The Regulatory Backbone Of Indian Pharma: Cdsco's Vision, Biosimilars, And Policy Insights

(BD= Bulk Drug, FF= Final Formulation)⁵

Biosimilars: Need and Regulatory Framework in India

What Are Biosimilars?

Biosimilars, referred to in India as "similar biologics," are biotherapeutic products highly similar to a previously approved reference biologic . Due to their derivation from living organisms, they are inherently more complex than conventional small-molecule generics .

Why Are Biosimilars Important?

• They offer cost-effective alternatives to expensive biologics, improving patient access to treatments for chronic conditions .
• They contribute to healthcare system sustainability by reducing expenditure, benefiting governments and insurers.
• They promote innovation and growth in India's biopharmaceutical sector, reinforcing the country's status as a global supplier.¹

CDSCO Guidelines on Similar Biologics

In August 2016, CDSCO and the Department of Biotechnology (DBT) released the "Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India".

The guidelines provide a clear regulatory framework for the approval of biosimilars in India. These guidelines address the requirements related to manufacturing, quality, preclinical and clinical evaluation, and post-marketing surveillance for products shown to be similar to an already approved reference biologic. The aim is to ensure the safety, efficacy, and quality of biosimilars while streamlining the regulatory pathway for their development and marketing in India.

Key Takeaways from CDSCO-DBT 2016 Guidelines on Similar Biologics

1. Introduction
   • Defines "Similar Biologic" as a product comparable in terms of quality, safety, and efficacy to a licensed reference biologic.
   • Regulatory pathway includes:
     • Comparability exercises for quality, preclinical, and clinical data.
     • Manufacturing requirements aligned with modern biotechnology.
     • Post-marketing responsibilities to ensure long-term safety.
   • These guidelines are non-substitutive of legal Acts but must comply with the Drugs and Cosmetics Act, 1940, and related rules.
2. Background & Objectives
   • CDSCO evaluates drug safety, efficacy, and quality; DBT (via RCGM) oversees development and preclinical stages.
   • Earlier approvals were based on case-by-case, abbreviated pathways.
   • Objective: Uniform regulatory pathway to assess and approve similar biologics by:
     • Encouraging development with clarity.
     • Allowing reduced preclinical/clinical data when justified.
3. Applicable Regulations and Guidelines
   • Governed under:
     • Drugs and Cosmetics Act, 1940 and Rules, 1945
     • Rules 1989 under the Environment (Protection) Act, 1986
   • Relevant guidance documents include:
     • Recombinant DNA Safety Guidelines (1990)
     • IBSC Guidelines (2011)
     • CDSCO Clinical Trial Guidelines (2008)
     • Earlier Similar Biologics Guidelines (2012)
4. Competent Authorities
   • IBSC: It is involved in Institutional review, biosafety clearance, and authorization for microorganism exchange.
   • RCGM (DBT): It authorizes research, evaluates preclinical data, and monitors genetically modified cell banks.
   • GEAC (MoEF): It approves products involving GMOs or LMOs.
   • CDSCO (DCGI): It is an apex authority for clinical trial approval, marketing licenses, and imports for research.
5. Scope
   • Applicable to recombinant DNA-derived, well-characterized proteins developed via modern biotechnology.
   • Similar Biologic development requires
     • Reference biologic must be approved in India or ICH countries (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use).
     • Detailed comparability in quality before further development.
     • Guidelines cover both indigenous and imported products.
6. Principles for the Development of Similar Biologics
   1. Selection of Reference Biologic
      • Must be:
        • Innovator product
        • Approved with a complete data package
        • Used consistently across all comparability studies
   2. Manufacturing Process
      • Manufacturing must:
        • Be consistent and GMP-compliant
        • Include:
          `
          • detailed upstream & downstream processes
          • critical process parameters
          • comparability data between clinical and commercial batches
   3. Quality-Based Considerations
      • Analytical methods: Must detect subtle differences; validated as per ICH Q2, Q5C, Q6B.
      • Characterization must include:
        • Physicochemical and structural properties
        • Biological activity and immunogenicity
        • Process/product-related impurities
      • Specifications and Stability:
        • Acceptance criteria based on clinical batch and reference product
        • Real-time and accelerated stability studies required
   4. Quality Comparability Study
      • Must show no significant difference in critical quality attributes (CQAs) and key quality attributes (KQAs).
7. Preclinical Data Requirements
   1. Prerequisite Before Conducting Preclinical Studies
