Regulatory Compliance for Commercialization of Biotech Products

Dr. Murali Krishna

Biotech Consortium India Limited New Delhi

24.12.08

Biotechnology in the past – making bread and cheese, brewing beer

– crossbreeding plants

What Is Biotechnology?

Harnessing the natural biological processes of living systems for the benefit of mankind

Modern biotechnology – genetic engineering

Regulatory Requirements for Biotechnology Products and Processes

• Biotechnology encompass a range of products for different application areas viz: healthcare, agriculture, industrial and environment.

• Traditional biotech products have been governed by product specific regulations like Drugs and Cosmetics Act, Food Safety Regulations etc.

• Application of modern biotechnology tools resulted in additional safety concerns and emergence of biotech specific regulations for genetically modified organisms(GMOs)

A genetically modified organism (GMO) or genetically engineered organism (GEO) is an organism whose genetic material has been altered (introduced or silenced) using genetic engineering techniques.

These techniques, are also known as recombinant DNA technology

Transgenic organisms, a subset of GMOs, are organisms which have inserted DNA that originated in a different species.

What are GMOs

• Basic biological research

• Medical biotechnology

– Vaccines

– diagnostics …

• Somatic gene therapy

• Pharmaceuticals

– antibiotics, insulin, growth hormone ...

• Enzymes for food manufacture

– Rennet for cheese production

• Agriculture

– New plant cultivars

Where are GMOs used today?

WHAT IS UNIQUE?

A GMO carries new gene(s)

New gene(s) can be Introduced from any source

-bacteria, virus, fungi, animals - thus overcoming taxonomic or

reproductive barrier

A Big Breakthrough!

India’s biotechnology regulatory system is primarily based on the “Rules for the Manufacture, Use, Import, Export and Storage of Hazardous Microorganisms/ Genetically Engineered Organisms or Cells, 1989 (Rules, 1989)” notified under the Environment (Protection) Act, 1986.

Elaboration of a series of guidance documents has been published by the Department of Biotechnology (DBT) in 1990, 1998, 1999 and 2008.

Existing Regulatory Framework

The 1989 Rules cover the entire spectrum of activities relating to research, development and use of Genetically Modified Organisms (GMOs) and their products.

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

Coverage of 1989 Rules

Implementing Agencies

Department of Biotechnology

State Governments

Ministry of Environment

Forests & Climate Change

1) The Recombinant DNA Advisory Committee (RDAC).

2) Institutional Biosafety Committee (IBSC)

3) Review Committee on Genetic Manipulation (RCGM)

4) Genetic Engineering Appraisal Committee (GEAC)

5) State Biotechnology Coordination Committee (SBCC)

6) District Level Committee (DLC)

Advisory

Approval

Monitoring

Statutory Bodies

Recombinant DNA Safety Guidelines, 1990

Revised guidelines for research in transgenic plants & guidelines for toxicity and allergenicity evaluation of transgenic seeds, plants and plant parts, 1998

Guidelines for generating preclinical and clinical data for rDNA vaccines, diagnostics and other biologicals, 1999

Guidelines and Standard Operating Procedures (SOPs) for Confined Field Trials of Regulated, Genetically Engineered (GE) Plants, 2008

Guidelines for the Safety Assessment of Foods Derived from Genetically Engineered Plants - 2008

Protocols for Food and Feed Safety Assessment of GE crops – 2008

Guidelines and handbook for Institutional Biosafety Committees (IBSCs), 2011

Guidelines on Similar biologics: Regulatory requirements for Marketing Authorization in India, 2012

Relevant Guidelines

Drugs and Cosmetics Act, 1940

Seeds Act, 1966

Biological Diversity Act, 2002

Food Safety and Standards Act, 2006

Policies such as National Seeds Policy, Drug Policy, National Environment Policy, Foreign Trade Policy etc.,

