Recombinant

Therapeutic Proteins

Presentation By:

S.P. Shani

Deputy Drugs Controller

(I)

Regulation for r-DNA Technology based

Therapeutic proteins - Indian Scenario

The Guidelines on Similar Biologics was prepared by CDSCO and DBT laid down the regulatory pathway for similar biologic claiming to be similar to an already authorized reference biologic.

CDSCO is the national regulatory authority in India that evaluates safety, efficacy and quality of drugs in the country.

DBT through Review Committee on Genetic Manipulation/ Institutional Biosafety Committee is responsible for overseeing the development and preclinical evaluation of recombinant biologics.

Definition of New Drug

• As per under Rule 122-E New Drug is defined “A drug, including bulk drug substance which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labeling thereof and has not been recognized as effective and safe by the licensing authority mentioned under Rule 21 for the proposed claims.

• A drug already approved by the Licensing Authority mentioned in Rule 21 for certain claims , which is now proposed to be marketed with modified or new claims , namely , indications, dosage, dosage form ( including sustained release dosage form) and route of administration.

All vaccines and r-DNA products are New Drugs

vide G.S.R. 45 (E) dated 24/01/2011.

122-A clearance required for imported r-DNA

products

122-B clearance required for Indigenously

manufactured r-DNA products.

Regulatory Requirement for Market Authorization of r-DNA

products

Central Licensing*

• For Biologicals, Large volume parenterals (LVP), Blood bank and blood

products, r-DNA & Some Medical Devices

STATE LICENSING

AUTHORITY

CLAA

Approval and

Grant of License

Joint Inspection

by State and

Central

Inspectors

Manufacturer

License Prepared by

State Licensing

Authority

Examination of

Report

Regulations for Clinical Trials

Drugs and Cosmetics Rules- Schedule Y(See

Rule 122-A, 122-B, 122-D, 122-DA, 122DB, 122-E)

Guidance for Industry (Specific for Biological

Products )

Good Clinical Practice Guidelines issued by

Central Drugs Standard Control Organization

Ethical Guidelines for Biomedical Research on

Human Subjects issued by Indian Council of Medical

Research

Technical Review and

Forward the file to

Concern DI’s

for validation

Manufacturers

for submission

Submission of application

in CRU After acceptance

By Pre screening officers

And FTS No. generated

Clinical Trial, Marketing Authorization and Licensing process of r-

DNA products : flow chart in India

Pre-screening 1. Check administrative

2. Check legal document

3. Check fees

1st Level

Review

Central Registry

Unit

DDC (I)

ADC (I) Summary Basis of

approval

DI’s

TDA’s

DCG(I)

File signed and

send back to

concerned officer for

issue the letter

Letter send to

CRU for issue 2nd Level

Review

On Site Evaluation

CMC Evaluation

NDAC

Zonal

Hard and Soft

copies

IND

Preclinical studies

Evaluation

RCGM

There are three Competent Authorities involved in

approval process namely :

a) Review Committee on Genetic Manipulation

(RCGM)/IBSC under Department of Biotechnology

(DBT), Ministry of Science and Technology.

b) Genetic Engineering Appraisal Committee (GEAC)

under the Ministry of Environment and Forests

(MoEF) and

c) Central Drugs Standard Control Organization

(CDSCO) under Ministry of Health & Family

Welfare

Competent Authorities

a) Review Committee on Genetic Manipulation (RCGM) under

Department of Biotechnology (DBT), Ministry of Science

and Technology – is responsible for authorizing

import/export for research and development and review of

data up to preclinical evaluation.

b) Genetic Engineering Appraisal Committee (GEAC) under

the Ministry of Environment and Forests (MoEF) - is

responsible for review and approval of activities involving

large scale use of genetically engineered organisms

(LMOs) and products thereof in R&D, industrial production,

environmental release and field applications.

Functions of Competent Authorities

c) Central Drugs Standard Control Organization (CDSCO)

under Ministry of Health & Family Welfare headed by DCG

(I) - It is the apex regulatory body and is responsible for

the approval of new drugs, for grant of import/export

license, clinical trial approval and permission for marketing

and manufacturing.

