Annex 2 to the Good manufacturing practices guide - Manufacture of biologics (GUI-0027): General guidance

On this page

• Personnel
• Premises and equipment
• Animals
• Documentation
• Production
• Starting and raw materials
• Seed lot and cell bank system
• Operating principles
• Quality control

Personnel

C.02.006 and C.02.029

Staff (including those concerned with cleaning, maintenance or quality control) working in areas where biologics are manufactured and tested should receive training, and periodic retraining, specific to the products manufactured and to their work. Training should include specific security measures to protect product, staff and the environment.

The health status of staff should be taken into consideration. Where necessary, staff engaged in production, maintenance, testing and animal care (and inspections) should be vaccinated appropriately, as per health directives, and have regular health checks.

Any changes in the health status of staff that could affect the quality of the product should preclude work in the production area. Appropriate records should be kept. Production of BCG vaccine (attenuated Mycobacterium tuberculosis, Bacillus Calmette-Guerin strain) and tuberculin products should be restricted to staff, who are carefully monitored. Health monitoring of staff should be in keeping with the risk and medical advice sought for staff involved with hazardous organisms.

Where required to minimize the opportunity for cross-contamination, restrictions on the movement of all staff (including quality control, maintenance and cleaning staff) should be based on quality risk management (QRM) principles. In general, staff should not go from areas where they are exposed to live micro-organisms, genetically modified organisms, toxins or animals to areas where other products, inactivated products or different organisms are handled. If this is unavoidable, contamination control measures should be in place and based on QRM principles.

Premises and equipment

C.02.004, C.02.005, C.02.007 and C.02.029

As part of the control strategy, the degree of environmental control of particulate and microbial contamination of the production premises should be adapted to the active ingredient, bulk process intermediate or drug in a dosage form and the production step. The potential level of contamination of the starting materials and the risks to the product should be considered.

Manufacturing and storage facilities, processes and environmental classifications should be designed to prevent the extraneous contamination of products. Preventing contamination is more appropriate than detecting and removing, although contamination is likely to become evident during processes such as fermentation and cell culture. Where processes are not closed and thus exposure the product has been exposed (for example, when adding supplements, media, buffers, gasses), control measures should be put in place. Such measures include engineering and environmental controls with a consideration to QRM principles.

In addition to an environmental monitoring program and in adherence to the GUI-0119 guidance, other methods should be used to detect the presence of specific microorganisms (host organism, yeasts, moulds, anaerobes and so on) where indicated by the QRM process.

Dedicated production areas should be used to handle live cells. Dedicated production areas should be used to manufacture pathogenic organisms (for example, containment level 3 or 4 areas).

Manufacture in a multi-product facility may be acceptable where the following or equivalent (as appropriate to the product types involved) considerations and measures are part of an effective control strategy to prevent cross-contamination:

• knowledge of key characteristics of all cells, organisms and any adventitious agents (for example, pathogenicity, detectability, persistence, susceptibility to inactivation) within the same facility
• consideration of the working environment when developing the control strategy where production is characterized by multiple small batches from different starting materials
  • noting factors such as the health status of donors and the risk of total loss of product
• potential routes of cross-contamination are addressed and single-use components and engineering measures such as closed systems are used to prevent live organisms and spores from entering non-related areas or equipment
• control measures to remove the organisms and spores before the subsequent manufacture of other products take the heating, ventilation and air conditioning (HVAC) system into account
  • cleaning and decontamination for organisms and spores are validated
• environmental monitoring, specific for the micro-organism being manufactured, where the micro-organisms are capable of persistence in the manufacturing environment and where methods are available, in adjacent areas during manufacture and after completion of cleaning and decontamination
  • attention given to risks arising with use of certain monitoring equipment (such as airborne particle monitoring) in areas handling live and/or spore forming organisms
• products, equipment, ancillary equipment (for example, for calibration and validation) and disposable items removed in a manner that prevents contamination of other areas, other products and different product stages (for example, prevent contamination of inactivated or toxoided products with non-inactivated products)
• campaign-based manufacturing is followed by validated cleaning and decontamination procedures

To better understand how to reduce the chance of contamination, consult:

• Cleaning validation guide (GUI-0028)

For finishing (secondary) operations, the need for dedicated facilities will depend on the considerations outlined in this section, along with:

• other considerations, based on the nature of the product
• the characteristics of other products, including any non-biological products, in the same facility

Other control measures for finishing operations may include the need for:

• specific addition sequences
• mixing speeds
• time and temperature controls
• limits on exposure to light and containment
• cleaning procedures in the event of spillages

The measures and procedures necessary for containment (for instance, for environment and operator safety) should not conflict with those for product quality.

