Guidance document on submission information for biologic drugs (Division 4, Schedule D): Overview

On this page

• Introduction
• How to use this document
• Acronyms and abbreviations
• Definitions
• Notes about this guidance document
• Notes about guidance documents in general

Introduction

Division 4 in Part C of the Food and Drug Regulations (FDR) is for regulations that are specific to biologic drugs. This guidance document outlines the regulatory requirements and expectations, including submission data, to support Division 4.

Health Canada published the Regulations Amending Certain Regulations made under the Food and Drugs Act (Agile Regulations) on December 18, 2024, in Canada Gazette, Part II (CGII). The regulatory amendments for biologic drugs, a component of the Agile Regulations, consist of 12 regulations. A new Division 4 (10 regulations) replaces the former Division 4. The other regulations are in Divisions 2 and 8 (2 regulations), instead of in the new Division 4, because expectations about storage and pre-market review of biologic drugs are based in those parts of the FDR, respectively. Key points about the changes:

• The coming into force date is July 1, 2025 for the new Division 4. The coming into force date is December 18, 2024 for the new and revised regulations in Divisions 2 and 8, respectively. Requirements – Division 4 and Requirements – Other explain the regulations under both coming into force dates.
• The former Division 4 dates from the 1950s and 1960s, so is about 75 years old when the new Division 4 comes into force in 2025. Most of the regulations in the former Division 4 were outdated, overly prescriptive or unnecessarily product-specific. They did not reflect advances in science and technology.
• The new regulations maintain and support the flexible and outcome-based practices that currently and appropriately address biologic drugs. The outcome-based approach better addresses advancements in science and technology. The new Division 4 maintains the original intent behind the former regulations. Modernizing requirements for biologic drugs allows the FDR to align more closely with modern science and current practice.
• This document explains how there is no change to current practice.

Objective

This guidance document explains the new regulations for biologic drugs in comparison to current practice and to the former Division 4 regulations. This is to help stakeholders transition from the former Division 4 to the new Division 4.

Most of the content in Division 4 relates to requirements that extend throughout the product lifecycle for biologic drugs. As part of the renewal of Division 4:

• the regulation about storage is included in Division 2 instead of in the new Division 4 because it relates to good manufacturing practices and
• the regulation about on-site evaluations is included in Division 8 instead of in the new Division 4 because it relates to pre-market review

For currently authorized biologic drugs, there is no expected need for additional filing of information to support the measures outlined in the new regulations. Current practices in Health Canada’s regulation of biologic drugs already reflect the expectations set out in the new regulations.

Scope

This guidance document applies to drugs listed on Schedule D to the Food and Drugs Act (FDA) (biologic drugs):

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

This document is for those who fabricate, package/label, test, store, import, distribute and wholesale biologic drugs.

The content of this document does not intend to cover every conceivable case. Other approaches for complying with data information can be considered with appropriate scientific justification and as new technologies emerge. International guidance, like that of the European Medicines Agency (EMA) or the International Council for Harmonisation (ICH), may be used to provide a rationale if Health Canada does not provide specific guidance.

How to use this document

This guidance document is designed to:

• guide stakeholders through the transition from the former Division 4 to the new Division 4 and
• be a reference tool

Like other guidance documents, Health Canada will periodically review and update this document as needed. Sections that are no longer relevant, such as references to the former Division 4, may be removed.

A notice, which explained the proposed regulatory amendments for biologic drugs, was published at the same time the draft Agile Regulations were published in Canada Gazette, Part 1 (CGI) on December 17, 2022. The comments and questions received about the draft CGI regulations were used to:

• further revise the regulatory amendments for publication in CGII and
• expand the CGI Notice into this guidance document

Acronyms and abbreviations

BRDD:

Biologic and Radiopharmaceutical Drugs Directorate

CGI:

Canada Gazette, Part I

CGII:

Canada Gazette, Part II

DIN:

drug identification number

Div 4:

Division 4

FDA:

Food and Drugs Act

FDR:

Food and Drug Regulations

GMP:

good manufacturing practices

NOC:

notice of compliance

OSE:

on-site evaluation

ROEB:

Regulatory Operations and Enforcement Branch

WHO:

World Health Organization

YBPR:

yearly biologic product report

Definitions

At the time of writing, the following are the original definitions from the original sources. These definitions apply in this guidance document.

Biological auxiliary material (Matériel biologique auxiliaire):

Raw material from a biological source which is intended to be used as a processing aid in the fabrication of the drug. It may be absent from the drug or may remain as an impurity in the drug at the end of the manufacturing process (e.g., biological additives used to supplement cell culture medium in production fermenter, human antithrombin III used to complex and remove human thrombin).^{Footnote 1}

Biological source material (Matériel d’origine biologique):

• “(a) biological material sourced or derived from humans;
• (b) animals, including insects, or any biological material sourced or derived from them;
• (c) plants or any biological material sourced or derived from them; or
• (d) micro-organisms, including bacteria, viruses, fungi and bacteriophages, or any biological material sourced or derived from them.”^{Footnote 2}

Biological starting material (Matériel biologique de départ):

Raw material from a biological source which is intended to be used in the fabrication of a drug and from which the active ingredient is derived either directly (e.g., plasma derivatives, ascitic fluid, bovine lung, etc.) or indirectly (e.g., cell substrate, host/vector production cells, eggs, viral strains, etc.).^{Footnote 1}

Raw material (Matière première):

Any substance other than packaging material or an in-process drug that is intended for use in drug manufacture, including substances that appear in the master formula but not in the drug, such as solvents and processing aids.^{Footnote 3}

Notes about this guidance document

In this document:

• "DIN holder" refers to the manufacturer who was issued the drug identification number (DIN)
• "sponsor" refers to the:
  • individual, corporate body, institution or organization that conducts a clinical trial as per Division 5
  • manufacturer (holder of a DIN or notice of compliance (NOC)) of a marketed drug product
• "shall" expresses a requirement (such as a regulation that the user is obliged to satisfy in order to comply with the regulatory requirements)
• "should" expresses a recommendation that is advised but not required
• "may" and “can” express an option that is permissible within the limits of the guidance document
• “former” refers to regulations before their coming into force under the Agile Regulations (as in the “former C.04.015” (lot release) before July 1, 2025)
• “new” or “revised” refer to regulations after their coming into force under the Agile Regulations (as in the “new C.04.007” (lot release) on and after July 1, 2025)

For the regulations referenced in this document:

• “subsection” means numbering with numbers in round brackets (such as (1), (2))
• “paragraph” means numbering with lowercase letters in round brackets (such as (a), (b)) that is preceded by numbering with numbers in round brackets (such as (1), (2))
• “subparagraph” means numbering with lowercase Roman numerals in round brackets (such as (i), (ii)) that is preceded by numbering with lowercase letters in round brackets (such as (a), (b))

In the English guidance document, there is a 1 term for “drug”. In the French guidance document, there are 2 terms for “drug”. In English, the terms “drug” and “New Drug Submission” match terminology in the Food and Drugs Act and Regulations, and are also the terms commonly used. In French, the terms “drogue” and “présentation de drogue nouvelle” are used to match terminology in the Food and Drugs Act and Regulations; otherwise, the equivalent and more prevalent term “médicament” is used.

Notes about guidance documents in general

The following text is standard for all Guidance documents.

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. They should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As always, Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, to help us adequately assess the safety, efficacy and quality of a drug. We are committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the relevant sections of other applicable guidance documents.

References