      • Must comply with RCGM requirements, including:
        • Product/process consistency
        • Characterization and specifications
        • IBSC and (optionally) IAEC approvals
      • Submission includes:
        • Details on reference and similar biologic
        • Site info, personnel involved, GLP compliance
   2. Pharmacodynamic and Toxicology Studies
      • Must be comparative in nature using the final clinical formulation.
      • Include:
        • Single and repeat-dose toxicity
        • Use the same route/dose as the reference unless justified
        • Immune toxicity testing, local tolerance, and histopathology
   3. Immune Responses in Animals
      • Compare antibody response to similar and reference products
      • Assess host cell proteins, immune complex formation, and local tolerance
8. Clinical Trial Application Requirements
   1. Pharmacokinetic (PK) Studies
      • Should confirm bio-comparability using:
        • Normal healthy volunteers and/or patients
        • Single-dose or multiple-dose studies
        • Parallel or crossover designs
      • Variables considered:
        • Half-life, absorption, route, indication
   2. Pharmacodynamic (PD) Studies
      • Should be comparative, validated, and use relevant surrogate markers
      • May be combined with PK studies
      • Acceptable ranges must be predefined and justified
   3. Confirmatory Safety and Efficacy Study
      • Mandatory unless waived; includes:
        • Phase III trials in ≥100 evaluable patients
        • Comparative parallel, blinded design
        • Exception only if: analytical, preclinical, PK/PD data remove residual uncertainty
        • Immunogenicity must still be captured
   4. Safety and Immunogenicity
      • Requires combined Phase III + IV data from ≥300 patients
      • Study immune response, especially neutralizing antibodies
   5. Safety and Immunogenicity
      • Requires combined Phase III + IV data from ≥300 patients
      • Study immune response, especially neutralizing antibodies
   6. Extrapolation of Indications
      Allowed if:
      • Same MOA and receptors
      • Proven similarity in quality, non-clinical, and at least one clinical indication
      • Not permitted for indications not covered by the reference biologic
9. Market Authorization Application
   • Submit as per CDSCO 2008 guidance
   • Additional data required if manufacturing scale/process differs from clinical trial batches
   • Must include comparability data for such changes
10. Post-Marketing Requirements
    1. Pharmacovigilance Plan
       • Due to limited pre-approval data:
         • PSURs every 6 months for 2 years, then annually for 2 more years
         • Should be integrated into a Risk Management Plan
    2. Adverse Drug Reaction (ADR) Reporting
       • All serious unexpected ADRs to be reported as per Schedule Y
    3. Phase IV (Post-Marketing) Studies
       • Required unless justified otherwise
       • Includes ≥200 patients
       • Primary endpoint: safety
       • Secondary: efficacy and immunogenicity
       • To be completed within 2 years
       • Protocol submitted with marketing application
11. Application Forms
    • CDSCO & RCGM forms include:
      • Form 44: Clinical trial/marketing
      • Form 30/29: Test licenses
      • Form 8/9/10: Import licenses
      • Form 40/41/45: Registration certificates
12. Archiving & Retention
    • All quality, preclinical, and clinical data to be archived for a minimum of 5 years
    • Retain samples like test substances, slides, sera, tissues until expiry
    • SOP must define the responsible authority and procedures

Regulatory Pathways: Key Protocols for Biosimilar Approval

The 2016 CDSCO guidelines include distinct regulatory pathways for different scenarios involving recombinant pharmaceutical products, particularly those derived from Living Modified Organisms (LMOs). These are outlined in the form of flowcharts in Annexure I. Below is a detailed breakdown of each protocol:

Protocol I: Indigenous Development of Non-LMO End Products

Scenario: Development, manufacture, and marketing of pharmaceutical products in India, where the product is derived from LMOs, but the final product is not an LMO.

Steps Include:

• R&D clearance from IBSC and RCGM
• Preclinical study approval from RCGM
• Clinical trial approval from CDSCO
• Market authorization from CDSCO

This protocol focuses on ensuring biosafety during early development despite the end product not being an LMO.

Protocol II: Indigenous Development Where the Final Product Is an LMO

Scenario: Development, manufacture, and marketing in India of pharma products where the end product itself is a Living Modified Organism.

Key Additional Step:

• Requires Genetic Engineering Appraisal Committee (GEAC) approval after RCGM
• Environmental risk assessment becomes critical

The GEAC involvement is due to the environmental and biosafety risks posed by LMO end products.

Protocol III: Import of Finished Formulations (End Product Is an LMO)

Scenario: Import and marketing of finished pharmaceutical products that are LMOs.

