dk/1024/visUKLSArtikel.asp

10
th

Oct. 2006

Nandkumar Chodankar

7
/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 / un
-
packaging, mixing the APIs


The company in charge of labeling or relabeling
or providing supplementary labels for API.


10
th

Oct. 2006

Nandkumar Chodankar

8
/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.

Evolution of Indian Pharmaceutical Industry

10
th

Oct. 2006

Nandkumar Chodankar

10
/28

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

10
th

Oct. 2006

Nandkumar Chodankar

11
/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

10
th

Oct. 2006

Nandkumar Chodankar

12
/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

10
th

Oct. 2006

Nandkumar Chodankar

13
/28

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.

Indian Historical Background

10
th

Oct. 2006

Nandkumar Chodankar

14
/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.


10
th

Oct. 2006

Nandkumar Chodankar

15
/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

10
th

Oct. 2006

Nandkumar Chodankar

16
/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.


10
th

Oct. 2006

Nandkumar Chodankar

17
/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.

10
th

Oct. 2006

Nandkumar Chodankar

18
/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?)

10
th

Oct. 2006

Nandkumar Chodankar

19
/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


10
th

Oct. 2006

Nandkumar Chodankar

20
/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)

10
th

Oct. 2006

Nandkumar Chodankar

21
/28

Impact of Increase in the audit frequency

Positive Impact


Other side of the impact

Audits have increased the
awareness of GMP
requirement among the
staffs (Training)

Though this is good way of
training, is not recorded as
training in the training
documentation

Observation, lead to
discussions & debates
during and after audits for
finding solutions. This is
Good as a training aid.

These kind of discussions
lead to confusion and the end
result is sometime negative
Need to Edit the Observation

Preparation of audit
minutes for management
awareness, Review of the
audit reports.

Increase in the time required
for these activities, the paper
work and documentation (to
prepare suitable answers) etc.

10
th

Oct. 2006

Nandkumar Chodankar

22
/28

Impact of Increase in the audit frequency

Positive Impact

Other side of the impact

Preparation of the answers
and implementing
corrective measures for
every audit. (Continuous
improvement)

Time required for review
and approval of corrective
action from the higher
management has increased.

Changes suggested in
SOPs during audits to
meet ICH guidelines

Sometimes such changes are
not practical and may not be
possible to implement.

Overall commitment for
corrective measures

(Continuous Compliance
preparedness)

May not be possible to
implement as planned due to
circumstances and thus
creates a bad impression in
the mind of the staff

10
th

Oct. 2006

Nandkumar Chodankar

23
/28

Impact of Increase in the audit frequency

Positive Impact


Other side of the 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 )

This delay indirectly
reduces the importance of
the auditors concern. The
audit observation should be
made available immediately
to have greater effect.

10
th

Oct. 2006

Nandkumar Chodankar

25
/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.

10
th

Oct. 2006

Nandkumar Chodankar

26
/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.


10
th

Oct. 2006

Nandkumar Chodankar

27
/28


I will like to thank the following individuals
for making this presentation possible;


Laurie Cook


Lalit Sharma

10
th

Oct. 2006

Nandkumar Chodankar

28
/28




To Vacuum

Impact of European Legislation on Indian API manufacturers

S

E

K

H

S

A

R

I

A

Pump

Receiver

Multi

Mill

To Recovery

Crystallization Reactor

Blender

Sifter

Mother Liquor

Tank

S

E

K

H

S

A

R

I

A

S

E

K

H

S

A

R

I

A

U

T

I

L

I

T

Y

U

T

I

L

I

T

Y

U

T

I

L

I

T

Y

Multi

Mill

Blender

Mill

Dryer

Packaging

Sifter

Dissolution

Reactor