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Annex 2 to the Good manufacturing practices guide - Manufacture of biologics (GUI-0027): Quality risk management principles

This guidance has been adapted from:

Both annexes are in the following Pharmaceutical Inspection Cooperation Scheme (PIC/S) document:

The methods used to manufacture biologics are a critical factor in shaping the appropriate regulatory control. Biologics can be defined therefore largely by reference to their method of manufacture. This annex provides guidance on the full range of bulk product intermediates and drugs in dosage form defined as biologics in Canada.

This annex is divided into 2 main parts:

  1. Part A contains supplementary guidance on the manufacture of biologics, from control over seed lots and cell banks through to finishing activities and testing.
  2. Part B contains further guidance on selected types of biologics.
    • provides guidance on the full range of bulk product intermediates and drugs in dosage form defined as biologics, with the exception of gene, cell and tissue therapies

These 2 parts are shown in Table 1. Note that this table is for illustration purposes and is not meant to describe the precise scope. Also note that the level of good manufacturing practice (GMP) requirements increases from early to later steps in the manufacture of biologics. GMP principles should always be adhered to.

Health Canada has included some early steps of manufacture within the scope of this guide. This does not imply that those steps will be routinely subject to inspection by us.

In certain cases, other legislation may apply to the starting materials for biologics:

  1. Basic donor screening and testing requirements under the Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO Regulations) provide a good basis for determining appropriate screening and testing for tissues and cells. (The CTO Regulations do not apply to biologics.) Such tissues and cells may provide the active ingredient for some biologics that are within the scope of this guide.
  2. Appropriate containment should be established and maintained in facilities where any genetically modified micro-organism is handled. An appropriate containment level should be established and maintained. All measures must comply with the GMP requirements in Division 2 of the Food and Drug Regulations (FDR).

Pathogens are classified by risk group based on the inherent characteristics of the pathogen. The Public Health Agency of Canada (PHAC) regulates facilities where human pathogens or toxins in Risk Group 2, 3 and 4 are handled and stored under the Human Pathogens and Toxins Act and the Human Pathogens and Toxins Regulations. PHAC or the Canadian Food Inspection Agency (CFIA) regulate the importation of animal pathogens, infected animals, animal products or by-products (for example, tissue, serum) or other substances that may carry an animal pathogen or toxin or parts thereof. These are regulated under the Health of Animals Act and Health of Animals Regulations.

Canadian Biosafety Handbook (CBH), 2nd edition is a national guidance document for safely handling and storing human and terrestrial animal pathogens and toxins in Canada. A companion document to the Canadian Biosafety Standard (CBS), 3rd edition, it sets out the physical containment, operational practice, and performance and verification testing requirements to ensure the safe handling and storing of human and terrestrial animal pathogens and toxins.

Table 1. Illustration of manufacturing activities within the scope of Annexes 2B and 14
Type of source material Example product Application of this guide to manufacturing steps
1. Animal or plant sources: non-transgenic Heparins, insulin, enzymes, proteins, allergen extract, immunosera Collection of plant, organ, animal material or fluidFootnote 1Footnote 3 Cutting, mixing and/or initial processingFootnote 3 Isolation and purificationFootnote 3 Formulation, fillingFootnote 3
2. Virus or bacteria, fermentation, cell culture Viral or bacterial vaccines; enzymes, proteins Establishment and maintenance of MCB,Footnote 2 WCB, MVS, WVSFootnote 3 Cell culture and or fermentationFootnote 3 Inactivation when applicable, isolation and purificationFootnote 3 Formulation, fillingFootnote 3
3. Biotechnology fermentation, cell culture Recombinant products, Mab, allergens, vaccines Establishment and maintenance of MCB,Footnote 2 WCB, MVS, WVSFootnote 3 Cell culture and or fermentationFootnote 3 Isolation, purification, modificationFootnote 3 Formulation, fillingFootnote 3
4. Animal sources: transgenic Recombinant proteins Master and working transgenic bankFootnote 3 Collection, cutting, mixing and or initial processingFootnote 3 Isolation, purification, modificationFootnote 3 Formulation, fillingFootnote 3
5. Plant sources: transgenic Recombinant proteins, vaccines, allergens Master and working transgenic bankFootnote 3 Growing, harvesting Initial extraction, isolation, purification, modificationFootnote 3 Formulation, fillingFootnote 3
6. Human sources Urine derived enzymes, hormones Collection of fluidFootnote 3 Mixing, and or initial processingFootnote 3 Isolation, purificationFootnote 3 Formulation, fillingFootnote 3
7. Human sources Products from cells and tissues not classified as gene, cell or tissue therapy (ATMP) Donation, procurement and testing of starting tissue or cells Initial processing, isolation, purificationFootnote 3 Cell isolation, culture, purification, combination with non-cellular componentsFootnote 3 Formulation, combination, fillingFootnote 3
8. Products from blood and plasma Albumin, coagulation factors, immune globulins Collection, preparation, distribution, testing Importing for use in the manufacture of a drug, thawing and pooling processes, notifications of serious adverse reactions or eventsFootnote 3 Isolation, testing, purificationFootnote 3 Formulation, fillingFootnote 3

