Biologic drugs (Schedule D drugs) – Division 4 proposed regulatory amendments: Notice to stakeholders

On this page

• About this notice
• Purpose of proposed amendments
• Scope
• Implementing proposed regulations for biologic drugs
  • Definitions
  • Prohibitions on sale
  • Biological source material
  • Prevention of contamination
  • Reference preparations
  • Lot release
  • Periodic quality reporting
  • Labelling, labelling exemption, labelling of prescription drugs
  • Storage
  • On-site evaluations
  • Expiry date
  • Corresponding regulations
  • Consequential amendments
• Contact us

About this notice

Health Canada published in Canada Gazette, Part I (CGI) proposed amendments to the Food and Drug Regulations (FDR) and the Medical Devices Regulations under the Food and Drugs Act (FDA). These amendments are part of the Regulations Amending Certain Regulations made under the Food and Drugs Act (Agile Regulations). One component under this initiative is proposed amendments to modify Division 4 in Part C of the FDR for biologic drugs.

This notice provides explanations for the proposed revisions, to help interested stakeholders provide feedback on the proposed amendments. It explains the proposed amendments in comparison to current practice and to the current regulations in Division 4.

In summary, the proposed regulatory changes are intended to maintain and support current flexible and outcome-based practices. For currently authorized biologic drugs, there is no expected need for additional filing of information to support the measures outlined in the proposed amendments. Current practices in Health Canada's regulation of biologic drugs already reflect the expectations set out in the amended regulations.

Purpose of proposed amendments

Division 4 in Part C of the FDR dates from the 1950s and 1960s, so is over 70 years old. Most of the existing regulations in Division 4 for biologic drugs are product-specific. They have not been updated in years to reflect changes in science and technology.

The proposed amendments maintain the original intent behind the existing regulations. The flexible and outcome-based regulations that would replace the existing regulations propose to:

• support the practices that currently and appropriately address biologic drugs and
• better address advancements in science and technology

Scope

This notice applies to drugs listed on Schedule D to the FDA (biologic drugs):

• Division 4 in Part C of the FDR sets out regulations that are specific to biologic drugs
• Schedule D in the FDA sets out the biologic drugs to which Division 4 applies

All revised regulations explained in this notice are in the revised Division 4 except for 2, which are in Divisions 2 and 8.

This notice is intended for those who are involved in fabricating, packaging/labelling, testing, storing, importing, distributing and wholesaling biologic drugs.

Note: The term "DIN holder" in this notice refers to sponsors, distributors or manufacturers.

Implementing proposed regulations for biologic drugs

Division 4 applies additional requirements to biologic drugs to appropriately address the risks associated with their particular nature.

Under Part C in the FDR, all of the regulations in the following divisions apply to biologic drugs, unless specific regulations exempt biologic drugs:

• Divisions 1 and 8: submission requirements
• Division 1A: establishment licensing requirements
• Division 2: good manufacturing practices requirements and
• Division 5: clinical trial requirements

The regulations in Division 4 are specific to biologic drugs and apply in addition to Divisions 1, 1A, 2, 5 and 8.

The amendments to Division 4 propose to:

• replace the existing Division 4 regulations (C.04.001 to C.04.683) with updated Division 4 regulations (C.04.001 to C.04.010)
• add a new regulation in Division 2 (C.02.012.1)
• amend a regulation in Division 8 (C.08.003.1)

The proposed amendments would maintain the original intent behind the overly prescriptive, product-specific or outdated regulations from C.04.050 to C.04.683. Replacing those regulations with flexible and outcome-based regulations would support the flexible and outcome-based practices that currently and appropriately address biologic drugs. There are also proposed consequential amendments (for example, updates to the references to Division 4 numbering in other parts of the FDR).

Definitions

Regulation

Proposed C.04.001 – see the regulatory text in CGI

The proposed C.04.001 replaces the current C.04.001.

