Key Notes on Revised Schedule M: Biological products

Last Updated on January 15, 2025 by The Health Master

Biological products

Key considerations for Biological products for compliance under revised Schedule M are outlined below.

Continued from: Key Notes on Revised Schedule M: Sterile products

Good Manufacturing Practices for Pharmaceutical Products

Revised Schedule M: Specific Requirements for Manufacture of Biological Products

Key requirements

• Source materials and methods used in manufacturing biological products are critical factors for their regulatory control.
• Biological products are derived from cells, tissues, or microorganisms and can be highly variable.
• Special considerations are needed to ensure consistency in product quality during the manufacture of biological products.
• The revised Schedule M provides guidance for the manufacture, control, and testing of biological products for human use.

Key points of revised Schedule M

• It applies to the manufacture, control, and testing of biological products from starting materials to finished products.
• Manufacturing processes include growing microorganisms and eukaryotic cells, extracting substances from biological tissues, using recombinant DNA (rDNA) techniques, and propagating microorganisms in embryos or animals.
• Medicinal products of biological origin manufactured by these procedures include allergens, antigens, vaccines, hormones, cytokines, monoclonal antibodies, enzymes, animal immune sera, fermentation products, and Advanced Therapy Medicinal Products (ATMPs).
• The manufacture, control, and administration of biological products require special considerations due to the nature of these products and their processes.
• Unlike conventional pharmaceutical products, biological products involve biological processes and materials, which can be variable.
• Strict controls are necessary to minimize contamination risks.
• Many biological materials cannot be terminally sterilized using heat, gas, or radiation. Aseptic processing must be conducted to minimize the introduction of contaminants.
• Control of biological products usually involves biological analytical techniques, which can be more variable than physicochemical determinations.
• Because of the risks inherent in producing and manipulating pathogenic microorganisms, GMP emphasizes the safety of the recipient, personnel, and the environment.

Containment:

• Airborne dissemination of live microorganisms and viruses must be prevented.
• Proper precautions are necessary to avoid contaminating the drainage system.
• Dedicated production areas are required for handling high-risk organisms.
• Containment requirements for specific products like BCG and poliovirus must be followed.
• Air-handling systems should minimize cross-contamination between areas.
• Primary containment equipment must be designed and maintained to prevent the escape of biological agents.
• Activities with aerosol formation must be contained to prevent contamination.
• Areas handling high-risk organisms must have negative air pressure.
• Air vent filters must be hydrophobic and subject to integrity testing.

Clean Rooms:

• Environmental monitoring of clean rooms should be tailored to the specific manufacturing process.
• The environmental monitoring program should include methods to detect specific microorganisms used in production.

Production:

• Strict controls are necessary to prevent unwanted bioburden, endotoxins, and viruses.
• QRM principles should guide the implementation of contamination control measures.
• Inoculum preparation areas should be designed to control contamination risk.
• Growth media should be sterilized in-situ whenever possible.
• Data from continuous monitoring of fermentation processes should be recorded.
• Measures should be taken to avoid recontamination of treated products.
• Purification equipment and components must be carefully controlled and validated.
• Procedures must be in place to address adverse donor health information.
• Antibiotics may be used during early stages of production with specific justifications and limitations.

Campaign Production:

• The decision to use campaign production must be justified based on a risk assessment.
• Campaign changeover procedures, including decontamination and cleaning, must be validated.
• Campaign production requires careful consideration of facility layout and design.

Labelling:

• Information on the inner and outer labels should be clear, legible, and approved by the licensing authority.
• Labels must be suitable for low and ultra-low storage temperatures.

Validation:

• Biological processes, handling of live materials, and campaign production require thorough process and cleaning validation.
• QRM should be used to determine the scope and extent of validation.
• Critical biological processes must be validated, including inoculation, fermentation, inactivation, and purification.
• Cleaning validation must confirm the effectiveness of cleaning procedures.
• Process revalidation may be triggered by process changes or at predetermined intervals.

Quality Control:

• Special considerations should be given to the nature of the materials being sampled for quality control.
• Reference and retention samples must be stored appropriately.
• Microbiological tests for cell-based products should be conducted on cultures free of antibiotics.
• All analytical methods used in quality control must be well-characterized and validated.

Documentation:

• Manufacturing batch records must provide a complete account of the manufacturing activities.
• Starting materials may require additional documentation on source, origin, and supply chain.

Use of Animals:

• The presence of live animals in the production area should be avoided whenever possible.
• Areas used for animal testing should be well-separated from production areas.
• Measures must be taken to prevent and monitor infections in source or donor animals.
• Traceability must be maintained for products manufactured from transgenic animals.

Complaints:

• The person responsible for handling complaints should have appropriate training or experience in the specific features of biological product quality control.
• Complaints can be categorized into product quality complaints and adverse reactions/events.
• Product quality complaints, such as faulty manufacture, product defects, or adulteration, must be thoroughly investigated.
• Adverse reaction/event reports must be entered into a separate register and investigated to determine if they are related to product quality.
• Pharmacovigilance systems are crucial for the safety monitoring of biological products.
• The licensing authority must be informed of any complaints leading to a recall or restriction on supply.

Product Recalls:

• A robust Recall and Rapid Alert System for Drugs (including Biologicals and Vaccines) must be in place.

Please note: This information is for general guidance only and may not be exhaustive. Refer to the official regulations and any applicable guidance documents for specific requirements and interpretations.

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Compiled by:
Rakesh Dahiya, SDCO cum Licensing Authority, FDA Haryana

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Next: Key Notes on Revised Schedule M: API (Active Pharmaceutical Ingredients) ….coming soon

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