Introduction to Biomanufacturing BE308 Regulations PDF

Introduction to Biomanufacturing BE308 Industrial Scaleup Instructor Dr. Sumit Murab [email protected] https://sites.google.com/iitmandi.ac.in/murab-group  Regulators in India CDSCO (Central Drug Standa...

Introduction to Biomanufacturing BE308 Industrial Scaleup Instructor Dr. Sumit Murab [email protected] https://sites.google.com/iitmandi.ac.in/murab-group  Regulators in India CDSCO (Central Drug Standard Control Organization) is a regulatory authority of India and which access and concentrates mainly on the safety and effectiveness of the drugs in the country. DBT (Department of Biotechnology) and RCGM (Review Committee of Genetic Manipulation) is accountable for the pre-clinical evaluation of recombinant biologics. Gives a clear idea to confirm the safety, quality and efficacy of the similar biologic product. The significant aim of this guideline is to authorize and comply with regulatory requirements for authorization of similar biologics in India. Applicable Regulations and Guidelines The Similar Biologics are regulated as per the Drugs and Cosmetics Act, 1940, the Drugs and Cosmetics Rules, 1945 (as amended from time to time) and Rules for the manufacture, use, import, export and storage of hazardous microorganisms/ genetically engineered organisms or cells, 1989 (Rules, 1989) notified under the Environment (Protection) Act, 1986. Various applicable guidelines are as follows: 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: Submission of Clinical Trial Application for Evaluating Safety and Efficacy Requirement for permission of New Drug Approval Post approval changes in Biological products: Quality, Safety and Efficacy Documents Preparation of Quality Information for Drug Submission for New Drug Approval: Biotechnological/Biological Products Guidelines and 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) IBSC is required to be constituted by any person including research institutions handling hazardous microorganisms and/ or genetically engineered organisms. IBSC is responsible for ensuring biosafety on-site, along with initial review of applications to be recommended to RCGM. IBSC is also assigned with the responsibility to review and authorize firm for exchange of aforesaid organisms for the purpose of research. Review Committee on Genetic Manipulation (RCGM) RCGM is functioning from the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India. In the context of Similar Biologics, RCGM is responsible for authorizing the conduct of research and development, exchange of genetically engineered cell banks for the purpose of research and development and review of data up to preclinical evaluation. Genetic Engineering Appraisal Committee (GEAC) GEAC functions under the Ministry of Environment and Forests (MoEF) as statutory body for review of applications and approval of activities where final drug product contains genetically modified organisms/ living modified organisms. (RCGM and GEAC are statutory committees set up as per provisions of Rules, 1989) Central Drugs Standard Control Organization (CDSCO) CDSCO, headed by the Drug Controller General of India (DCGI) is the apex regulatory body under Ministry of Health & Family Welfare (MoHFW), Government of India, which is responsible for the approval of clinical trials as well as new drugs. In the context of Similar Biologics, CDSCO is responsible for clinical trial approval (also grants permission for import of drugs for clinical trial and export of clinical samples for biochemical and immunological analysis) and permission for manufacturing and marketing. Zonal offices of CDSCO are responsible for authorizing import of drugs for examination, test and analysis for research and development. Principles for Development of Similar Biologics It is mandatory to prove the similar biologicals meet the acknowledged levels of the reference biologic products to make sure the public health. The consistency of production process may vary depends on reference biologic. Selection of reference biologic: It is necessary for development of similar biologic. It depends upon the DBT & CDSCO. The reference biologic should be Licensed in India and should be discoverer product. If it is not licensed in India, it should be widely distributed for minimum of 4 years in accordance with their regulatory guidelines. The same reference biologic product should be utilized to fill the complete of the whole study Manufacturing process This process should be stable and strong. In case if the host cell line is used for the manufacture of reference biologic, the same should be used for Three batches should carry out the replicate fermentation the similar biologic product. In order to initiate and characterize the cell banks the guidelines framed by the ICH can be used such as Q5A,Q5B,Q5D guidelines are preferred. Fermentation process must be operated in a controlled environment Some of the outcomes are listed below: Factors such as PH, temperature and dissolved oxygen a) Molecular biologic considerations: should be noted The information based on the host cell cultures, vectors, gene sequences, promoters are used in the manufacturing of similar biologics. If there is Production should be replicatable and scalable. any up-right translational manufacturing such as Data should remain sustained for all the batches. glycoylation, oxidation should be detailed. b) Fermentation process development: Downstream Process development It is used for protein purification processes. The functioning step during purification to recovery state should be described briefly. It should explain the refolding process, particular activity at various doses, Dose response curve. There should be a continuous recovery in three batches. In case of submitting the clinical trial application. A proper GMP should be maintained during the manufacture and production process. The data includes- i) Detailed description of drug substance ii) Critical quality attributes of product iii) Critical process parameters iv) Stability data v) Comparability of product manufactured at clinical scale against reference biologics. vi) Data from consistency batches and /or process validation batches as applicable. Quality based considerations for similar biologics a) Analytical methods: Selected based upon the critical quality attributes of the product.eg: Multiple, orthogonal methods are preferred for characterization. Methods used to measure those attributes are batch release, stability studies and in-process controls are checked according to the ICH