State Licensing Authority works with CDSCO in each state

and is responsible for issuance of license to manufacture

similar biologics in India.

Functions of Competent Authorities…contd

All recombinant biopharmaceuticals are considered as a

new drugs and their approval is regulated by provisions

of Drugs and Cosmetics Act and allied rules (Rule

122DA, 122DAA, 122E, 122A, 122B and Schedule Y

specially) as well as the “Guidance for Industry”

developed by the CDSCO.

Ministry of Health & Family Welfare's constituted New

Drug Advisory Committee (NDAC) on 31/03/2012 to

advise Drugs Controller General (India) in matters

related to approval of New Drugs including

biopharmaceutical products and Clinical Trials.

Recombinant Therapeutic Proteins

Similar Biologic can only be developed against an

authorized reference biologic that has been approved using

a complete data package in India.

In case the reference biologic is not authorized in India, it

should have been licensed and marketed for atleast 4 years

with significant safety and efficacy data.

In case of no medicine or only pallitive therapy is available

or in national healthcare emergency, this period of 4 years

may be reduced or waived off.

Scope

Any product can be considered as Similar Biologic only if it

is proven to be similar using extensive quality

characterization against reference biologic. Further product

development should only be considered once the similarity

of the product/molecule is demonstrated in quality.

Scope

Filing of Information as per CTD

Module I: Administration/Legal Information Module II: Overall Summaries Module III: Quality Information (Chemical, Pharmaceutical and Biological) Module IV: Non-Clinical Information Module V: Clinical Information

For Biological section Comprehensive Information is asked as per

CTD Module:-

ADOPTION OF COMMON TECHNICAL DOCUMENTS

In order to harmonize the documentation submission for the purpose of

• Clinical Trial

• Marketing Authorisation and Licensing

• Post Approval Changes in biological products

Comprehensive guidelines for submission of applications as per Common

Technical Document (CTD) has been implemented and same has been posted on

official website (www.cdsco.nic.in) on 4th Dec, 2008

These guidelines facilitate

1. Submission of Clinical Trial application for Evaluating Safety and Efficacy.

2. Requirement for permission of new drugs approval.

3. Post approval changes in biological products: Quality safety and Efficacy

Documents

4. Preparation of the quality information for drug submission for new drug

approvals: Biotechnological / Biological Product.

The CTD comprises of five modules which are as follows :-

• Module I : Administrative/Legal Information

• Module II : Summaries

• Module III : Quality Information (Chemical, Pharmaceutical and Biological)

• Module IV : Non-Clinical Information

• Module V : Clinical Information

Various SOPs’ and checklists for all the critical function of dossier review

have been introduced in the system. A prescreening mechanism is in place which

facilitates the stake holder for the submission of the application in the appropriate

manner.

The staff have been trained in the GCP, GMP and dossier evaluation in

order to update the knowledge.

Contd…

Common application prescribed for imported vaccine/r-DNA product

and indigenously manufactured vaccine/r-DNA product.

Application made as per Form-44 for import or manufacture or

undertake clinical trial.

Form-44 also accompanied with information as per Schedule-Y

(Requirement and Guidelines on Clinical Trial for import and

manufacture of Vaccine/r-DNA product).

Need for generation of Safety / Efficacy data as per GCP

Guidelines under Schedule ‘Y’

Regulatory requirements for clearance under Rule 122A/B

(New Drugs)

(Imported/Indigenously manufactured)

Drugs and Cosmetic Act Prescribes various applications Forms and

approvals & license certificates

• FORM 44 (See rules 122A, 122B, 122D and 122 DA)

Application for grant of permission to import or

manufacture a New Drug or to undertake clinical trial.

• FORM 40 (Rule 24-A)

Application for issue of Registration Certificate for

import of drugs into India under the Drugs and

Cosmetics Rules 1945

• FORM 27D (Rule 75)

Application for grant or renewal of license to

manufacture for sale or for distribution of vaccine

• SCHEDULE D(I)

(Rule 21 (d) and Rule 24 A)

Information and undertaking required to be submitted by

the manufacturer or his authorized agent with the

Application Form for a Registration Certificate. The format

shall be properly filled in for each application in Form 40..

