Biomanufacturing BE308: Regulators and Guidelines

Introduction to Biomanufacturing BE308

• Course title: Introduction to Biomanufacturing
• Course number: BE308
• Instructor: Dr. Sumit Murab
• Instructor email: [email protected]
• Website: https://sites.google.com/iitmandi.ac.in/murab-group
• Focus: Industrial Scaleup

Regulators in India

• CDSCO (Central Drug Standard Control Organization): Regulatory authority in India focusing on drug safety and efficacy.
• DBT (Department of Biotechnology) and RCGM (Review Committee of Genetic Manipulation): Responsible for pre-clinical evaluation of recombinant biologics.
• Aims to ensure safety, quality, and efficacy of similar biological products.
• Authorize and comply with regulatory requirements for similar biologics in India.

Applicable Regulations and Guidelines

• Governed by the Drugs and Cosmetics Act, 1940, the Drugs and Cosmetics Rules, 1945.
• Environment (Protection) Act, 1986 Rules for hazardous microorganisms, genetically engineered organisms or cells (1989).
• Relevant guidelines include:
  • Recombinant DNA Safety Guidelines (1990).
  • Guidelines for generating preclinical and clinical data for rDNA vaccines, diagnostics, and other Biologicals (1999).
  • CDSCO guidance for industry (2008)
  • Guidelines & Handbook for Institutional Biosafety Committees (IBSCs) (2011)
  • Guidelines on Similar Biologics: Regulatory Requirements for Marketing authorization in India (2012)

Competent Authorities

• Institutional BioSafety Committee (IBSC): Responsible for biosafety review and authorization of microorganisms and genetically engineered organisms for research.
• Review Committee on Genetic Manipulation (RCGM): Authorizes research, development, exchange of genetically engineered cell banks, and pre-clinical evaluation data.
• Genetic Engineering Appraisal Committee (GEAC): Statutory body for reviewing genetically modified organisms/living modified organisms activities.
• Central Drugs Standard Control Organization (CDSCO): Apex regulatory body for clinical trial approvals, drug import/export, and manufacturing/marketing approvals.

Principles for Development of Similar Biologics

• Mandatory to prove similar biologics meet acknowledged levels of the reference biologic to ensure public health and consistency in production.
• Selecting a reference biologic is crucial depending on DBT and CDSCO guidelines.
• Licensed, well-distributed reference biologics are preferred for minimum 4 years.
• Same reference biologic should be used in the complete study.

Manufacturing Process

• Stable and robust manufacturing process is essential.
• Identical host cell lines are crucial if used for the reference biologic.
• ICH guidelines (Q5A, Q5B, Q5D) are guidelines for cell bank initiation and characterization.
• Molecular biological considerations, such as host cell cultures, vectors, and gene sequences, are critical.
• Fermentation process must be controlled, replicable and scalable, tracking factors such as pH, temperature, and oxygen levels.
• Data on all manufacturing batches must be maintained.

Downstream Process Development

• Focuses on protein purification processes.
• Describes the purification steps & refolding process.
• Dose-response curve is essential to describe the activity of the product at various doses.
• Continuous recovery over three batches required during the purification process.
• Maintaining GMP during the manufacture & production process. Record detailed descriptions of drug substances, critical quality attributes of the product, and critical process parameters.
• Critical data for comparability (clinical scale vs reference biologics), stability, and validation batches.

Quality Based Considerations for Similar Biologics

• Analytical Methods: Employ multiple, orthogonal methods for characterizing products (batch release, stability studies, in-process controls); follow ICH Q2, Q5C, Q6B guidelines.
• Product Characterization: Detail physicochemical, biological, immunological properties; include functional assays, purity, and contamination assessments.
• Structural and Physicochemical Properties (primary and higher order structure). Accuracy and precision in measurements.
• Biological Activity: In accordance with reference biologic; matching the mechanism of action, and considering clinical effects.
• Immunological Properties: Understand associated impurities, post-translational modifications, and factors such as specificity, affinity, and binding strength analysis.
• Purity and Impurities: Identification of product variants, impurities including aggregated products, host-cell related impurities, and process-related impurities.
• Specifications: Specifications methodologies are distinct from analytical methods, with acceptance limits based on available data.
• Stability: Shelf life regulation in conditions/containers identified by ICH Q5C guidelines.
• Quality Comparability Study: Compare the similar biologic to a reference biologic using appropriate methodologies in accordance with CDSCO's guidance for industry 2008. Three batches for quality consistency assessment.

Data Requirements for Pre-Clinical Studies

• A): Applicant provides pre-clinical study protocols, toxicology study data (drug administration, dosage, absorption, elimination rate, mechanism of action, toxicity).
• B): Includes pharmacodynamic studies. In-vitro studies for cell proliferation & in-vivo studies for biological and pharmacodynamic activity assessment per rodent & non-rodent species guidelines. Includes toxicity studies. The study procedure and animal selection justification is mandatory.
• C): Reporting on the immune response in animals, antibody response, serum sample analysis (comparing with reference biologic responses). Reporting to RCGM for review.

Data Requirements for Clinical Trial Application

• A): Pharmacokinetic studies comparing similar & reference biologic in healthy volunteers including half-life, linearity, and route/conditions for administration
• B): Pharmacodynamic studies comparing similar & reference biologic in healthy animals. Assessing response & efficacy within a phase III design. Should be contrast in nature.
• C): Confirmatory safety and efficacy studies: matching clinical compatibility and end points. Systemic and functional comparability of similar and reference biologic.
• D): Post-marketing safety and immunogenicity data based on pre-clinical and post-clinical data.

Data Requirements for Marketing Authorization Application

• Pharmacovigilance plan; including ADR reporting within 15 days to CDSCO, and Periodic Safety Update Reports (PSURs) submitted every six months.
• Post-market studies: detailed studies noted in the Pharmacovigilance plan, submitted to CDSCO. Records related to risk assessments.

This quiz focuses on the regulatory framework governing biomanufacturing in India, as discussed in the course Introduction to Biomanufacturing BE308. Key regulatory authorities, applicable regulations, and safety measures are highlighted to ensure compliance in the biomanufacturing industry. Test your understanding of these critical components now!