Explanation in comparison to current practice

• There is no change to current practice.
• One definition is the same, 2 are proposed to be added and 1 is proposed to be repealed.
  • The definition of "drug" for Division 4 remains the same.
  • A new definition for "biological source material" is proposed to be added. This is a general definition for biological source materials that applies to all Division 4 drugs.
  • A new definition for drug identification number (DIN) "holder" is proposed to be added. The definition refers to "manufacturer" in order to align with Divisions 1 and 8, as it is the manufacturer who applies for and receives the DIN, as well as files drug submissions.
  • The definition of "date of manufacturing" in the current C.04.001 is proposed to be repealed. The definition is not needed because the corresponding product-specific regulations in Division 4 that use the definition are proposed to be replaced.

Prohibitions on sale

Regulations

Proposed C.04.002 and C.04.003 – see the regulatory text in CGI

The proposed C.04.002 and C.04.003 replace the current C.04.001.1.

Explanation in comparison to current practice

• These proposed prohibitions support the provisions of Division 4.
• The proposed C.04.002 prohibits the sale of biologic drugs and their active ingredients by importers or distributors unless they comply with the provisions of Division 4.
• The proposed C.04.003 provides a similar sale prohibition for biologic drugs and their active ingredients that are fabricated, packaged, labelled or tested in Canada by any person, which includes a party other than the DIN holder, unless they comply with the provisions of Division 4.

Biological source material

Regulation

Proposed C.04.004 – see the regulatory text in CGI

The proposed C.04.004:

• incorporates concepts from the current C.04.016 to C.04.018
• maintains the original intent behind approximately 31 provisions about biological source materials from the current C.04.050 to C.04.683
• replaces the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated

Explanation in comparison to current practice

• There is no change to current practice.
• The proposed outcome-based amendment is to ensure that biological source materials are suitable for use in the fabrication of the drug, are collected under medical or veterinary supervision, with record-keeping to allow for the tracing of the material.
• For currently authorized biologic drugs, there would be no need to file additional information to support the suitable control of biological source materials. The regulation of biologic drugs in Canada has always included considerations for the suitability of starting materials from biologic sources.
• The current Division 4 states that records are to be kept. It does not specify the period of time during which these records must be kept and implies that records must be kept indefinitely. The proposed amendment clarifies the record retention expectations for DIN holders.
• The proposed amendment puts a time limit on an activity that DIN holders already do, which is record retention for biological source material to support the safety, quality and efficacy of the biologic drug. The proposed amendment applies record retention to tracing biological source material (C.04.004(1)(b)), where the DIN holder determines the retention period (C.04.004(2)), which cannot be less than 5 years (C.04.004(3)).

Prevention of contamination

Regulation

Proposed C.04.005 – see the regulatory text in CGI

The proposed C.04.005(1) and (2):

• are based on the current C.04.013 and C.04.014, respectively
• maintain the original intent behind approximately 10 provisions about the prevention of contamination from the current C.04.050 to C.04.683
• replace the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated

Explanation in comparison to current practice

• There is no change to current practice.
• The proposed outcome-based amendment is a general framework to minimize the potential for contamination of drugs, active ingredients and biological source material between processes. The proposed C.04.005(1) adds to the current C.04.013 the explicit oversight for biological source materials and the concept of protecting the drug by minimizing the risk of contamination in transmission chains involving personnel. The proposed C.04.005(2), meanwhile, is the same as the current C.04.014.
• For currently authorized biologic drugs, there is no expected need for additional filing of information to support measures in place to prevent cross contamination. Current practice in the regulation of biologic drugs in Canada already includes expectations for appropriate segregation between manufacturing steps in instances where cross-contamination with an infectious agent could be of concern.
• Infectious agents or the impacts of their propagation during the manufacturing process for a biologic drug (for example, infection of a cell culture for a recombinant product) may have negative consequences for the quality and safety of the finished product, even if infectious agents are not directly communicable to humans. All materials of biologic origin should be sourced and controlled appropriately, and appropriate controls should be in place where cross-contamination could reasonably be foreseen.

Reference preparations

Regulation

Proposed C.04.006 – see the regulatory text in CGI

The proposed C.04.006:

• maintains the original intent behind approximately 70 provisions about reference preparations from the current C.04.050 to C.04.683
• replaces the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated

Explanation in comparison to current practice

• There is no change to current practice.
• The proposed amendment clearly outlines the expectation that reference preparations be appropriate for their intended function.
• Unless there are extenuating circumstances (such as product efficacy failure, observed potency drift), a DIN holder should not need to file information for existing products other than for reportable changes that are identified in the guidance on post-Notice of Compliance (NOC) quality changes.

