Biologics are the medicinal/ therapeutic/ diagnostic/ preventive preparations composed or derived from living organisms and their spin-off for human use. They include serums, vaccines, antitoxins, blood, antigens and blood components, gene therapy, tissues etc. Biotechnology is used as a unique approach in manufacturing such medicinal agents. The Central Drugs Standard Control Organization (CDSCO) is the regulatory authority for manufacturing and import of biological products in India.
Biotechnology provides innovative solutions to medical field with more than 200 biologic medicines and vaccines. These developments benefits millions of patients worldwide and more than 600 products under development. At present these products can also be produced by manufacturers other than the innovator, with the expiry of some of patents. These new biotechnological medicines commonly referred to as ‘similar biologics’ offer a major opportunity to provide greater access to reasonable healthcare for several life saving medicines.
India has emerged as one of the leading providers to the world market for ‘similar biologics’. These are considered to become the most important economic and therapeutic element of the pharmaceutical market in India.
Applicable Regulations:
The ‘Similar biologics’ are regulated under the Drugs and Cosmetics Act, 1940, the Drugs and Cosmetics Rules, 1945 for the manufacture, use, import, export and storage of harmful microorganisms or genetically engineered organisms or cells, Rules, 1989 notified under the Environment (Protection) Act, 1986.
Applicable Guidelines :
Recombinant DNA Safety (Guidelines, 1990)
Generating preclinical and clinical data for rDNA vaccines, diagnostics and other biological Guidelines, 1999
Guidelines and Handbook for IBCs, 2011
CDSCO guidance for industry, 2008:
Clinical Trial Application Submission for Evaluating Safety and Efficacy
Conditions for permission of New Drugs Approval
Biological products Post approval changes : Quality, Safety and Efficacy Document
Quality Information for Drug Submission for New Drug Approval: Biotechnological or Biological Products
Types of Application
If the reference biologic is not authorized in India then it should have been registered and marketed for at least four years with important safety and efficacy data. If no medicine or only palliative treatment is available or in national healthcare emergency and this period of four years may be reduced.
Submission of various application forms to regulatory agencies is as follows:
| Stage | Agency involved | Application | Approval |
| Manufacturing License for test, analysis and examination | State FDA / CDSCO | Form 30 | Form 29 |
| Preclinical studies permission | RCGM | Form C3 | Form C4 |
| Submission of preclinical study report | RCGM | Form C5 | Form C6 |
| Clinical trial | CDSCO | Form 44 | Permission letter |
| Manufacturing and Marketing permission | CDSCO | Form 44 | Form 45/46 (Finished product) |
| Form 46A (Bulk product) | |||
| Manufacturing License | State FDA/ CDSCO | Form 27 D | Form 28 D |
| Registration and Import License | CDSCO | Form 40/ Form 8 | Form 41/Form 10 |
1. Manufacturing Process
The manufacturing of ‘similar biologic’ should be highly consistent and robust. The data requirements for review of process at preclinical submission stage includes a complete description of the manufacturing activity from development and characterization of cell banks, stability of clone, cell culture or fermentation, harvest, excipients, formulation, purification, Initial packaging interactions (if different from reference biologic), etc. and the result on product characteristics as indicated below:
Molecular Biology Considerations
Fermentation Process Development
Downstream Process Development
2. Quality Based Considerations for Similar Biologics
i) Analytical Methods
The analytical methods should be selected for establishing product comparability under the critical quality attributes of the product. For some attributes (e.g. product aggregation) it is customary to use multiple, orthogonal methods for characterization. New analytical methods should be applied to detect even “slight differences” in all applicable quality attributes. Pharmacopoeia monograph of India should be followed (if available).
ii) Product Characterization
The study for include physicochemical, biological activity, immunological properties, functional analysis, purity, contamination, strength, and content. Principles defined in the guideline (ICH Q6B) should be followed. Pharmacopoeia Monograph of India should be followed (if available).
iii) Specifications
The specifications are established around critical quality attributes of the product with the intent of confirm consistency in product quality and comparability to reference biologic.
iv) Stability
To put shelf-life and storage condition of drug product substance then its real time stability test should be conducted.
Studies on drug substance and product should be carried out using containers and conditions based on actual storage containers and conditions, according to applicable guidelines.
Accelerated Studies and stressed Studies is comparing the ‘similar biologic’ to the mentioned biologic will be of value in choosing the similarity of the products by having comparable degradation profiles.
3. Quality Comparability Study
This study is carried out between similar biologic and reference biologic. The applicant should submit a full quality dossier as per CDSCO instruction for industry, 2008 with the reference biologic before the applicant request to take the ‘similar biologic’ to clinical progress. First 3 consecutive standardized batches which have been used to demonstrate consistency of the manufacturing should be used.
4. Data Requirements for Preclinical Studies
4.1 Prerequisite before Conducting Preclinical Studies
Similar biologic basic information
Information about the drug, route of administration, absorption and rate of elimination, index for therapeutic, dose, vehicle, mode of administration, dose response etc.
Bio-equivalence range (if available)
Tissue specific localization (if available)
Data for Available toxicity on reference biologic.
Mode of action.
Similar biologic basic information
Known / proposed clinical use
Target population
Dosage (frequency and intervals)
Route / alternate routes of administration
Toxicology data of adjutants
Diluents
Presentation e.g. pre filled syringe
4.2 Preclinical Studies (Pharmacodynamic and Toxicology Studies)
4.3 Immune Responses in Animals
Based on the successful evaluation of preclinical study reports RCGM will direct the applicant to approach DCGI to conduct appropriate phase of clinical trial as per the Central Drugs Standard Control Organization requirements.
5. Clinical Trial Application
Data Requirements
Pharmacokinetic Studies
Single Dose Comparative PK Studies
Multiple Dose Comparative PK Studies
Pharmacodynamic Studies
Confirmatory Safety
Efficacy Study
Safety and Immunogenicity Data
Extrapolation of Efficacy and Safety Data
For more details on the clinical trials refer to our blog article.
6. Data Requirements for Market Authorization Application
Application for market authorization should be submitted by the applicant as per CDSCO guidance document for industry, 2008.
Commercial manufacturing is approved either at a different scale and/or with a separate process as compared to that used for trial of manufacturing phase III clinical batches
7. Post-Market Data for Similar Biologics
Even though ‘similar biologics’ are not new drug and their risk will be similar to reference biologic products. It is important to submit the Risk Management Plan to monitor and notice both known inherent and potential unknown safety signals that may occur from the similar biologics. The risk management plan should consist of the following:
Pharmacovigilance Plan
Reporting for Adverse Drug Reaction
Post Marketing Studies (PMS)