Annex 2 to the Good manufacturing practices guide - Manufacture of biologics (GUI-0027): Guidance on product types

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• Animal-sourced products
• Allergen products
• Animal immunosera products
• Vaccines
• Recombinant products
• Monoclonal antibody products
• Transgenic animal products
• Transgenic plant products
• Products from human blood or plasma

This guidance applies to animal materials, which includes materials from establishments such as abattoirs. As the supply chains can be extensive and complex, controls based on quality risk management (QRM) principles must be applied.

Appropriate pharmacopoeial monographs, including the need for specific tests at defined stages, are also required. There should be documentation to demonstrate the supply chain traceability and clear roles of participants in the supply chain. Such documentation should include a sufficiently detailed, up-to-date process map.

Animal-sourced products

Organizations should implement monitoring programs for animal diseases that are of concern to human health. They should:

• consider reports from trustworthy sources on disease prevalence when compiling their assessment of risk and mitigation factors
  • trustworthy sources include the World Organization for Animal Health (OIE, Office International des Epizooties)
• supplement these reports with information on health monitoring and control program(s)
• include sources (such as farm or feedlot) from which the animals are drawn
• document the control measures in place for transporting the animals to the abattoirs

For more information, consult the following Canadian Food Inspection Agency web pages:

• Humane transport – Animal welfare
• Codes of practice for the care and handling of farm animals

Abattoirs are used to source animal tissues should be shown to operate to stringent standards. Account should be taken of reports from agencies and/or organizations that verify compliance with food, safety and quality, veterinary and plant health legislation and requirements.

Control measures for the biological starting or raw materials at establishments such as abattoirs should include the appropriate elements of a quality management system to assure a satisfactory level of operator training, materials traceability control and consistency.

Control measures for processing starting or raw materials should be in place. The measures should prevent delays that may affect the quality of materials. Any delays need to be documented so that their effect can be assessed throughout the manufacturing and supply chain. This includes the movement of material between sites of initial collection, partial and final purification(s), storage sites, hubs, consolidators and brokers. Details of such arrangements should be recorded within the traceability system and any breaches recorded, investigated and actions taken.

Regular audits of the starting or raw material supplier should be undertaken to verify compliance with controls for materials at the different stages of manufacture. Issues must be investigated to a depth appropriate to their significance, for which full documentation should be available. Systems should also be in place to ensure that effective corrective and preventive actions are taken.

Allergen products

Materials may be manufactured by extraction from natural sources or manufactured by recombinant DNA technology.

Source materials should be described in sufficient detail to ensure consistency in their supply. Details include common and scientific name, origin, nature, contaminant limits and method of collection. Those from animals should be from healthy sources. Appropriate biosecurity controls should be in place for colonies (for example, mites, animals) used to extract allergens. Allergen products should be stored under defined conditions to minimize deterioration.

Production process steps, including pre-treatment, extraction, filtration, dialysis, concentration or freeze-drying, should be described in detail and validated.

Modification processes to manufacture modified allergen extracts (for example, allergoids, conjugates) should be described. Intermediates in the manufacturing process should be identified and controlled.

Allergen extract mixtures should be prepared from individual extracts from single-source materials. Each individual extract should be considered as 1 active ingredient.

Animal immunosera products

Care should be taken for the control of antigens of biological origin to assure their quality, consistency and freedom from adventitious agents. The preparation of materials used to immunize the source animals (for example, antigens, hapten carriers, adjuvants, stabilising agents) and the storage of such materials immediately prior to immunization should follow documented procedures.

The immunization, test bleed and harvest bleed schedules should conform to those approved in the clinical trial authorization (CTA) or marketing authorization (MA).

The manufacturing conditions for preparing antibody sub-fragments (for example, Fab or F(ab')₂) and any further modifications must be in accordance with validated and approved parameters. The consistency of those products that are made up of several components should be assured.

Vaccines

Where eggs are used, the health status of all source flocks (whether specified pathogen-free or healthy flocks) should be assured.

The integrity of containers used to store bulk process intermediate product and the hold times must be validated.

Vessels containing inactivated products should not be opened or sampled in areas containing live biological agents.

The sequence for adding active ingredients, adjuvants and excipients during the formulation of a bulk process intermediate or a drug in dosage form must comply with specifications.

