Regulatory Legislation and Guidelines

for Recombinant Drugs,

Pharmaceuticals and Biologicals

K.K. Tripathi*
Department of Biotechnology (Ministry of Science
and Technology),
Government of India, New Delhi

*The views expressed in the presentation are those of the individual and thy have nothing to do with the organization with which
he is associated

m
 Biotech Industry and rDNA Research
Indian Companies in modern biotechnology
¦ver 900 companies operating in all sectors of
biotechnologyu
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Indian Institutions in modern Biotech Research

¦ver 90 Institutions engaged in rDNA Research
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 A TYPICAL CASE OF STAKEHOLDERDS· INTERACTION
SHAPING THE FUTURE OF TRANSGENICS

[Central government 0 3ant to enforce EP Act through

sate governments as per biosafety guidelines
[Politicians 0 3ant protection of public interests and
safety of environment 3ith punishment to guilty as per La3
[Public general ‰ seeks information and are more concerned
for future 3ith benefits and risks of rDNA products
[Scientists 0 3ant to set an example by providing more
products 3ith modern biotech research
[©edia ‰ 3ant report regularly and vie3s of all 3ithout
3rong interpretations
[Ihdustry 0 request to protect their investment and
enforce la3 at the same time
Consensus is building on to protect public interest, punish
guilty and ensure maximum safety to environment 3ith no

(relatively lo3 risk !!!
The public should be vie3ed as a
´partnerµ and a level of trust needs
to be created. Developing this style
3ill be a major challenge for business
leaders as 3ell as university/industry
scientists and government regulators.
The Public perception is most important in the
success/failure of rDNA product and safety
aspects to environment/humans/animals etc.

^
 ühy Regulations are Necessary for Using G©Os and
Products Thereof?
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IGN¦RENCE ¦ LAW IS N¦T EXECUSED

Œ
GENETICALLY ©ODIFIED ORGANIS©S (G©Os) AND
r-DNA PRODUCTS GOVERNED BY
†Environment (Protection) Act, 1986;
- Rules, 1989 of EPA
†Industries (Development & Regulation) Act, 1951
- New Industrial Policy & Procedures, 1991
- EXIM Policy
†Drugs & Cosmetics Act, 1940
- Rules 1945
†Pharmaceutical Policy 2002

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Indian EPA implementation structure for G©Os
(1989 RULES)
In order to contain possible hazards to
environment from the release of GM¦s, the
Ministry of Environment and orests has
notified in December 1989, the ³Rules for the
manufacture, use, import, export and storage of
hazardous Micro-organisms/ Genetically
Engineered ¦rganisms or Cells´ under the
Environment (Protection) Act (EPA)1986.

´
 APPLICATIONS OF 1989 RULES
Manufacture, import and storage of microorganisms
and gene technological products

Genetically engineered organisms/ microorganisms

and cells and correspondingly to any substance and
products and food stuffs, etc., of which such cells,
organisms or tissues form part

New gene technologies in addition to cell

hybridization and genetic engineering

½
 STATUTORY BODIES
1. The Recombinant DNA Advisory Committee (RDAC):
2. Institutional Biosafety Committee (IBSC)
3. Review Committee on Genetic Manipulation (RCGM)
4. Genetic Engineering Approval Committee (GEAC)
5. State Biotechnology Coordination Committee (SBCC)
6. District Level Committee (DLC)

m
INSTITUTIONAL BIOSAFETY CO©©ITTEE (IBSC)
Constituted by an occupier or any person including
R&D institutions handling GM¦s

Comprises Head of Institution, scientist doing rDNA

work, medical expert and DBT nominee

Assists the occupier or any person including R&D

institution prepare an emergency plan as per
guidelines of RCGM

Copies of emergency plan to be made available to

District Level Committee/State Biotechnology
Coordination Committee and the Genetic Engineering
Approval Committee (GEAC)
mm
 REVIEü CO©©ITTEE ON GENETIC
©ANIPULATION (RCG©)
RCGM is functioning in the Department of
Biotechnology. Its functions are:
To review the reports in all approved/ongoing projects
involving high risk category and controlled field
experiments research in four areas namely human and
animal healthcare, agriculture, industry and
environmental management6
To visit site of experimental facilities periodically
where projects with biohazard potential are being
pursued and also at a time prior to the commencement
of the activity to ensure that adequate safety measures
are taken as per the guidelines.
To issue clearance for import/export of etiologic
agents and vectors, germplasms, organelle, etc.
needed for experimental work/training and research. m
 GENETIC ENGINEERING APPROVAL
CO©©ITTEE (GEAC)
The GEAC is functioning under the Ministry of
Environment and orests to examine and issue the
clearance from the view point of environmental
safety on a case by case basis for:

Activities involving large scale use of hazardous

micro-organisms and recombinants in research and
industrial production from environmental angle.