Air handling units should be designed, constructed and maintained to minimize the risk of cross-contamination between different manufacturing areas and may need to be specific for an area. Consideration, based on QRM principles, should be given to the use of single-pass air systems.

Positive pressure areas should be used to process sterile products. Negative pressure in specific areas at the point of exposure of pathogens is acceptable for containment reasons. Negative pressure areas or safety cabinets used for aseptic processing of materials with particular risks (such as pathogens) should be surrounded by a positive pressure clean zone of appropriate grade. These pressure cascades should be clearly defined and continuously monitored with appropriate alarm settings.

Equipment used during the handling of live organisms and cells, including those for sampling, should be designed to prevent any contamination during processing.

Primary containment should be designed and periodically tested to ensure the prevention of escape of biological agents into the immediate working environment.

The use of 'clean in place' and 'steam in place' ('sterilization in place') systems should be used where possible. Valves on fermentation vessels should be completely sterilized by steam.

Air vent filters should be hydrophobic and validated for their scheduled lifespan with integrity testing at appropriate intervals based on appropriate QRM principles.

Drainage systems must be designed so that effluents can be effectively neutralized or decontaminated to minimize the risk of cross-contamination. Risk of contamination of the external environment has to be minimized according to the risk associated with the biohazardous nature of waste materials.

Due to the variability of biologics or manufacturing processes, relevant/critical raw materials (such as culture media and buffers) have to be measured or weighed during the production process. In these cases, small stocks of these raw materials may be kept in the production area for a specified duration based on defined criteria such as for the duration of manufacture of the batch or of the campaign.

Animals

C.02.007, C.02.009, C.02.010 and C.02.012

A wide range of animal species can be used to manufacture biologics. The animals can be divided into 2 broad types of sources:

1. live groups, herds and flocks
   • examples include vaccines, immunosera, allergens and transgenic products
2. animals from which materials are derived post-mortem and from establishments such as abattoirs
   • examples include enzymes, anticoagulants and hormones

In addition, animals may also be used in quality control, either in:

• generic assays, such as pyrogenicity or
• specific potency assays, such as pertussis vaccine (mice), pyrogenicity (rabbits) and BCG vaccine (guinea pigs)

As well as compliance with TSE guidelines (refer to the references), other adventitious agents that are of concern (zoonotic diseases, diseases of source animals) should be monitored and recorded. Specialist advice should be obtained when establishing a health program for monitoring and recording. Instances of ill health occurring in the source/donor animals should be investigated with respect to their suitability and the suitability of in-contact animals for continued use (in manufacture, as sources of starting and raw materials, in quality control and safety testing). All decisions must be documented.

A look-back procedure should be in place. This procedure will help to inform the decision-making process on the continued suitability of the bulk process intermediate(s) or drug(s) in dosage form where animal-sourced starting or raw materials have been used or incorporated. The decision-making process may include re-testing retained samples from previous collections from the same donor animal (where applicable) to establish the last negative donation. The withdrawal period of therapeutic agents used to treat source/donor animals must be documented and used to determine the removal of those animals from the program for defined periods.

Care should be taken to prevent and monitor infections in the source/donor animals. Measures should include sourcing, facilities, husbandry, biosecurity procedures, testing regimes, control of bedding and feed materials. This is particularly relevant to specified pathogen-free animals where pharmacopoeial monograph requirements must be met. Housing and health monitoring should be defined for other categories of animals (for example, healthy flocks or herds).

For products manufactured from transgenic animals, where such animals are created from the source animals, traceability should be maintained.