Where organisms with a higher containment level (for example, pandemic vaccine strains) are used in manufacture or testing, appropriate containment arrangements must be in place. The approval of such arrangements should be obtained and the approval documents be available for verification.

Recombinant products

Process condition during cell growth, protein expression and purification must be maintained within validated parameters. This is to assure a consistent product with a defined range of impurities that is within the capability of the process to reduce to acceptable levels. The type of cell used in production may require that increased measures be taken to assure freedom from viruses. For production involving multiple harvests, the period of continuous cultivation should be within specified limits.

The purification processes to remove unwanted host cell proteins, nucleic acids, carbohydrates, viruses and other impurities should be within defined validated limits.

Monoclonal antibody products

Monoclonal antibodies may be manufactured from murine hybridomas, human hybridomas or recombinant DNA technology. Control measures appropriate to the different source cells (including feeder cells if used) and materials used to establish the hybridoma/cell line should be in place to assure the safety and quality of the product.

This should include assurances that source cells and materials are free from viruses, and that these are within approved limits. Note that data originating from products generated by the same manufacturing technology platform may be acceptable, to demonstrate suitability.

Criteria to be monitored should be verified and are within approved limits at the end of a production cycle and for early termination of production cycles.

The manufacturing conditions for preparing antibody sub-fragment (for example, Fab, F(ab')₂, scFv) and any further modifications, such as radio labelling, conjugation and chemical linking, must be in accordance with validated parameters.

Transgenic animal products

Consistency of starting material from a transgenic source is likely to be more problematic than is normally the case for non-transgenic biotechnology sources. Consequently, there is an increased requirement to demonstrate batch-to-batch consistency of the product.

A range of species may be used to produce biologics, which may be expressed into body fluids (for example, milk) for collection and purification. Animals should be clearly and uniquely identified and backup arrangements should be in place in the event of loss of the primary marker.

Housing and care of the animals should minimize the exposure of the animals to pathogenic and zoonotic agents. Appropriate measures to protect the external environment should be established.

A health-monitoring program should be established and all results documented. Any incident should be investigated and its impact on the continuation of the animal and on previous batches of product should be determined. Care should be taken to ensure that any therapeutic products used to treat the animals do not contaminate the product.

The genealogy of both the founder animals and production animals must be documented. Since a transgenic line will be from a single genetic founder animal, materials from different transgenic lines should not be mixed.

The conditions under which the product is harvested should be in accordance with CTA or MA conditions. The harvest schedule and conditions under which animals may be removed from production should be performed according to approved procedures and acceptance limits.

Transgenic plant products

Consistency of starting material from a transgenic source is likely to be more problematic than is normally the case for non-transgenic biotechnology sources. Consequently, there is an increased requirement to demonstrate batch-to-batch consistency of product in all respects.

Additional measures, over and above those given in the general guidance section, may be required to prevent contamination of master and working transgenic banks by extraneous plant materials and relevant adventitious agents. The stability of the gene within defined generation numbers should be monitored.

Plants should be clearly and uniquely identified. The presence of key plant features, including health status, across the crop should be verified at defined intervals through the cultivation period to assure consistency of yield between crops.

Security arrangements for protecting crops should be in place, wherever possible, to minimize exposure to contamination by microbiological agents and cross-contamination with non-related plants. Materials such as pesticides and fertilizers should be prevented from contaminating the product. A monitoring program should be established and all results documented. Incidents should be investigated and their impact on the continuation of the crop in the production program should be determined.

Conditions under which plants may be removed from production should be defined. Acceptance limits should be set for materials (for example, host proteins) that may interfere with the purification process. Results should be within approved limits and verified.

Environmental conditions (temperature, rain) that may affect the quality attributes and yield of the recombinant protein, from planting, cultivation, harvest and interim storage stages, should be documented.

When drawing up the criteria, consider the principles outlined in documents such as:

• WHO guidelines on good agricultural and collection practices (GACP) for medicinal plants
• EMA's good agricultural and collection practice for starting materials of herbal origin – Scientific guideline

For information on the data requirements for plant-derived biologic drug submissions in Canada, consult:

• Plant molecular farming (PMF) Applications: Plant-derived biologic drugs for human use

Products from human blood or plasma

The quality and safety of products from human blood or plasma relies on the:

• control of source materials and their origin
• subsequent manufacturing procedures, including infectious marker testing, virus removal and virus inactivation

Starting material for manufacturing products from human blood or plasma imported from other countries and intended for use or distribution in Canada must meet the requirements of the marketing authorization.