Proposals relating to the release of genetically

engineered organisms and products into the
environment including experimental field trials6

m
 IN ORDER TO EVALUATE PROPOSALS, DBT HAS
ISSUED FOLLOüING GUIDELINES:
Recombinant DNA Safety Guidelines, 1990
Recombinant DNA Safety Guidelines and
Regulations, 1994
Revised Guidelines for Safety in
Biotechnology, 1994
Revised Guidelines for Research in
Transgenic Plants, 1998
Guidelines for generating pre-clinical and
clinical data for rDNA vaccines, diagnostics
and other Biologicals, 1999.
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The applicant is to follow the provisions of the
Drugs Act for commercial release of the product.
This shall include inspection of the production
facilities, according temporary license to produce
trials batches, sending products from 5 trial
batches to CRI, Kasauli or CDL, Kolkata, receiving
the test report by DCG (I) and finally granting
approval to manufacture and marketing the
product.
Both DCG (I) and GEAC can impose conditions of
surveillance on the product during marketing.
Marketing under EPA can be for a period of two to
four years initially and this can be renewed on the
basis of an application. Post-market surveillance
data may be required to be generated and
submitted to DCG (I) and GEAC by the applicantsmŒ
   

 


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 SUGGESTED ©©ODIFICATION IN THE STEPS
Proposal
Institutional Biosafety Committee with DBT Nominee
RCGM¶s approvals
Based on the pre-clinical data, RCGM conveys its
recommendations to the applicant (copy to the DCG (I)
for further n.a. and to GEAC for information)
RDAC/DCG(I) approves the protocol and recommends
for conducting human clinical trials; DCG(I) Examines
the Human Clinical Trials data and Recommends to
GEAC directly
GEAC approval for Environmental/Commercial
Release m´
   (
Inter-©inisterial Committee setup by

The ©inistry of Environment & Forests

Ne3 Delhi
Report on Recombinant Pharma Sector

(Discussed on January 23, 2005)

m½
 Recommendations of the Task Force on r-Pharma

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 The step-3ise regulatory procedures /protocols
for five categories
Protocol-I:Indigenous product development, manufacture and
marketing of pharmaceutical products derived from L©Os but
the end product is not a L©O.
Protocol-II:Indigenous product development, manufacture and
marketing pharmaceutical products 3here the end product is a
L©O.
Protocol-III:Import and marketing of L©Os as
Drugs/Pharmaceuticals in finished formulations 3here end-
product is a L©O.
Protocol-IV:Import and marketing of L©Os as Drugs/Pharmaceuticals
in bulk for making finished formulation 3here end product is a
L©O.
Protocol-V:Import and marketing of products derived from L©Os as
Drugs/Pharmaceuticals and bought in bulk and/or finished
formulations 3here end product is not a L©O.

m
Protocol ± I Indigenous product development derived from L©OS but end product
not a L©O.
Risk Group III and above Risk Group I & II
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LMOs but end product is not a LMO.
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 Protocol ± II Indigenous Product development 3here end Product is a
L©O

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IBSC

RCGM
(approves pre- clinical trials)

Pre-clinical trials conducted

RCGM
(evaluates toxicity and allergenicity data and
Containment facilities and recommends CT)

DCGI GEAC
(approves Human CT and protocols) (recommends Human $

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 A
Protocol ² II Contd.

HUMAN
CT conducted

GEAC
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(examines
approves Market
environmental risk
Authorization under
versus benefits and
Drugs & Cosmetics
accords approval for
Rules based on clinical
environmental release
trials data)
under Rule 1989)

DCGI
(Post Release Monitoring)

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 Protocol ² III Import and marketing of L©Os as drugs in finished
formulations
Applicant

GEAC
(examines data generated in the Country of origin and other countries where
the product has been tested and accords µIn Principle¶ approval for import
and conduct of clinical trials. GEAC recommends to DCGI)

DCGI
(approves Human CT and protocols)

HUMAN
CT conducted

DCGI GEAC
(approves Market Authorization under Drugs & (examines environmental risk
Cosmetics Rules based on clinical trials data) versus benefits and accords
approval for environmental release
under Rule 1989).
DCGI
(Post Release Monitoring) Œ
 Protocol ± IV Import of LM¦s as drugs in bulk for making
finished formulations.
Applicant

GEAC
(examines data generated in the Country of origin and other countries where the
product has been tested and accords ³in principal´ approval for limited import for
conduct of clinical trials, GEAC informs DCGI and directs the applicant to setup
IBSC)

IBSC

RCGM
(approves activity, recommends to DCGI for clinical
trials and forward views to GEAC on containment
facilities)

DCGI GEAC
(approves Human CT and protocols) (recommends Human CT)

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 Protocol ² IV Contd.

HUMAN
CT conducted
DCGI
(approves Market Authorization under GEAC
Drugs & Cosmetics Rules based on clinical (examines environmental risk
trials data) versus benefits and accords
approval for environmental
release under Rule 1989)
DCGI
(Post Release Monitoring$

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Protocol ² V Import and marketing of products derived from
LMOs as Drugs and bought in bulk and/or finished formulations.
Applicant

DCGI
(Examination of complete dossier including human clinical
trials protocols and trials if conducted and to accord
approval for Human CT and protocols after obtaining the
comments of RCGM)

HUMAN
CT conducted

DCGI
(approves Market Authorization under Drugs &
Cosmetics Rules based on clinical trials data)

DCGI
(Post Release Monitoring$

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Protocol ² V Import and marketing of products derived from LMOs
as Drugs and bought in bulk and/or finished formulations.