Procedures for animal quarantine and husbandry should conform to:

• Good Laboratory Practices (GLP) principles set by the Organisation for Economic Co-operation and Development
• Canadian Council on Animal Care (CCAC) guidelines
• other relevant international guidelines (for example, Directive 2010/63/EU)

Special consideration is required for non-human primates used for production or quality control. International guidance documents should be consulted (for example, World Health Organization requirements and EC Recommendations).

For different animal species, key criteria should be defined, monitored and recorded. These may include age, weight and health status of the animals.

Animals, biological agents and tests should be the subject of an identification system to prevent any risk of confusion and to control all identified hazards.

Documentation

C.02.020 to C.02.024

Starting and raw materials may need additional documentation on the source, origin, distribution chain, method of manufacture and controls applied. This documentation is needed to assure an appropriate level of control, including the microbiological quality of the materials. These specifications are in line with the marketing authorization.

For imported biological drugs, detailed summaries (for example, Certified Product Information Document) of the current fabrication, packaging, labeling and testing procedures are maintained by the legal agent in Canada and master production documents are available on site at the fabricator.

Some product types may require specific definition of what materials constitute a batch, particularly cells.

Where human cell or tissue donors are used, full traceability is required from starting and raw materials. This includes all substances that come into contact with the cells or tissues through to confirming the receipt of the products at the point of use while maintaining individual privacy and confidentiality of health-related information.

Traceability records for where human cell or tissue donors are used, must be kept for 30 years after the product's expiry date. Particular care should be taken to maintain the traceability of products for special cases, such as donor-matched cells.

The arrangements necessary to achieve traceability and retention should be incorporated into technical agreements between the responsible parties.

Production

C.02.011 to C.02.012

Given the variability of many biologics, steps to increase process robustness should be reassessed during product quality reviews. This will reduce process variability and enhance reproducibility at the different stages of the product lifecycle such as process design.

Since cultivation conditions, media and reagents are designed to promote the growth of cells or microbial organisms, typically in an axenic state, attention should be paid to ensure there are robust steps in place to prevent or minimize the occurrence of unwanted bioburden and associated metabolites and endotoxins. For products from cells and tissues where production batches are often small, the risk of cross-contamination between cell preparations from different donors with various health status should be controlled under defined procedures and requirements.

Starting and raw materials

C.02.007, C.02.009 to C.02.012 and C.02.029

The source, origin and suitability of biological starting and raw materials (for example, cryoprotectants, feeder cells, reagents, culture media, buffers, serum, enzymes, cytokines, growth factors) should be clearly defined. Where the necessary tests take a long time, it may be permissible to process starting materials before test results are available.

The risk of using a potentially failed material and its potential impact on other batches should be clearly understood and assessed under the principles of quality risk management (QRM). In such cases, release of a drug in a dosage form is conditional on satisfactory test results. The identification of all starting materials should be in compliance with the requirements appropriate to the manufacturing stage.

For more guidance, consult:

• Good manufacturing practices guide for drug products (GUI-0001)

The risk of starting and raw materials being contaminated along the supply chain must be assessed, with particular emphasis on TSE. Materials that come into direct contact with manufacturing equipment or the product (such as media used in media fill experiments and lubricants that may contact the product) must also be taken into account.

The risks of contamination and the consequences to the drug in a dosage form are the same regardless of the stage of manufacture. A control strategy to protect the product and prepare solutions, buffers and other additions should be based on the principles and guidance. Refer to the appropriate sections of the Annex 1 to the Good manufacturing practices guide – Manufacture of sterile drugs (GUI-0119).

The controls required for the quality of starting and raw materials and on the aseptic manufacturing process assume greater importance, particularly for products, when final sterilization is not possible. A clinical trial authorization (CTA) or marketing authorization (MA) provides for an allowable type and level of bioburden (for example, at bulk process intermediate stage). In contrast, the control strategy should address the means by which this is maintained within the specified limits.

Where sterilization of starting and raw materials is required, heat should be used if possible. Other appropriate methods may also be used to inactivate biological materials (such as irradiation and filtration).

Reduction in bioburden associated with procuring living tissues and cells may require other measures to be used, such as antibiotics at early manufacturing stages. This should be avoided, but where it is necessary, their use should be justified. They should be removed from the manufacturing process at the stage specified in the CTA or MA.