guidelines, ICH Q2,Q5C,Q6B b) Product characterization: The similar biologic product should includethe characterization and properties of physicochemical, biological, immunological properties, functional assays, purity, contamination and strength. i) Structural and Physicochemical properties: It includes the determination of primary and higher order structure of products along with the important physicochemical properties. It also includes the accuracy and the precision. Quality based considerations for similar biologics ii) Biological activity: The biological products have many number of biotic activity. The product should initiate the mechanism of action and clinical effects. It should be matched to that of standards if not it should be marked as per ICH guidelines. iii) Immunological properties: The recombinant biologics may influence the associated impurities and post translational modifications of the product. It may also examine the factors such as specificity, affinity, binding strength iv) Purity and impurities: Some of the analytical procedures can also be done. Product allied variants: glycoforms, isomers Product allied impurities: aggregated products Host-cell related impurities Process related impurities Quality based considerations for similar biologics c) Specifications: Specifications methods are not more same as that of analytical methods. Acceptance limits are set based on the instance of the biologic data. d) Stability: To regulate the shelf-life of the product. This is connected on containers and conditions based on the ICH guidelines ICH Q5C iv) Quality Comparability study: Quality comparison is analyzed between the similar biologic and reference biologic. The complete dossier should be given as per CDSCO guidance for industry 2008.Three batches are subjected for demonstrating the consistency of the quality system. Data requirements for pre-clinical studies: A) The applicant should present the data created along with pre- clinical study protocols to RCGM for acquiring permission. Toxicology studies should start once, the permission from RCGM. Some of the information’s are required such as: Information on drug administration, dosage, absorption and eliminate rate Mechanism of Action Available toxicity data Data requirements for pre-clinical studies: B) Pre-clinical studies: It is performed before the clinical studies. It is necessary for the contrasting the similar biologic and reference biologic. Factors such as dosage form, strength and route of administration should be justified. i) Pharmacodynamic studies: In-vitro: Comparative tests and reference biologics.eg: Cell proliferation assay. In-vivo: Assessment of biological and Pharmacodynamic activity. ii) Toxicological studies: In in vivo toxicity studies, one repeat dose toxicity must be performed, during this study the animal utilized for this study should give a proper justification for sacrificing. These studies are performed based on the two species i.e rodent and non-rodent species as stated by the schedule Y with permission on RCGM. Data requirements for pre-clinical studies: The dose toxicity testing will consists of: IAEC approval Historical control QA statement Vehicle control Animal feed Vehicle control for recovery groups Discussion on the results 1X reference biologic for study duration Conclusion 5X high dose similar biologic. The protocol and the study reports should consists of : Methodology before euthanasia C) Immune response in animals: Events directly after euthanasia Antibody response in animals is differentiated with reference biologic that of a similar biologic. The serum samples are Biochemical parameters experimented for reaction to host cell proteins. After the Hematology finalization of pre-clinical studies, the reports are submitted to RCGM for review and consideration. Statistical methods. The final report of study should consists of RCGM approval of protocol IBSC approval of report Data requirements for clinical trial application: The applicants have to submit the application for the b) Pharmacodynamic studies: conduct of clinical trial as per CDSCO 2008 guidance. These studies are also contrast in nature. Design a) Pharmacokinetic studies: considerations involved here are: These studies are conducted in health volunteers to Comparative contrast between the similar biologic and reference biologic. Some of the factors have been considered. Parallel arm (or) cross over Half life Pharmacodynamic studies are conducted only in healthy animals. The response/efficacy of the Linearity to pharmacokinetic parameters instance biologic Conditions and diseases to be treated Should be same to that in order to rationalize the design. It is a section of phase III clinical trials. Route of administration Indications. Design considerations: Single dose, comparative PK studies Parallel arm Cross-over Data requirements for clinical trial application: c) Confirmatory safety and efficacy study: This is mandatory for all the similar biologics in order to demonstrate its safety and efficacy. Well matched clinical compatibility and end points should be justified according to their design. If trials are not essential it should be given clarification and applicants should submit their application according to CDSCO. It makes sure a difference between similar biologic and reference biologic The clinical trials are confirmed based on the conditions below: 1. Systemic and functional comparability of similar and reference biologic 2. Comparable 3. Post-marketing d) Safety and immunogenicity data: Evaluation based on pre-clinical trials and post clinical data which presents with the complete set of safety and immunogenicity data. Data requirements for marketing authorization application The applicant should present their application according to the CDSCO guidance document as per 2008. The report and protocol of phase III clinical trial is mandatory. The comparability test between the similar and reference biologic should also be attached. Post-market data for similar biologics: The similar biologic is same that of a reference biologic and it is necessary to submit the risk assessment plan. The plan involves: a) Pharmacovigilance plan: The plan is like it is necessary to submit the PSURs (Periodic Safety Update Reports) and should be submitted every six month after the submission of application. b) ADR reporting: Serious adverse events should be reported within 15 days as per schedule c) Post-marketing studies: The post-marketing studies are noted on the pharmacovigilance plan and updated studies should be submitted to CDSCO.