Steps Include:

• Import license application through CDSCO
• GEAC approval required
• No indigenous R&D steps

This pathway avoids early-stage R&D oversight in India but enforces biosafety via import scrutiny and GEAC clearance.

Protocol IV: Import of Bulk LMOs for Local Formulation

Scenario: Import of bulk LMO material for making finished formulations in India.

Steps:

• GEAC and RCGM clearance required
• Local formulation under CDSCO oversight
• Marketing license post-manufacture

This pathway supports local formulation using imported LMO substances under strict regulatory conditions.

Protocol V: Import of Non-LMO End Products Derived from LMOs

Scenario: Import of products (bulk or finished) derived from LMOs but where the end product is not itself an LMO.

Steps:

• CDSCO manages most of the approvals
• GEAC approval generally not required
• RCGM oversight may still be required depending on the derivation source

This is the least complex protocol among imports due to the non-LMO nature of the end product.⁷

Draft CDSCO Guidelines 2025 on Similar Biologics: Purpose, Revisions, and Stakeholder Engagement

In a significant move to align with evolving global standards and scientific advancements, the Central Drugs Standard Control Organization (CDSCO), in collaboration with the Department of Biotechnology (DBT), has released the Draft Guidelines on Similar Biologics – Regulatory Requirements for Marketing Authorization in India, 2025. Published on 6th May 2025, the draft is now open for public consultation. Stakeholders are invited to review the proposed changes and submit their comments and suggestions within 30 days of publication. Once finalized, the scope for further modifications will be minimal, making this consultation phase a critical opportunity for industry experts, researchers, and regulatory professionals to contribute.

Purpose of the Draft Guidelines

1. Scientific and Regulatory Alignment:
   • To update the 2016 guidelines in line with international standards such as WHO TRS 1043 (2022).
   • Reflects the latest advancements in analytical and biotechnological sciences.
2. Support Industry & Regulatory Clarity:
   • Provides a clear, science-based and flexible regulatory pathway for market authorization of similar biologics in India.
   • Helps manufacturers design better development strategies and reduce unnecessary studies.
3. Public Consultation Objective:
   • To gather comments/suggestions from stakeholders (industry, researchers, regulators, etc.).
   • Ensure the final document is inclusive, scientifically robust, and implementable.

Key Revisions and Changes in 2025 Draft Guidelines

1. Scientific Considerations Introduced
   • Emphasis on stepwise comparability using orthogonal analytical tools.
   • Focus on strengthening in vitro studies over traditional in vivo animal studies.
2. Updated Licensing Framework
   • Clearer and more comprehensive principles for licensing of similar biologics.
   • Inclusion of newer statistical approaches for establishing similarity ranges.
3. Revised Quality Section
   • Introduction of next-generation analytical methods.
   • Detailed guidance on the use of reference standards and the development of in-house standards.
4. Minimizing Animal Use (3Rs Principle)
   • Strong shift toward reducing animal testing.
   • Waiver of in vivo studies is possible under clearly defined conditions.
5. New Sections and Enhancements
   • Risk Management Plan (RMP) and Post-Market Surveillance elaborated.
   • Clear guidance on extrapolation of efficacy/safety data to other indications.
6. Updated Clinical Study Guidelines
   • Inclusion of confirmatory PK/PD study requirements.
   • Conditions for waiver of clinical efficacy/safety studies are provided.
7. Clarified Statistical Requirements
   • Use of mean ± SD, min-max, or tolerance intervals for similarity assessments.
   • Stronger emphasis on critical quality attributes (CQAs) and batch consistency.
8. New Annexures Added
   • Pathways for:
     • Indigenous development.
     • Imported similar biologics.
   • Annexures on critical quality attributes, statistical tools, and toxicology study requirements.

These guidelines represent a major regulatory evolution for biosimilars in India and aim to simplify development, enhance global alignment, and support patient safety.⁸

Key Highlights from Central Drug Testing Laboratory (Cdtl) Mumbai's Annual Report 2021-22

The CDTL Mumbai Annual Report 2021–22 provides a comprehensive view of India's maturing drug regulatory framework. From testing nearly 3,000 drug samples and preparing over 40 in-house reference standards to contributing to international pharmacopoeial development and publishing research on complex molecules like Remdesivir and Olaparib, the lab stands as a testament to CDSCO's expanding regulatory capacity. Particularly during the COVID-19 crisis, CDTL's rapid testing of critical biologics demonstrated the robustness and responsiveness essential for biosimilar regulation.