Traceability for human tissues and cells used as starting materials for biologics should be maintained from the donor to the batch of a drug in a dosage form. The manufacturer and the supplier of tissues and cells should implement appropriate measures for transferring health donor information. This information may become available after the starting material has been received and may have an impact on the quality or safety of the biologics manufactured.

For example:

• There may be some instances where processing cells and tissues used as starting materials for biologics will be conducted at tissue establishments.
• Tissue and cells are released by the individual responsible for the quality management system in the tissue establishment before shipping to the product manufacturer, after which normal biologics starting material controls apply. The test results of all tissues/cells supplied by the tissue establishment should be available to the manufacturer of the biologics. Such information must be used to make appropriate decisions for segregating and storing materials. In cases where manufacturing must begin before test results are received by the tissue establishment, tissue and cells may be shipped to the manufacturer, provided controls are in place to prevent cross-contamination with tissue and cells that have been released by the individual responsible for the quality management system in the tissue establishment.
• To transport human tissues and cells to the manufacturing site, the responsible parties must have a written agreement. The manufacturing sites should have documentary evidence of adherence to the specified storage and transport conditions.
• Traceability requirements must be maintained throughout the process, from tissue establishments through to the recipient(s), and vice versa. This includes materials that come into contact with the cells or tissues.
• The responsible parties (for example, manufacturers, tissue establishments, sponsors, market authorization holders) must have a technical agreement. This agreement defines the tasks of each party, including the individual responsible for the quality management system and a person in charge of the quality control department.

For guidance on temperature control related to handling, storing and distributing of drugs, consult:

• Guidelines for environmental control of drugs during storage and transportation (GUI-0069)

Where human or animal cells are used in the manufacturing process as feeder cells, appropriate controls over the sourcing, testing, transporting and storing should be in place.

Seed lot and cell bank system

C.02.007, C.02.011 and C.02.029

The unwanted drift of properties might occur from repeated subcultures or multiple generations. To prevent this, the production of biologics obtained by microbial culture, cell culture or propagation in embryos and animals should be based on a system of master and working virus seed lots and/or cell banks.

The number of generations (doublings, passages) between the seed lot or cell bank, bulk process intermediate and drug in a dosage form should be consistent with specifications in the CTA or MA.

As part of product lifecycle management, establishment of seed lots and cell banks, including master and working generations, should be performed under appropriate GMP conditions. This should include an appropriately controlled environment to protect the seed lot and cell bank and the staff handling it. During the establishment of the seed lot and cell bank, no other living or infectious material (for example, virus, cell lines or cell strains) should be handled at the same time, in the same area or by the same persons.

Once master and working cell banks and master and working seed lots are established, quarantine and release procedures should be followed. Procedures should include adequate characterization and testing for contaminants. Additional information can be found in ICH documents Q5A, Q5B and Q5D.

The consistency of the characteristics and quality of successive batches of product should be closely monitored. This is done to ensure the ongoing suitability of the master and working cell banks as well as the master and working seed lots. Evidence of the stability and recovery of the seeds and banks should be documented and records should be kept such that trends may be evaluated.

Seed lots and cell banks should be stored and used in such a way as to minimize the risks of contamination (for example, stored in the vapour phase of liquid nitrogen in sealed containers) or alteration. Ensuring compliance with measures for storing different seeds and/or cells in the same area or equipment should prevent mix-up and consider the infectious nature of the materials, to prevent cross-contamination.

Storage containers should be sealed, clearly labelled and kept at an appropriate temperature. A stock inventory must be kept. The storage temperature should be recorded continuously and, where used, the liquid nitrogen level monitored. Deviation from set limits and corrective and preventive action taken should be recorded.

It's desirable to split stocks and to store the split stocks at different locations so as to minimize the risks of total loss. The controls at such locations should provide the assurances outlined in the preceding paragraphs.

The storage and handling conditions for stocks should be managed according to the same procedures and parameters. Once containers are removed from the seed lot/cell bank management system, they should not be returned to stock.

Operating principles

C.02.005, C.02.007, C.02.011, C.02.012 and C.02.029

Management should consider the effects of changes to operating principles, including cumulative effects (for example, to the process), on the quality, safety and efficacy of the finished product/drug in dosage form.

