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
1
Biotech Industry and rDNA Research
Indian Companies in modern biotechnology
Over 900 companies operating in all sectors
biotechnology,
of
 Biopharmaceuticals- >49
 Transgenic Crops/Seeds- >60
 Industrial Products- 15 (Probiotics, Enzymes)
Indian Institutions in modern Biotech Research
Over 90 Institutions engaged in rDNA Research
 Public Funded Institutions- >57
 Private Institutions (Teaching & Research)- >37
 Universities- >115
2
Total number of organisations involved in rDNA Research- 256
A TYPICAL CASE OF STAKEHOLDERDS’ INTERACTION
SHAPING THE FUTURE OF TRANSGENICS
Central government - want to enforce EP Act through
sate governments as per biosafety guidelines
Politicians - want protection of public interests and
safety of environment with punishment to guilty as per Law
Public general – seeks information and are more concerned
for future with benefits and risks of rDNA products
Scientists - want to set an example by providing more
products with modern biotech research
Media – want report regularly and views of all without
wrong interpretations
Ihdustry - request to protect their investment and
enforce law at the same time
Consensus is building on to protect public interest, punish
guilty and ensure maximum safety to environment with no
3
(relatively low) risk !!!
The public should be viewed as a
“partner” and a level of trust needs
to be created. Developing this style
will be a major challenge for business
leaders as well 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.
4
Why Regulations are Necessary for Using GMOs and
Products Thereof?
GMOs and and their products are to play important role
including human and animal health care system, agriculture,
industrial products, environment management
Concurrently, there could be unintended hazards and risks
from the use of GMOs and products thereof, if the new
technology was not properly assessed before use
A GMO can be safe but this can be unsafe too depending
upon the trans-genes, the host organism and the environment
where the GMO is being tested
GMOs can be microorganisms, plants, and animals
5
6
GENETICALLY MODIFIED ORGANISMS (GMOs) 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
7
Indian EPA implementation structure for GMOs
(1989 RULES)
In order to contain possible hazards to
environment from the release of GMOs, the
Ministry of Environment and Forests has
notified in December 1989, the “Rules for the
manufacture, use, import, export and storage of
hazardous Micro-organisms/ Genetically
Engineered Organisms or Cells” under the
Environment (Protection) Act (EPA)1986.
8
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
hybridization and genetic engineering
to
cell
9
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)
10
INSTITUTIONAL BIOSAFETY COMMITTEE (IBSC)
Constituted by an occupier or any person including
R&D institutions handling GMOs
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)
11
REVIEW COMMITTEE ON GENETIC
MANIPULATION (RCGM)
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 management.
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. 12
GENETIC ENGINEERING APPROVAL
COMMITTEE (GEAC)
The GEAC is functioning under the Ministry of
Environment and Forests 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 trials.
13
IN ORDER TO EVALUATE PROPOSALS, DBT HAS
ISSUED FOLLOWING 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.
Revision of Guidelines is a continuous process
14
General approval procedures for recombinant products
Proposal
Institutional Biosafety Committee with DBT Nominee
RCGM’s approvals
Based on the pre-clinical trial data, RCGM conveys its
recommendations to the applicant and copy to the DCG(I) and to
GEAC
RDAC approves the protocol and recommends for conducting
human clinical trials
IBSC examines the human clinical trial data and sends it for
RCGM and DCG (I) for Recommendation to GEAC for
environmental release
GEAC approval for Environmental Release
15
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 applicants
16
A Biosafety System
Guidelines
People
Biosafety Review
Process
17
SUGGESTED MMODIFICATION 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
18
The Mashelkar Committee
Inter-Ministerial Committee setup by
The Ministry of Environment & Forests
New Delhi
Report on Recombinant Pharma Sector
(Discussed on January 23, 2005)
19
Recommendations of the Task Force on r-Pharma
a. The step-wise regulatory procedures/protocols for
Regulation of Recombinant Pharma Products derived
from
Living Modified Organisms (LMOs).
b. Time lines for approvals.
c. Recommendations on other Linked issues.
d. Inter-ministerial Standing Committee on Biotechnology
Regulation.
e. Proposed independent institutional mechanism - National
Biotechnology RegulatoryAuthority/Commission.
20
The step-wise regulatory procedures /protocols
for five categories
Protocol-I:Indigenous
product
development,
manufacture
and
marketing of pharmaceutical products derived from LMOs but
the end product is not a LMO.
Protocol-II:Indigenous product development, manufacture and
marketing pharmaceutical products where the end product is a
LMO.
Protocol-III:Import
and
marketing
of
LMOs
as
Drugs/Pharmaceuticals in finished formulations where endproduct is a LMO.
Protocol-IV:Import and marketing of LMOs as Drugs/Pharmaceuticals
in bulk for making finished formulation where end product is a
LMO.
Protocol-V:Import and marketing of products derived from LMOs as
Drugs/Pharmaceuticals and
bought in bulk and/or finished
formulations where end product is not a LMO.
21
Protocol – I Indigenous product development derived from LMOS but end product
not a LMO.
Risk Group III and above
Applicant
Risk Group I & II
IBSC
IBSC
RCGM approves pre-clinical trials
RCGM approves pre-clinical trials
Pre-clinical trial conducted
Pre-clinical trial conducted
RCGM recommends human CT to
DCGI and forwards views on
containment facilities to GEAC
RCGM recommends human CT
DCGI approves human CT
Human CT conducted
DCGI approves market
authorization under Drugs and
Cosmetic Rules based on the
clinical trials data
DCGI - Post release monitoring
DCGI approves human CT
GEAC examines
environmental risk v/s
benefit based on the
information on
containment facilities and
data on clinical trials
Environmental
Clearance
Rule1989
Human CT conducted
DCGI approves market
authorization under Drugs and
Cosmetic Rules based on the
clinical trials data
DCGI - Post release monitoring
22
Protocol – I
Indigenous product development derived from
LMOs but end product is not a LMO.