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*GEAC approval procedure will be compliant with the

µGood Practices in Environmental Regulation adopted
by MoE .

m
 Other Recommendations
Y The products emanating from mono-clonals derived
from rDNA technology in the form of therapeutic
proteins/drugs would attract the provisions of Rule
1989 of EPA, and can be treated under Protocol I as
Risk Category I & II.

Y If there is a change in the host organism or expression

construct, fresh permission will be required to be
sought from RCGM for the change by providing
adequate data on bio-equivalence. If the data is found
to be inadequate then RCGM may prescribe limited
pre-clinical and/or clinical studies to be conducted to
establish bio-equivalence. This would also be
applicable to finished imported products intended for
marketing.


 Other Recommendations (contd)---

Y No imported recombinant pharma product should be allowed to

be introduced in the Indian market without adequate evaluation of
clinical trial data or clinical evaluation in the Country. The Task
orce recommends that the efficacy and safety of the imported
product should be evaluated for its efficacy on the Indian
population before issue of market authorization.

Y or import of GM¦ / LM¦ for research/contract manufacturing or

similar service, where the product (which is not an LM¦) is to be
exported out of India, a procedure should be laid down so that the
companies can explore opportunities for this business while the
safety aspect is also adequately addressed. A suggested
procedure is: IBSC to examine proposal and recommend to
RCGM; RCGM to approve if within Risk Group I and II. If
organism is of Risk Group III or above, GEAC permission will be
required. DCG(I) need not play any role.


 Other Recommendations (contd)---
Y Enzymes /industrial products from GM¦s would attract the
provisions of Rule 1989 of EPA. In such cases, RCGM may be
authorized to approve such proposals under intimation to GEAC.

Y The expertise in the various regulatory agencies under Rules 1989 of

EPA should be further strengthened.

Y There is a need for creation of an independent inspection facility to

audit the manufacturing and containment facilities set up by the
applicants involved in the production of recombinant drugs. This
would also ensure acceptability of the Indian r-DNA pharmaceutical
products in the global market. Since there is no single agency with
adequate field level support system to carry out an independent
inspection, the Task orce recommends that the Government may set
up a separate agency for this purpose.

Y ¦n the issue of seeking approvals of PPA/DCGI/GEAC under Rules

1989 of EPA and PQ¦ by Customs Authorities on the imports of
microorganisms, GM¦s/ LM¦s for R&D purpose it is suggested that
the earlier practice of permitting the import with the approval of
RCGM should continue and PPA/DCGI to issue instructions to
Custom Authorities to clear the consignment based on RCGM ^
approval.
Inter-ministerial Standing Committee on Biotechnology
Regulation
Constitution of a standing inter-ministerial committee to redress and look into
various regulatory aspects and make issue-based recommendations on
case-by-case basis. Prior to any deviation from the proposed regulatory
mechanism, which when comes in vogue, the views of this inter-ministerial
committee should be obtained in the first instance.
The suggested composition of the committee is as follows:
Chairman -To be an Eminent Scientist
Chairman, GEAC -Member
Chairman, RCGM -Member
Member-Secretary, GEAC -Member
Member-Secretary, RCGM -Member
Joint Secretary (Seeds), MoA -Member
DDG, ICAR (Crop Sciences) -Member
Joint Secretary (MoE ) -Member
Joint Secretary ( ood Processing) -Member
Adviser (Industry, DBT) -Member
DG/Representative (ICMR) -Member
DCG(I) -Member
Experts on Immunobiologicals, Biogenerics, Plant Breeding, Molecular Biology,
£
Environmental Sciences and other relevant areas may be co-opted from time to time.
National Biotechnology Regulatory Authority/
Commission
UAlternate models of a µNational Biotechnology Regulatory
Authority¶

UAmendment of EPA and harmonization Seeds Act/ Drugs &

Cosmetics Rules/ P A Act may be necessary to obviate the
approvals required under these statues.

UHarmonization is an essential prerequisite for establishing

the national biotechnology regulatory authority.

URecommended an inter-ministerial group to examine the

model proposed and make specific proposals with respect
to the implementation including the budgetary
requirements.
Œ
 Capacity Building and its Relevance
Capacity building needs are considered to be the
key milestones to be successfully crossed by the
developing regions including at least some
developing countries in the region to enable the
confidence building exercise. In other words
there should be societal acceptance of the
technologies of living modified organisms
(LM¦s) and in this context capacity building
needs become most relevant aspect in the safe
use of LM¦s

è
Institution Building
Risk assessment capacities
Involvement of stakeholders
Development and strengthening of legal and
regulatory structures
Capacity Building Efforts- Indian expertise and
experience that can be shared in the region
Skills in biotechnology process and applications
Human resources strengthening and development

´
Thank You

½