Presentation By: S.P.

Shani Deputy Drugs Controller (I)

Recombinant Therapeutic Proteins

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.

Regulatory Requirement for Market Authorization of r-DNA products

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 manufactured r-DNA products. Indigenously

Central Licensing*
CLAA Approval and Grant of License
Manufacturer
License Prepared by State Licensing Authority

STATE LICENSING AUTHORITY

Joint Inspection by State and Central Inspectors

Examination of Report

For Biologicals, Large volume parenterals (LVP), Blood bank and blood products, r-DNA & Some Medical Devices

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 )

Regulations for Clinical Trials

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

Clinical Trial, Marketing Authorization and Licensing process of rDNA products : flow chart in India Manufacturers Hard and Soft for submission
copies
Submission of application in CRU After acceptance By Pre screening officers And FTS No. generated

Pre-screening Central Registry Unit DDC (I) ADC (I)

Summary Basis of approval

1. Check administrative 2. Check legal document 3. Check fees

Zonal

DCG(I)
On Site Evaluation

1st Level Review

Letter send to CRU for issue

Preclinical studies Evaluation

RCGM

CMC Evaluation

2nd Level Review

NDAC
IND

DIs TDAs

File signed and send back to concerned officer for issue the letter

Technical Review and Forward the file to Concern DIs for validation

Competent Authorities
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

Functions of 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 Authoritiescontd

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.

Recombinant Therapeutic Proteins

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.

Scope
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.

Filing of Information as per CTD

For Biological section Comprehensive Information is asked as per CTD Module: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

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 Submission of Clinical Trial application for Evaluating Safety and Efficacy. Requirement 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 approvals: Biotechnological / Biological Product.

1. 2. 3. 4.

Contd
The CTD comprises of five modules which are as follows : Module I Module II Module III Module IV Module V : Administrative/Legal Information : Summaries : Quality Information (Chemical, Pharmaceutical and Biological) : Non-Clinical Information : 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.

Regulatory requirements for clearance under Rule 122A/B (New Drugs) (Imported/Indigenously manufactured)

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

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 manufacture for sale or for distribution of vaccine

to

Contd
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

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

Contd
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

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 products 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