1. Monthly Sample Receipt, Reporting, and Status

   Total samples received and analysed from April 2021 to March 2022
   Month/Year	Received	Reported*	Pass	Fail NSQ	Under analysis at the end of the month
   Apr- 2021	111	176	172	4	153
   May-2021	165	129	122	7	186
   Jun-2021	288	171	165	6	299
   Jul- 2021	269	230	223	7	337
   Aug-2021	224	255	250	5	297
   Sep-2021	278	256	247	9	319
   Oct-2021	270	240	236	4	349
   Nov-2021	262	271	264	7	340
   Dec-2021	268	274	263	11	331
   Jan-2022	256	195	191	4	305
   Feb-2022	256	195	191	4	305
   Mar-2022	416	285	272	13	436
   Total	2,958	2,698	2,618	80	–
   *Note: Samples reported include the samples received in previous months/years

   
   This table presents a month-wise breakdown of the total number of samples received, analyzed (reported), passed, and failed, along with the number of samples still under analysis at the end of each month. It shows that CDTL Mumbai received a total of 2,958 samples from April 2021 to March 2022. Out of these, 2,698 samples were analyzed and reported, with 2,618 found compliant (pass) and 80 marked as non-compliant (fail). Notably, March 2022 saw the highest influx of samples (416), possibly due to year-end regulatory filings. The "under analysis" column indicates that backlog management is ongoing, reflecting the laboratory's continuous testing load. The month-wise trend also highlights increased workload during mid and later quarters of the year, especially from July to December. The data demonstrates both the volume and pace of regulatory sample handling at the national level.
   
   
2. Category-Wise Status of Samples Tested
   
   

   Category-wise status of samples tested during the period April 2021 to March 2022
   Sample Type	Received during the year (2021-22)	Pass	Fail	Total Reported
   Import	586	527	22	549
   Registration	650	609	11	620
   Zonal Survey Samples	642	531	2	533
   New Drugs	112	108	4	112
   Miscellaneous	54	40	1	41
   Legal Samples	815	715	40	755
   Inter Laboratory Comparison	93	86	_	86
   Proficiency	2	1	_	1
   Medical Device	4	1	_	1
   Total	2,958	2,618	80	2,698

   This table classifies the tested samples by their regulatory origin or purpose and provides insights into the diversity of CDTL's work. The highest number of samples came under Legal (815) and Registration (650) categories, followed by Zonal Survey Samples (642) and Import Samples (586). These categories represent different regulatory checkpoints such as surveillance, approval, and customs clearance. The table also notes that 112 New Drug samples were received — critical from a drug approval and innovation perspective — with a high compliance rate (96%). Inter-laboratory comparison and proficiency testing samples reflect CDTL's commitment to internal quality checks and benchmarking. Overall, the table emphasizes the lab's essential role in maintaining regulatory oversight and supporting new drug and biosimilar evaluations across various segments of India's pharmaceutical pipeline.
3. Sample Output and Number of Tests Performed
   
   

   	Chemical Division
   Months	Backlog Sample	Samples Received	Total Samples	Reported Samples	No. of Tests Performed	HPLC Test
   April-2021	46	87	133	96	650	176
   May-2021	38	99	133	68	751	136
   June-2021	65	126	182	107	1,068	272
   July-2021	68	144	212	124	1,088	339
   Aug-2021	121	187	308	186	1,427	410
   Sept-2021	122	185	307	179	1,287	390
   Oct-2021	128	157	287	171	1,119	285
   Nov-2021	121	184	305	199	1,162	306
   Dec-2021	106	174	280	168	1,093	486
   Jan-2022	112	155	267	155	962	276
   Feb-2022	112	167	279	152	1,129	326
   March-2022	124	266	390	213	1,509	366
   Total	1,163	1,931	3,083	1,818	13,245	3,768

   
   

   	Biological Division
   Months	Backlog Sample	Samples Received	Total Samples	Reported Samples	No. of Tests Performed	HPLC Test
   April-2021	59	76	135	87	505	143
   May-2021	48	72	120	77	662	125
   June-2021	43	96	136	76	839	160
   July-2021	43	136	179	93	799	180
   Aug-2021	53	67	120	81	609	133
   Sept-2021	39	71	115	87	647	140
   Oct-2021	28	65	99	64	416	98
   Nov-2021	35	83	118	71	446	92
   Dec-2021	47	83	130	86	513	115
   Jan-2022	44	49	93	68	368	76
   Feb-2022	25	68	93	57	314	61
   March-2022	38	97	135	66	573	92
   Total	502	963	1,473	913	6,691	1,415

4. Revenue Generation from Regulatory Testing
   • CDTL Mumbai collected ₹25,38,435 in testing fees during 2021–22.
   • This was mainly from registration samples, new drugs, and miscellaneous regulatory submissions.
   • Revenue was deposited into the Government of India account via Bharat Kosh.