Other Applicable Regulatory Instruments

Stages of Biotech Product Development

Lab Scale up and

Evaluation Commercialization

• Clinical Trials • Field Trials • Fermentation process

Regulations

Product Development : Time and Money Consuming

Bio fertilizers are governed by Essential Commodities Act 1956 and Fertilizer (Control) Order 1985

Bio fertilizers covered under the Order are viz: (Azospirillium, Phosphobacteria, Rhizobium, Azatobacter)

Conditions for licensing of biofertilizers is governed by Schedule III So 391(E) 24.3.2006

Part A : Specification of Bio-fertilizers (So 2803(E) 3.11.2009.

Part B : Tolerance Limit

Part C : Procedure to draw samples

Part D : Method of Analysis.

Regulation of Bio fertilizers

Production and Sale of Biopesticides is governed by The Insecticide Act 1968

This Act is to Regulate the Import, Manufacture, Sale Transport and Use of Insecticides

Relevant Sections of the Act are 9, 9(3), 9(3b), 9(4) and 13

Relevant Rules are

– Rule 9: Grant of License

– Rule 16 ,17,18 and 19: Packing and Labeling

– Rule 35 : Manner of Packing

– Rules 37 : Medical Examination

Regulation of Bio pesticides

Central Insecticides Board & Registration Committee

IVDs are those substances that are intended to be used for use in Diagnosis of disease or disorders in human beings or animals

IVDs are considered as Drugs as defined in the Sub-Clause (i) of Clause (b) of Section 3 of the Drugs and Cosmetic Act 1940 and Rules 1945

Ministry of Health and Family Welfare through Drug Controller General of India (DCGI) is the highest responsible Authority

In Vitro Diagnostics (IVDs)

• Diagnostic Kits for HIV/ HBs Ag, HCV and kits for determining blood groups

Notified

• Diagnostic kits for Malaria, TB, Typhoid, Dengue, Glucose Test etc. Non-Notified

Requirements for Import of IVDs in India

Steps in the development process include:

Standardization of manufacturing process

Quality considerations of similar biologics

Quality comparability studies with reference (Innovator biologics)

Pre-clinical studies including pharmacodynamic, toxicology and immune responses studies in animals.

Clinical trials for establishing safety and efficacy of the product

Post market studies

Case Study: Similar Biologicals

IBSC

IAEC

RCGM

DCGI (RDAC)

GEAC

State level Drug Controller’s office

Agencies Involved

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.

Stepwise Regulatory Procedures/ Protocols for five Categories

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

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 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 Protocol – II Contd.

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)

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 Contd./-

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)

Regulatory approvals required at each stage of development and testing such as molecular characterization, optimization of the production process, purification and characterization, pre-clinical testing and clinical trials.

Data requirements may vary on a case by case basis.

Guidelines for Similar Biologics jointly issued by DBT and DCGI provide the indicative requirements for the above.

Data Requirements for Similar Biologics

The development of a GE plant typically follows a step-wise process.

Laboratory research

Growth chamber and greenhouse

Confined field trials

Event approval for cultivation and food and feed use

Variety/hybrid approval

Seed production and distribution

Cultivation

Case Study: GE Plant

Core Characterization

Gene(s) – Source(s)

– Molecular characterization

– Insert / copy number / gene integrity

Protein(s) – History of safe use and

consumption

– Function / specificity / mode-of-action

– Levels

– Toxicology / allergenicity testing

Food/Feed Composition

– Proximate analysis

– Key nutrients

– Key anti-nutrients

– Animal performance assessment

Environmental

– Host organism

– Safety to non-target organisms

– Soil degradation, toxicity

– Outcrossing, weediness

Safety Considerations

National and international regulations/guidance in place for Biotechnology Products and constantly evolving.

It is extremely important for the technology developers to be aware of regulations and applicable guidelines.

Early stage planning is extremely important for timely and cost effective product development.

Conclusion

Thank You !!!