• As per the new recommendations, (i) GEAC has no role in the
regulation of LMOs falling under Risk Group 1 & II; (ii) GEAC has no
role in the approval of Phase-III clinical trials for risk group III &
above;
• Amendment of Rule 1989 is not required in respect of (i) as MoEF
may exercise the provisions of exemption under rule 20 which states
‘The Ministry of Environment and Forests shall, wherever necessary,
exempt an occupier handling a particular microorganism/genetically
engineered organism from rule 7-11” . Accordingly LMOs falling
under risk Group 1 & II may be exempted from GEAC clearance.
• Further, the specific provision stipulating prior approval of GEAC for
human clinical trials in recombinant pharma products are contained in
the 1999 DBT Guidelines for Generating Pre-Clinical Data for r-DNA
Based Vaccines, Diagnostics and other Biologicals. Since there is no
role of the GEAC for Phase-III clinical trials in case of therapeutic
proteins, the DBT guidelines need to be suitably amended.
• Under Protocol I there is no change in the role of RCGM and DCGI.
23
Indigenous Product development where end Product is a
LMO
Protocol – II
Applicant
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 CT)
A
A
24
A
Protocol – II Contd.
HUMAN
CT conducted
DCGI
(approves Market
Authorization under
Drugs & Cosmetics
Rules based on clinical
trials data)
GEAC
(examines
environmental risk
versus benefits and
accords approval for
environmental release
under Rule 1989)
DCGI
(Post Release Monitoring)
25
Protocol – III
Import and marketing of LMOs 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 ‘In Principle’ approval for import
and conduct of clinical trials. GEAC recommends to DCGI)
DCGI
(approves Human CT and protocols)
HUMAN
CT conducted
DCGI
(approves Market Authorization under Drugs &
Cosmetics Rules based on clinical trials data)
DCGI
(Post Release Monitoring)
GEAC
(examines environmental risk
versus benefits and accords
approval for environmental release
under Rule 1989).
26
Protocol – IV Import of LMOs 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 “in 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)
A
A
27
Protocol – IV Contd.
A
HUMAN
CT conducted
DCGI
(approves Market Authorization under
Drugs & Cosmetics Rules based on clinical
trials data)
DCGI
(Post Release Monitoring)
GEAC
(examines environmental risk
versus benefits and accords
approval for environmental
release under Rule 1989)
28
Protocol – 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)
29
Protocol – V Import and marketing of products derived from LMOs
as Drugs and bought in bulk and/or finished formulations.
• As per the new recommendations, (i) GEAC has no role in the import of
recombinant therapeutic proteins as drugs. (ii) RCGM to give their
comments on the import proposal to DCGI.
• Amendment of Rule 1989 is not required to accommodate the proposed
change as we MoEF may exercise the provisions of exemption under
rule 20 which states ‘The Ministry of Environment and Forests shall,
wherever necessary, exempt an occupier handling a particular
microorganism /genetically engineered organism from rule 7-11”.
Accordingly the import of recombinant drugs where the end product is
not a LMO may be exempted from GEAC clearance.
• DCGI is of the view that in Protocol V the word “after obtaining the
views of RCGM” to be deleted. They have suggested that RCGM
function to be combined with RDAC under the office of DCGI. This
would require a major amendment to Rules 1989.
30
Time lines for approvals
 RCGM approval for pre-clinical animal studies:
45 days
 RDAC approval for Human Clinical Trials protocol: 45 days

 RDAC (DCGI) examination of trial data and approval:Case
specific
 Simultaneous DCGI & GEAC* approvals: 45 days
*GEAC approval procedure will be compliant with the
‘Good Practices in Environmental Regulation adopted
by MoEF.
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Other Recommendations
 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.
 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.
32
Other Recommendations (contd)--
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
Force 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.

For import of GMO / LMO for research/contract manufacturing or
similar service, where the product (which is not an LMO) 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.
33
Other Recommendations (contd)---
 Enzymes /industrial products from GMOs would attract the
provisions of Rule 1989 of EPA. In such cases, RCGM may be
authorized to approve such proposals under intimation to GEAC.
 The expertise in the various regulatory agencies under Rules 1989 of
EPA should be further strengthened.
 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 Force recommends that the Government may set
up a separate agency for this purpose.
 On the issue of seeking approvals of PPA/DCGI/GEAC under Rules
1989 of EPA and PQO by Customs Authorities on the imports of
microorganisms, GMOs/ LMOs 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 34
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 (MoEF)
-Member
Joint Secretary (Food Processing)
-Member
Adviser (Industry, DBT)
-Member
DG/Representative (ICMR)
-Member
DCG(I)
-Member
Experts on Immunobiologicals, Biogenerics, Plant Breeding, Molecular Biology,
35
Environmental Sciences and other relevant areas may be co-opted from time to time.
National Biotechnology Regulatory Authority/
Commission
•Alternate models of a ‘National Biotechnology Regulatory
Authority’
•Amendment of EPA and harmonization Seeds Act/ Drugs &
Cosmetics Rules/ PFA Act may be necessary to obviate the
approvals required under these statues.
•Harmonization is an essential prerequisite for establishing
the national biotechnology regulatory authority.
•Recommended an inter-ministerial group to examine the
model proposed and make specific proposals with respect
to the implementation including the budgetary
requirements.
36
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
(LMOs) and in this context capacity building
needs become most relevant aspect in the safe
use of LMOs
37
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
38
Thank You
39