Critical operational (process) parameters, or other input parameters, that affect product quality must be identified, validated, documented and shown to be maintained within requirements.

A control strategy for the entry of articles and materials into production areas should be based on QRM principles. For aseptic processes, heat stable articles and materials entering a clean area or clean/contained area should preferably do so through a double-ended autoclave or oven. Heat labile articles and materials should enter through an air lock with interlocked doors, where they will undergo effective surface sanitization procedures.

Sterilization of articles and materials elsewhere is acceptable provided that they:

• are protected by multiple wrappings, as appropriate to the number of stages of entry to the clean area and
• enter through an airlock with the appropriate surface sanitization precautions

The growth-promoting properties of culture media should be suitable for the media's intended use. If possible, media should be sterilized in situ. In-line sterilizing filters for routine addition of gases, media, acids or alkalis, anti-foaming agents and so on to fermenters should be used where possible.

Addition of materials or cultures to fermenters and other vessels and sampling should be carried out under carefully controlled conditions to prevent contamination. Care should be taken to ensure that vessels are correctly connected when adding or sampling takes place.

Continuous monitoring of some production processes (such as fermentation) may be necessary. This information should be part of the batch record. Where continuous culture is used, special consideration should be given to the quality control requirements for this type of production method.

Centrifugation and blending of products can lead to aerosol formation. Containing such activities to minimize cross-contamination is necessary.

Accidental spillages, especially of live organisms, must be dealt with quickly and safely. Qualified decontamination measures should be available for each organism or groups of related organisms. Where different strains of single bacteria species or similar viruses are involved, the decontamination process may be validated with 1 representative strain, unless there is reason to believe that they may vary significantly in their resistance to the agent(s) involved.

If obviously contaminated, such as by spills or aerosols, or if a potential hazardous organism is involved, production and control materials, including paperwork, must be adequately disinfected. Otherwise, the information should be transferred by other means.

In cases where a virus inactivation or removal process is performed during manufacture, measures should be taken to avoid the risk of non-treated products contaminating treated products.

For products that are inactivated when a reagent is added (for example, micro-organisms in the course of vaccine manufacture), the process should ensure the complete inactivation of live organism. In addition to the thorough mixing of culture and inactivant, consideration should be given to product-contact surfaces exposed to live culture and, where required, be transferred to a second vessel.

A wide variety of equipment is used for chromatography. QRM principles should be used to devise the control strategy on matrices, the housings and associated equipment when used in campaign manufacture and in multi-product environments. Re-using the same matrix at different stages of processing is discouraged. Acceptance criteria, operating conditions, regeneration methods, life span and sanitization or sterilization methods of columns should be defined.

For guidance on the use of irradiated equipment and materials, consult:

• Guide to validation of terminal sterilization process of drugs (GUI-0074)

There should be a system to assure the integrity and closure of containers after filling where drugs in dosage form or bulk product intermediates represent a special risk. Procedures should be in place to deal with any leaks or spillages. In particular, filling and packaging operations should have procedures for maintaining the product within any specified limits (for example, time and/or temperature).

Activities in handling vials containing live biological agents must be performed in such a way to prevent the contamination of other products or egress of the live agents into the work or external environment. The viability of such organisms and their biological classification should be considered as part of the management of such risks.

Care should be taken to prepare, print, store and apply labels, including text for patient-specific products of the contents on all packaging.

For autologous products, the unique patient identifier should be on the outer packaging. If there is no such packaging, it should be on the immediate packaging.

The compatibility of labels with ultra-low storage temperatures, where such temperatures are used, should be verified.

Donor (human or animal) health information that becomes available after procurement and affects product quality should be taken into account in recall procedures.

Quality control

C.02.011 to C.02.015, C.02.018 to C.02.019, C.02.025 to C.02.027

In-process controls are important for ensuring the consistency of the quality of biologics, more so than for conventional drugs. In-process control testing should be performed at appropriate stages of production to control those conditions that are important for the quality of the drug in dosage form.

Consideration should be given to including drugs in dosage form made from materials that can be stored for extended periods of time (days, weeks or longer) in the ongoing stability program.