Plasma imported from other countries should only be purchased from approved suppliers (such as blood establishments, including external warehouses). They should be named in the specifications for starting materials as defined by the fractionation plant or manufacturer, and be accepted by the competent authority (for example, following an inspection) of the importing country and by the individual responsible for the quality management system of the importing fractionation plant. Certification and release of plasma (plasma for fractionation) as starting material is mentioned near the end of this section.

Supplier qualification, including audits, should be performed according to written procedures by the fractionation plant or manufacturer of the drug in dosage form. Suppliers should be re-qualified at regular intervals using a risk-based approach.

The fractionation plant or manufacturer of the drug in dosage form should establish written contracts with their blood establishment suppliers. As a minimum, the following key aspects should be addressed:

• definition of duties and respective responsibilities
• quality system and documentation requirements
• donor selection criteria and testing
• requirements for separating blood into blood components/plasma
• freezing of plasma
• storage and transport of plasma
• traceability and post donation/collection information (including adverse events)

The test results of all units supplied by the blood establishment should be available to the fractionation plant/manufacturer of the product. Any fractionation step subcontracted should be defined in a written contract.

A formal change control system should be in place to plan, evaluate and document all changes that may affect the quality or safety of the products or their traceability. The potential impact of proposed changes should be evaluated. The need for additional testing and validation, especially viral inactivation and removal steps, should be determined.

An adequate safety strategy should be in place to minimize the risk from infectious agents and emerging infectious agents. This strategy should involve a risk assessment that:

• defines an inventory holding time (internal quarantine time) before processing the plasma (for instance, to remove look-back units)
• considers all aspects of virus reduction and/or testing for infectious agents or surrogates
• considers virus reduction capabilities, pool size and other relevant aspects of the manufacturing process

A system must be in place to trace each donation from the donor and the donation via the blood establishment through to the batch of final product and vice versa. Responsibilities for tracing the drug should be defined (there should be no gaps).

Contracts between the blood establishments (including testing laboratories) and the fractionation plant/manufacturer should ensure that traceability and post-collection measures cover the entire chain, from plasma collection to all manufacturers responsible for releasing the final products.

The blood establishments should notify the fractionating plant/manufacturer of:

• any event that may affect the quality or safety of the product, including serious adverse events and reactions
• other relevant information found after donor acceptance or release of the plasma (for example, post-collection information)

If the fractionation plant/manufacturer is in another country, the information should be forwarded to the manufacturer responsible for releasing in Canada any product manufactured from the plasma in question.

The notification procedure also applies when an inspection of a blood establishment by a competent authority leads to a withdrawal of an existing licence, certificate or approval.

The management of post-collection information should be described in the standard operating procedures.

To minimize microbiological contamination or a foreign material being introduced into the plasma pool, thawing and pooling of plasma units should be performed in an area that conforms, at a minimum, to the Grade D requirements. These requirements are defined in:

• Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119)

Appropriate clothing, including face masks and gloves, should be worn. All other open manipulations during the manufacturing process should be done under conditions that conform to the appropriate requirements outlined in GUI-0119.

Environmental monitoring should be performed regularly, especially during the "opening" of plasma containers, and during subsequent thawing and pooling processes. This should be done in accordance with GUI-0119.

In the production of plasma-derived products, appropriate viral inactivation or removal procedures should be used and steps should be taken to prevent cross-contamination of treated with untreated products. Dedicated and distinct premises and equipment should be used before and after viral inactivation treatment.

To avoid placing routine manufacture at risk of contamination from viruses used during validation studies, the validation of methods for virus reduction should not be conducted in production facilities. Validation should be in accordance with international recommendations and the principles and guidance contained in the appropriate sections of:

• Guide to validation – drugs and supporting activities (GUI-0029)

The starting material should comply with the requirements of all relevant monographs of the relevant pharmacopoeia and of the conditions laid down in the respective marketing authorization dossier. These requirements should be defined in the written contract (described earlier in this section) between the blood establishment and the fractionating plant/manufacturer and should be controlled through the quality system.