For more information on post-NOC quality changes, refer to:

• Post-NOC quality changes guidance

Lot release

Regulation

Proposed C.04.007 – see the regulatory text in CGI

The proposed C.04.007(1) and (2):

• are the equivalent of the current C.04.015
• maintain the original intent behind approximately 20 provisions about lot release from the current C.04.050 to C.04.683
• replace the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated

Explanation in comparison to current practice

• There is no change to current practice or to the existing lot release program.
• The proposed C.04.007(1) provides the authority for the Minister to ask for information, samples of the drug or its active ingredients, or material to be used to test the samples. The proposed C.04.007(2) sets out that the proposed C.04.007(1) indicates if a request is made for information or samples, then the DIN holder cannot sell the drug until the request is met and the Minister indicates that the drug is suitable for sale. This currently takes the form of a Lot Release Decision letter.
• Health Canada currently uses a risk-based, tiered approach outlined in the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs in administering its lot release program. The proposed amendments support the guidance, where both the regulations and the guidance will continue to provide flexibility by allowing for movement of biologic drugs between evaluation groups on a case-by-case basis, with each group having different levels of regulatory oversight, based on the degree of risk associated with the drug.
  • DIN holders of biologic drugs currently on the Canadian market are not expected to see a change from current practice concerning the provision of information or materials to support lot release as a consequence of the proposed regulatory amendments. As a risk-based oversight program, lot release activities and the materials required are evaluated periodically to assess if they are still appropriate. Changes in sample requirements or in materials needed to carry out testing would be communicated directly to the DIN holder either as an outcome of a Yearly Biologic Periodic Review (YBPR) or of a periodic review.

For more information on the lot release program, refer to:

• Guidance for sponsors: Lot release program for schedule D (biologic) drugs

Periodic quality reporting

Regulation

Proposed C.04.008 – see the regulatory text in CGI

Explanation in comparison to current practice

• There is a change to current practice, which is increased flexibility.
• The proposed amendment formalizes Health Canada's current discretionary practice of periodic quality reporting to monitor the state of control and consistency of the manufacturing process for biologic drugs. This is currently in place as Yearly Biologic Product Reports (YBPR). The proposed amendment aligns with current practice, which is that the use of periodic quality reporting is discretionary and risk-based (for instance, YBPRs are not mandatory for all biologic drugs at all times). The proposed amendment thus maintains current flexibility, where periodic quality reporting is for when the Minister makes such a request.
• The proposed amendment also introduces the flexibility for the Minister to extend the interval between periodic reports from an annual basis to a longer interval if circumstances warrant.
• Furthermore, the proposed amendment aligns with current practice, which is that the use of this type of reporting supports the lot release program with periodic information as necessary. The purpose of the proposed amendment is to ask for information when needed, which supports current practice. In principle, Health Canada's lot release program is a risk-based oversight strategy, for which Health Canada has a responsibility to revisit the current context over time. Periodic quality reporting gives Health Canada that context, and enables a streamlined and less resource-intensive lot release grouping for many products.
• Finally, periodic quality reporting supports the life cycle approach to biologic drugs to assess the ongoing safety and quality of the products, to verify the consistency of manufacturing processes and to highlight any trends.

Labelling, labelling exemption, labelling of prescription drugs

Regulation

Proposed C.04.009 and C.04.010 – see the regulatory text in CGI

The proposed C.04.009(1) to (7) and C.04.010(1) and (2):

• are the equivalent of the current C.04.019 and C.04.020, respectively
• maintain the original intent behind approximately 28 provisions about labelling from the current C.04.050 to C.04.683
• replace the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated

Explanation in comparison to current practice

• There is no change to current practice.
• These regulations should not require any changes to labelling for biologic drugs currently on the Canadian market.
• The proposed amendments:
  • introduce additional flexibilities into Division 4 for small containers and
  • provide additional transparency on current expectations (as applicable):
    • indication of human or animal source, including species of origin (C.04.009(1)(e) and (f))
    • safety statements (C.04.009(2)(g))
    • storage statements including templates for cycle storage claims (C.04.009(5)(c) and (d))
    • an exemption for expiry date on the label of stockpile drugs (C.04.009(7))
• Under the proposed C.04.009(2)(g), Health Canada may require certain labelling statements for safety reasons on a case-by-case basis. Statements for safety reasons could cover situations such as:
  • identification of dosage forms intended solely for pediatric or adult use
  • for multi-dose vials indications where administration of the entire content could be injurious
  • drugs that require dilution prior to administration or
  • differentiation between diluents and active components of a kit (for example, warning on a diluent vial that it is not for direct administration)
• Under the proposed C.04.009(6), flexibilities on labelling for small containers outlined in Division 1, while not in the current Division 4, have historically also been extended to DIN holders of biologic drugs. Labelling of small containers in the proposed C.04.009(6) has been slightly tailored to biologic drugs.

Although it is required that an expiry date be on a drug's label, there are situations involving stockpiles of biologic drugs that require an exemption from having the expiry date on the label. Under the proposed C.04.009(7):

• An exemption has been added in order to not put an expiry date on the label of a drug that is stockpiled for use in emergency situations.
• It also adds a requirement that the drug's expiry date be indicated by alternate means to communicate the date to the individuals who administer the drug. Thus, an expiry date that is available to the end user and stability data are still required, but the alternate means of conveying the expiry date as proposed by the DIN holder can be considered.
• The labelling exemption for expiry dating is limited to the requirement to have expiry dates directly on the immediate final container. This exemption is not expected to be widely used. It is foreseen only for biologic drugs that are to be stockpiled for emergency use by federal and provincial governments and agencies, where the need for the drug is sporadic and infrequent.

Storage

Regulation

Proposed C.02.012.1 – see the regulatory text in CGI

The proposed C.02.012.1:

• maintains the original intent behind approximately 17 provisions about storage from the current C.04.050 to C.04.683
• replaces the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated

Explanation in comparison to current practice

• There is no change to current practice or expectations.
• The proposed amendment would make explicit the implicit understanding that drugs should be prepared, stored and transported in a manner that preserves their quality.
• As part of the renewal of Division 4, the proposed amendment about storage is included in Division 2 as it relates to good manufacturing practices.

For further guidance on preserving the quality of drugs during storage, including during transportation, refer to:

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

On-site evaluations

Regulation

Revised C.08.003.1 – see the regulatory text in CGI

Explanation in comparison to current practice

• In line with current practice, the proposed amendment to C.08.003.1 would clarify the Minister's authority to consider information or material that could be examined on a risk-based, case-by-case basis during Health Canada's assessment of a drug submission.
• The proposed amendment provides greater transparency for the current practice of potentially considering information obtained from on-site evaluations (OSEs) and from foreign regulatory partners in the assessment of drug submissions.
• Health Canada currently applies a risk-based approach in deciding whether additional information regarding the implementation of the manufacturing process in proposed facilities is required to support decision-making related to a submission or its supplement for a biologic drug. The proposed amendment provides transparency regarding the consideration of information obtained directly at, or indirectly from, manufacturing sites in the decision-making process for the market authorization of biologic drugs.
• Most of the content in Division 4 relates to requirements that extend throughout the product lifecycle for biologic drugs. However, OSEs are a point-in-time activity directly related to pre-market review. As a result, the proposed amendment related to OSEs is included in Division 8 because OSEs are information used to assess a New Drug Submission (NDS), an Extraordinary Use New Drug Submission (EUNDS), an Abbreviated New Drug Submission (ANDS), an Abbreviated Extraordinary Use New Drug Submission (AEUNDS) or a supplement to any of those submissions. This point-in-time information is for consideration in the context of drug submission review, and is distinct from good manufacturing practices (GMP) inspections.

Expiry date

Regulation

No proposed amendment.