• SCHEDULE D (II)

(Rule 21 (d) and Rule 24 A)

Information required to be submitted by the manufacturer

or his authorized agent with the Application Form for the

registration of a bulk drug/formulation/special product for its

import into India.

Contd…

• FORM 8 (Rule 24)

Application for license to import drugs (Vaccine)

(excluding those specified in Schedule X) to the Drugs and

Cosmetics Rules, 1945

• FORM 9 ( Rule 24)

Form of undertaking to accompany an application for an import license

Contd…

Drugs and Cosmetic Act Prescribes various applications Forms and

approvals & license certificates

• FORM 45 (See rules 122 A, 122 D and 122 DA)

Permission to import Finished Formulation of the

New Drug.

• FORM 46 (See rules 122 B, 122 D and 122 DA)

Permission / Approval for manufacture of new drug

formulation

Drugs and Cosmetic Act Prescribes various applications Forms and

approvals & license certificates

• FORM 41 (Rule 27 A)

Registration Certificate to be issued for import of drugs

into India under Drugs and Cosmetics Rules, 1945

• FORM 10 (Rules 23 and 27)

Licence to import drugs (excluding those specified in

Schedule X) to the Drugs and Cosmetic Rules, 1945

• FORM 28D (Rule 76)

Licence to manufacture for sale or for distribution of Large Volume

Parenterals / Sera and Vaccines specified in Schedules C and C(I)

excluding those specified in Schedule X

a. Condition of License (Rule 78)

[(p) The license shall comply with the requirements of

[Good Laboratory Practise as laid down in Schedule L-I

and} Good Manufacturing Practices as laid down in

Schedule M.]

b. Rule 79

Inspection before grant or renewal of license

Contd…

CMC Evaluation as per Bio Similar Guidelines:

Development of Similar Biologics

1. Selection of Reference Biologic

RMP should be licensed in India and should be innovator product.

In case the reference biologic is not marketed in India, the reference

biologic should have been licensed and widely marketed for 4 years post

approval in innovator jurisdiction in a country with well established

regulatory framework.

The same reference biologic should be used throughout the studies

supporting the safety, efficacy and quality of the product

Dosage form, strength and route of administration of the similar biologic

should be the same as that of the reference biologic.

The active substance (active ingredient) of the reference biologic and that

of the similar biologic must be shown to be similar

2. Manufacturing Process

Molecular Biology Considerations

Details of Host cell cultures (including viral clearance), vectors, gene sequences,

promoters etc.

Details of Post-translational modifications ((glycosylation, oxidation, deamidation,

phosphorylation etc.)

Fermentation Process Development

Three batches of reproducible fermentation data at pilot scale

Carried out in controlled and monitored environment.

Fermentation kinetics data

Data to verify that the specific protein yield (amount of protein per unit cell mass) remains

constant for all fermentation batches.

Overall productivity is reproducible and scalable.

Downstream Process Development

Steps involved in purification of protein.

Batch size for protein purification.

Consistency of recovery in 3 consecutive batches of purification from 3 independent

batches of fermentation.

3. Product Characterization

Structural and Physicochemical Properties:

Determination of primary and higher order structure of the product

The target amino acid sequence of the similar biologic should be confirmed

and is expected to be the same as for the reference biologic.

In cases, where post translational modifications are taking place, these

modifications need to be identified and quantified.

In case any significant differences are found, these should be

scientifically justified and critically examined in preclinical studies and

clinical trials.

Biological Characterization:

Biological assays will be required to characterize the activity and establish

the product’s mechanism of action and clinical effects (in units of activity).

Assays should be calibrated against an international or national reference

standard, where available and appropriate. If no such standards are

available, an internal reference standard must be established as per the

ICH guidelines. If the methods of bioassay(s) are documented in the

specification, test(s) can be conducted accordingly.