Depending on the type of collection (for instance, either whole blood collection or automated apheresis), different processing steps may be required. All processing steps (such as centrifugation and/or separation, sampling, labelling, freezing) should be defined in written procedures.

Any mix-ups of units and of samples, especially during labelling, as well as any contamination (for example, when cutting the tube segments/sealing the containers) must be avoided.

Freezing is a critical step for recovering proteins that are labile in plasma (for example, clotting factors). Freezing should be performed as soon as possible after collection, following a validated method.

For further information, consult:

• European Pharmacopoeia monographs No. 0853 "Human plasma for fractionation" and No. 1646 "Human Plasma pooled and treated for virus inactivation"
• other relevant pharmacopoeia

The storage and transport of blood or plasma at any stage in the transport chain to the fractionation plant should be defined and recorded. The fractionation plant should be notified of any deviation from the defined temperature. Qualified equipment and validated procedures should be used.

Plasma for fractionation should only be released (for instance, from a quarantine status) through systems and procedures that assure the quality needed for the manufacture of the drug in dosage form. It should only be distributed to the plasma fractionation plant/manufacturer after the individual responsible for the quality management system of the blood establishment (or in case of blood/plasma collection in other countries, the person with equivalent responsibilities and qualifications) has provided proper documentation. The individual must document that:

• the plasma for fractionation complies with the requirements and specifications defined in the written contracts
• all steps have been performed in accordance with the national regulatory requirements and Blood Regulations, as applicable

On entering the fractionation plant, the plasma units should be released for fractionation by the individual responsible for the quality management system. This person should confirm that the plasma complies with the requirements of all relevant monographs and the conditions set out in the respective marketing authorization dossier.

Requirements for the plasma processes of pooling, pool sampling and fractionation/purification and virus inactivation/removal should be defined and followed thoroughly.

The methods used for plasma in the viral inactivation process should be undertaken with strict adherence to validated procedures and in compliance with the methods used in the virus validation studies. Detailed investigation of failures in virus inactivation procedures should be performed. Adherence to the validated production process is especially important in the virus reduction procedures, as any deviation could result in a safety risk for the final product. Procedures that take this risk into consideration should be in place.

Any plasma reprocessing or reworking may only be performed after a quality risk management exercise has been performed and using processing steps as defined in the relevant marketing authorization.

There should be a system in place to segregate/distinguish between plasma products or intermediates that have undergone a process of virus reduction from those that have not.

The processing of plasma/intermediates of different origins at the same plant in campaigns will depend on the outcome of a thorough risk management process. The process will take into consideration possible differences in epidemiology. If campaigns are permitted, they should include clearly segregated and defined validated cleaning procedures. The requirement for such measures should be based on international recommendations. The risk management process should consider whether it is necessary to use dedicated equipment in the case of contract fractionation programs.

For intermediate plasma products that are to be stored, the shelf life should be based on stability data.

The storage and transport of plasma intermediates and drugs in dosage form at any stage of the transport chain should be specified and recorded. Qualified equipment and validated procedures should be used.

Testing requirements for viruses or other infectious agents should be considered in the light of emerging knowledge of infectious agents and on the availability of appropriate, validated test methods.

The first homogeneous plasma pool (for example, after the cryoprecipitate has been separated from the plasma pool) should be tested using validated test methods for sensitivity and specificity, according to relevant pharmacopoeia monographs_.

Only batches from plasma pools tested and found negative for virus markers/antibodies and that comply with the relevant pharmacopoeia monographs, including specific virus cut-off limits, and approved specifications should be released.

The person in charge of the quality control department should be responsible for releasing intermediates intended for further in-house processing or delivery to a different site and releasing products in dosage form. This should be done in accordance with the approved marketing authorization.

The person in charge of the quality control department should be responsible for releasing intermediates and drugs in dosage form used in contract fractionation programs. This should:

• accord with the standards agreed to by the contract giver
• comply with the Good manufacturing practices guide for drug products (GUI-0001)

One plasma pool may be used to manufacture more than 1 batch and/or product. Retention samples and corresponding records from every pool should be kept for at least 1 year after the expiry date of the drug in dosage form that has the longest shelf-life derived from the pool.

There should be written procedures for documenting the storage and disposal of waste, disposable and rejected items (such as contaminated units, units from infected donors, out of date blood, plasma, intermediates or drugs in dosage form) safely.