The proposal is to rely on 5 current provisions (C.01.001(1), C.02.027, C.02.028, C.08.002(2)(f) and C.08.002(2)(g)) to:

• maintain the original intent behind approximately 23 provisions about expiry date from the current C.04.050 to C.04.683
• replace the current C.04.050 to C.04.683 because they are overly prescriptive, product-specific or outdated
• support that the drug shall have an expiry date and that the drug shall be labelled with the expiry date, as is done for pharmaceutical drugs

Explanation in comparison to current practice

The 5 current provisions are as follows:

• C.01.001(1): defines "expiration date"
• C.02.027: requires the DIN holder to establish the period that each packaged drug in dosage form and active ingredient will comply with the drug's specifications, which is interpreted to include data in support of the expiry date
• C.02.028: requires the DIN holder to monitor the stability of the packaged drug in dosage form and its active ingredient, which is interpreted to include data in support of the expiry date
• C.08.002(2)(f): requires the manufacturer to submit details of tests that control the potency, purity, stability and safety of the drug, which is interpreted to include data in support of the expiry date
• C.08.002(2)(g): requires the manufacturer to submit information to establish the safety of the new drug, which is interpreted to include information to support shelf-life, which is part of the "conditions of use recommended"

Corresponding regulations

Regulations and explanation

• The proposed repeal of the product-specific provisions from C.04.050 to C.04.683 is not expected to affect currently marketed biologic drugs.
• There are 2 other provisions that are also repealed in the context of the repeal of these product-specific provisions:
  • It is proposed to repeal the current C.04.002, which sets out that Division 4 does not apply to a drug in oral dosage form that contains micro-organisms if the drug is recommended solely for restoring, normalizing or stabilizing intestinal flora. This provision is no longer needed because such products are covered by the Natural Health Products Regulations (NHPR), which did not exist when C.04.002 was included in Division 4.
  • It is proposed to repeal the requirements regarding "date of issue" in the current C.04.003. It is outdated because the temperature ranges are incorrect. This provision would no longer be needed because the corresponding product-specific regulations in Division 4 that rely on "date of issue" are proposed to be replaced.

Consequential amendments

Explanation

The proposed consequential amendments would update regulations that refer to the amended regulations (for example, updates to the references to Division 4 numbering).

Regulations

Part A

• A.01.048(d) is about the exports and transhipments of drugs:
  • The proposed amendment would update references to the proposed new Division 4 numbering.

Part C

• Division 1, C.01.004(5) is about labelling:
  • The proposed amendment is for how Schedule D drugs would be excluded from some Division 1 labelling.
  • The exclusion from Division 1 labelling, which is currently in Division 4 (C.04.019), is proposed to be in Division 1 (C.01.004(5)(c)).
• Division 2:
  • The proposed amendment would replace the heading "Quality Control Department" with "Quality Control".
  • For C.02.019(4.1), which is about finished product testing, the proposed amendment would update the reference to the proposed new Division 4 numbering.
• Division 3, C.03.206 is about labelling with respect to the exclusion of Schedule C drugs from Division 4 labelling:
  • The proposed amendment would update the reference to the proposed new Division 4 numbering.
• Division 8:
  • C.08.009.04 is about COVID-19 drugs: The proposed amendment would update to the proposed new Division 2 numbering that is relevant for the purpose of Division 4 drugs.
  • C.08.011.2(2) is about Special Access Program (SAP) release drugs: The proposed amendment would update to the proposed new Division 2 numbering that is relevant for the purpose of Division 4 drugs.
• Division 10:
  • C.10.001(5) is about drugs for urgent public health need: The proposed amendment would update to the proposed new Division 2 numbering that is relevant for the purpose of Division 4 drugs.
  • C.10.002(2) is about drugs for urgent public health need: The proposed amendment would update to the proposed new Division 2 numbering.

Regulations Amending the Food and Drug Regulations (Interim Order Respecting the Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19)

• 20(e) is about COVID-19 drugs: The proposed amendment would update references to the proposed new Division 4 numbering.

Contact us

For questions about this notice or the revised Division 4 regulations, please contact:

• Centre for Policy, Pediatrics and International Collaboration (CPPIC)
• Biologic and Radiopharmaceutical Drugs Directorate (BRDD)
• Health Products and Food Branch (HPFB)
• Health Canada

Email: brdd-cppic_brdd-cppci@hc-sc.gc.ca

Related links

• Canada Gazette, Part I (CGI): Regulations Amending Certain Regulations made under the Food and Drugs Act (Agile Licensing)
• Guidance for sponsors: Lot release program for Schedule D (biologic) drugs
• Guidelines for environmental control of drugs during storage and transportation (GUI-0069)
• Post-NOC quality changes guidance