Immunological Characterization:

Evaluation by characterization(antibody or antibody-derived product);

comparison to reference biologic with respect to specificity, affinity, binding

strength and Fc function; and evaluation by animal studies

Purity and Impurities:

Product related variants (e.g., glycoforms, isomers etc.)

Product related impurities (e.g., aggregated, oxidized or deamidated

product)

Host cell related impurities (e.g., host cell protein, host cell DNA etc.)

Process related impurities (residual media components, resin leachates

etc.)

Differences observed in the purity and impurity profiles of the similar

biologic relative to the reference biologic should be evaluated to assess

their potential impact on safety and efficacy.

Specifications:

Acceptance limits should be set based on reference biologic data and data

from sufficient number of batches from preclinical or clinical batches.

Stability

Stability studies on drug substance and drug product should be carried out

using containers and conditions that are representative of the actual storage

containers and conditions, according to relevant guidelines (e.g. ICH

Q5C10, WHO TRS 82211).

Accelerated and stressed studies comparing the similar biologic to the

reference biologic

Preclinical studies evaluation as per Bio

Similar Guidelines The preclinical studies should be conducted prior to the initiation of any clinical after

getting approval from the RCGM.

The preclinical study design may vary depending upon the clinical parameters such

as therapeutic index, the type and number of indications applied.

The dosage form, strength and route of administration of the similar biologic should

be the same as that of the reference biologic and in case of any differences in these

parameters, it should be justified.

Following studies are required for preclinical evaluation:

Pharmacodynamic Studies

In vitro studies: (e.g. cell proliferation assays receptor binding assays).

In vivo studies:

In vivo evaluation of biological/ Pharmacodynamic activity may be dispensable if in

vitro assays are available, which are known to reliably reflect the clinically relevant

Pharmacodynamic activity of the reference biologic. In cases where the in-vitro

assays do not reflect the Pharmacodynamic, In vivo studies should be performed.

Toxicological Studies

In case of in vivo toxicity studies, at least one repeat dose toxicity study in a relevant

species is required to be conducted. The duration of the study would be generally not

less than 28 days with 14 days recovery period. However the duration may vary

depending on the dosage and other parameters on case by case basis.

Regarding the animal models to be used, the applicant should provide the scientific

justification for the choice of animal model(s) based on the data available in scientific

literature. However if the relevant animal species is not available and has been

appropriately justified, the toxicity studies need to be under taken in two species i.e.

one rodent and other non rodent species, as per the requirements of Schedule Y12

with due permission from the RCGM.

The dose should be calculated based on the therapeutic dose of the reference

biologic.

Other toxicity studies, including safety pharmacology, reproductive toxicity,

mutagenicity and carcinogenicity studies are not generally required for evaluation of a

similar biologic unless warranted by the results from the repeat dose toxicological

studies.

Immune Responses in Animals

Antibody response to the similar biologic should be compared to that

generated by the reference biologic in suitable animal model. The test

serum samples should be tested for reaction to host cell proteins.

Immunogenicity testing should be included as part of the sub-chronic

repeat dose study while developing the protocols.

The other parameters for evaluating immune toxicity include immune

complexes in targeted tissues may be considered while evaluating

histopathology observations, etc.

Guidance for

Industry • Submission of Clinical Trial

Application for Evaluating Safety

and Efficacy

• Requirements for permission of

New Drugs Approval

• Post approval changes in

biological products:

Quality safety and Efficacy

Documents • Preparation of the Quality

Information for Drug Submission

for New Drug Approval:

Biotechnological/Biological

Products

Post Approval Changes in Biological Products: Quality

Safety and Efficacy Documents (Document No. - PAC/

1108, Version – 1.1)

This section in the document Guidance of Industry deals with

requirements fulfilled by Indian firm before implementing the

following changes:

Notifiable Change e.g.: Generation of new Master Cell Bank (MCB)

from the same expression construct with same or closely related cell

line, change in approved therapeutic indication etc.

Supplement e.g.: change in the test specification of drug products/

drug substances

Annual Notification. e.g. Generation of a new Working Cell Bank

(WCB) etc.

Questions?

Thank You