Regulatory Legislation and Guidelines for Recombinant Drugs, Pharmaceuticals and Biologicals

jamaicanabsorbingBiotechnology

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

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1

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

2

Biotech Industry and rDNA Research

Indian Companies in modern biotechnology


Over

900

companies

operating

in

all

sectors

of

biotechnology
,


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


Total number of organisations involved in rDNA Research
-

256

3



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
(relatively low) risk !!!

4

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
.

5

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

6

7

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

8

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.

9

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


10

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)


11

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)

12

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
.

13

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
.

14

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

15



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


16

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

17

A Biosafety System

Guidelines

People

Biosafety Review

Process

18

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


19

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)

20

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.
T
ime 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.

21

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

end
-
product

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
.


22

Protocol


I

Indigenous product development derived from LMOS but end product


not a LMO
.

Applicant

IBSC

RCGM approves pre
-
clinical trials

Pre
-
clinical trial conducted

RCGM recommends human CT to
DCGI and forwards views on
containment facilities to GEAC

DCGI approves human CT

Human CT conducted

GEAC examines
environmental risk v/s
benefit based on the
information on
containment facilities and
data on clinical trials

DCGI approves market
authorization under Drugs and
Cosmetic Rules based on the
clinical trials data

DCGI
-

Post release monitoring

Risk Group III and above

Risk Group I & II

IBSC

RCGM approves pre
-
clinical trials

Pre
-
clinical trial conducted

RCGM recommends human CT

DCGI approves human CT

Human CT conducted

Environmental

Clearance


Rule1989

DCGI approves market
authorization under Drugs and
Cosmetic Rules based on the
clinical trials data

DCGI
-

Post release monitoring

23

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.


24

Protocol


II

Indigenous Product development where end Product is a


LMO

Applicant

IBSC

RCGM

(approves pre
-

clinical trials)

Pre
-
clinical trials conducted

RCGM

(evaluates toxicity and allergenicity data and

Containment facilities and recommends CT)

GEAC

(recommends Human

CT)

DCGI

(approves Human CT and protocols)

A

A

25

HUMAN

CT conducted

GEAC

(examines
environmental risk
versus benefits and
accords approval for
environmental release

under Rule 1989
)

DCGI

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

DCGI

(Post Release Monitoring
)

A

Protocol


II Contd.

26

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

GEAC

(examines environmental risk
versus benefits and accords
approval for environmental release
under Rule 1989).

DCGI

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

DCGI

(Post Release Monitoring)

27

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)

GEAC

(recommends Human CT)

DCGI

(approves Human CT and protocols)

A

A

28

Protocol


IV Contd.

HUMAN

CT conducted

GEAC

(examines environmental risk
versus benefits and accords
approval for environmental
release under Rule 1989)

DCGI

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

DCGI

(Post Release Monitoring
)

A

29

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
)

30

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.


31

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
.


32

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.

33

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.

34

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
approval.

35

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,

Environmental

Sciences

and

other

relevant

areas

may

be

co
-
opted

from

time

to

time
.

36

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.

37

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


38


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

39

Thank You