GMP requirements increase with the complexity of the activity. Stages where GMP requirements require compliance are shown in the Application of this guide to manufacturing steps column.

Refer to the glossary for an explanation of acronyms.

Footnotes

Footnote 1

Refer to the section on animal-sourced products for the extent to which GMP principles apply.

Return to footnote 1 referrer

Footnote 2

Refer to the section on seed lot and cell bank system for the extent to which GMP applies.

Return to footnote 2 referrer

Footnote 3

This guide refers to the noted manufacturing step.

Return to footnote 3 referrer

The manufacture of biologics involves certain specific considerations arising from the nature of the products and the processes. The ways in which biologics are manufactured, controlled and administered make it necessary to take precautions.

Conventional drugs are manufactured using chemical and physical techniques capable of a high degree of consistency. In comparison, the manufacture of biologics involves biological processes and materials, such as cultivating cells or extracting from living organisms. These biological processes may display inherent variability, so that the range and nature of byproducts may vary.

Thus, quality risk management (QRM) principles are particularly important for this class of materials. These principles should be used to develop the control strategy across all stages of manufacture. This will minimize variability and reduce the opportunity for contamination and cross-contamination.

Materials and processing conditions used in cultivation processes are designed to provide conditions for the growth of specific cells and microorganisms. This gives extraneous microbial contaminants the opportunity to grow. As well, some products may be limited in their ability to withstand a wide range of purification techniques, particularly those designed to inactivate or remove adventitious viral contaminants.

Key considerations to minimize such contamination events involve the following:

Specifications for biologics (such as those in pharmacopoeial monographs), clinical trial authorization (CTA) and marketing authorization (MA) will dictate whether and to what stage substances and materials can have a defined level of bioburden or need to be sterile. Similarly, manufacturing must be consistent with other specifications set out in the CTA or MA (for example, number of generations (doublings, passages) between the seed lot or cell bank).

For biological materials that cannot be sterilized (for example, by filtration), processing must be conducted aseptically to minimize the introduction of contaminants. For information on virus removal or inactivation manufacturing methods, consult:

Appropriate environmental controls and monitoring and, where feasible, in-situ cleaning and sterilization systems together with closed systems can significantly reduce the risk of accidental contamination and cross-contamination.

Control usually involves biological analytical techniques, which typically are more variable than physico-chemical techniques. A robust manufacturing process is therefore crucial, with in-process controls being particularly important in the manufacture of biologics.

Collection and testing of biologics that incorporate blood components must be done in accordance with an appropriate quality system. There are requirements on traceability that apply, starting with the donor (while maintaining donor confidentiality), through stages applicable at the blood establishment and to the institution where the product is used.

Biologics should comply with the applicable guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary drugs. Specific Health Canada requirements for managing BSE/TSE risks are described in the following guidance document:

Also consult CFIA's guidance:

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