   This demonstrates the active regulatory function and financial value of centralized drug testing as part of the drug approval pipeline.

5. Emergency Testing During COVID-19 CDTL played a critical role during the pandemic by prioritizing the testing of life-saving drugs such as:
   • Remdesivir (injection, sublingual tablets, oral solution)
   • Favipiravir
   • Amphotericin B
   • Umifenovir

   These drugs were tested on an urgent basis, including weekends and off days, to ensure quick turnaround for regulatory release and hospital use.

   It demonstrates the responsiveness of India's regulatory labs during public health crises, which includes biologic drug testing relevant to biosimilars.

6. Reference Standards Management
   • The lab handled 1603 reference materials, including:
     • 30 Indian Pharmacopoeia Reference Standards (IPRS)
     • 47 EP Pharmacopoeia CRS
     • 50 Candidate Materials from manufacturers
     • 186 Remnant Samples used for creating working standards
   • 46 Secondary Reference Standards were prepared in-house, which helps reduce dependence on costly imported standards and supports local testing of biosimilars.

   This shows CDTL's role in developing validated benchmarks for consistency in analytical testing — a vital component of biosimilar comparability.

7. Quality Assurance & Accreditation
   • Successfully completed NABL Reaccreditation (ISO/IEC 17025:2017) and IMS Recertification (ISO 9001, 14001, 45001).
   • Actively participated in Proficiency Testing (PT) and Inter-Laboratory Comparison (ILC) programs.
   • Expanded scope of testing to include new parameters (e.g., UV assay, sterility, BET, pH for skin creams).

   CDSCO and its labs are internationally compliant and technically capable of regulating biosimilars and complex generics.

8. Research and Method Development
   • 15 research papers published on method development and validation using HPLC and UV spectrophotometry, which are core methods in biosimilar characterization.
   • Research covered drugs such as:
     • Capmatinib
     • Ribociclib
     • Remdesivir (oral and sublingual)
     • Olaparib, Abemaciclib, Siponimod, etc.
   • 13 M. Pharm students completed project work on analytical research under CDTL guidance.

   CDSCO's labs are not only testing hubs but also centers for pharmaceutical research and academic training.

9. Standards Development & BIS Involvement
   • Central Drugs Testing Laboratory (CDTL) actively contributed to the Bureau of Indian Standards (BIS) and the International Organization for Standardization (ISO) committees for:
     • Medical devices (Intrauterine contraceptive devices, condoms, menstrual cups)
     • Cosmetic regulations
   • Reviewed and commented on international drafts and Indian standards in various ISO and BIS ballots.

   This shows alignment of Indian regulatory practices with global standard-setting bodies, improving harmonization, crucial for biosimilar acceptance globally.⁹

CONCLUSION

As India's central drug regulatory authority, CDSCO plays a pivotal role in ensuring that safe, effective, and quality medicines reach patients. Its evolving regulatory landscape—especially in the area of biosimilars—reflects a growing commitment to innovation, transparency, and global harmonization. The 2016 biosimilar guidelines laid a foundational framework for approval processes, while the 2025 draft guidelines aim to refine and strengthen regulatory pathways further, addressing emerging scientific and clinical considerations. Recent drug approvals and insights from the latest annual report underscore CDSCO's proactive efforts in aligning with global standards while catering to national healthcare needs. Moving forward, such regulatory advancements are expected to support faster access to life-saving therapies, foster local innovation, and strengthen India's position as a global pharmaceutical hub.

Footnotes

1. https://cdsco.gov.in/opencms/opencms/en/Home/?ut

2. Drugs and Cosmetics Act, 1940 – Wikipedia

3. https://cdsco.gov.in/opencms/opencms/en/Home/?ut

4. https://www.cdsco.gov.in/opencms/opencms/en/About-us/Functions/

5. https://cdscoonline.gov.in/CDSCO/cdscoDrugs

6. Biosimilars in India; Current Status and Future Perspectives – PMC

7. https://cdsco.gov.in/opencms/resources/UploadCDSCOWeb/2018/UploadAlertsFiles/BiosimilarGuideline2016.pdf

8. https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/DgSimilaBiologics25.pdf

9. https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/CDTL-Mumbai/AnnexureXI23.pdf

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