For cellular products, sterility tests should be conducted on antibiotic-free cultures of cells or cell banks. These tests provide evidence for absence of bacterial and fungal contamination and detect fastidious organisms where appropriate.

For biologics with a short shelf life (a period that does not permit release when sterility testing results are provided after 14 days or less) and that need batch certification before all quality control tests (such as sterility tests) are done, a suitable control strategy must be in place. It's important to have enhanced understanding of product and process performance. Such a strategy should consider the controls and attributes of starting and raw materials. The exact and detailed description of the entire release procedure, including the responsibilities of the staff involved in assessing production and analytical data, is essential. A continuous assessment of the effectiveness of the quality assurance system must be in place, including records kept in a manner that allow trends to be evaluated.

Where end-product tests are not available due to their short shelf-life, alternative methods of obtaining equivalent data to permit batch certification should be considered (such as rapid microbiological methods). The procedure for batch certification and release may be carried out in 2 or more stages:

1. assessment by designated person(s) of batch processing records, results from environmental monitoring (where available) that cover production conditions, all deviations from normal procedures and analytical results in preparation for initial certification by the person in charge of the quality control department
2. assessment of the final analytical tests and other information available for final certification by the person in charge of the quality control department, with a procedure to describe the measures to be taken (including liaison with clinical staff) when out-of-specification test results are obtained
   • these test results should be fully investigated, and documentation of the corrective and preventive actions taken, to prevent recurrence

The following notes explain periodic confirmatory testing requirements under C.02.019 of the Food and Drug Regulations (FDR) for specific scenarios. For an interpretation of section C.02.019 of the FDR, also consult the Good manufacturing practices guide for drug products (GUI-0001). This includes the use of the original laboratory performing confirmatory testing in exceptional cases with appropriate scientific justification.

1. Biologic drugs (finished products) that are not tested by an alternate laboratory must undergo periodic confirmatory testing, to demonstrate that:
   • foreign fabricators have manufactured drugs that comply with specifications
   • the storage and transportation conditions throughout the supply chain prior to receipt in Canada have not affected product quality
2. Some biologics may have unique stability profiles and the time lapse since manufacture may require periodic confirmatory testing to be assessed against stability specifications rather than release specifications.
3. Alternative proposals for reduced frequency in periodic confirmatory testing based on quality risk management principles will be considered case by case, with consideration given to:
   • the number of sales/ratio (for example, 10 units to test but only sell a total of 100 units)
   • whether the drug is an orphan drug or is for small patient populations
   • in the case of specialized testing, evidence demonstrating the product is tested in another recognized country
4. Exemptions in confirmatory testing applies to the packager, labeller, importer, or distributor of biologics that meet following conditions:
   • the drug is:
     • for human use,
     • in dosage form,
     • listed in Schedule D to the Food and Drugs Act,
     • not a vaccine and
     • composed of genetically modified autologous human nucleated cells or is delivered to cells using an adeno-associated virus vector and
   • the packager/labeller, distributor or importer has evidence that the drug has been:
     • tested against the specifications for that drug and
     • transported or stored under conditions that will not adversely impact the quality of the drug
5. Imported drugs identified as being exempt under #4 may be shipped directly to a health care facility or health care provider and given to a patient if the importer:
   • receives and reviews documentation that demonstrates the drug complies with the drug's specifications before importing
   • releases the product before it's administered to the patient. The release of the product, along with certain other activities (for example, reviewing and approving specifications, shipping, storing, other documentation) can be done remotely by the importer.
   • has measures in place to ensure that all requirements of the FDR for importing the drug are met
     • identifies roles and responsibilities
     • has appropriate quality agreements between all parties, including the foreign fabricator, importer and the receiver of the product
       • consult Good manufacturing practices guide for drug products (GUI-0001), section C.02.012, for information on quality agreements

In some cases, the Canada Border Services Agency (CBSA) will refer a shipment to Health Canada to verify if the import requirements are satisfied. We recommend that direct shipments be accompanied with the following information:

• a statement that the importer is shipping directly to the point of use and not to the importer's warehouse
• the invoice that includes the importer's drug establishment licence (DEL) number
• a copy of the importer's DEL

For more information on importing health products into Canada, consult: Importing and exporting health products for commercial use (GUI-0017)