Notice to stakeholders – Release of draft guidance document for consultation: Annex 4 to the Good manufacturing practices guide – Veterinary drugs

Health Canada was pleased to announce the release of Annex 4 to the Good manufacturing practices guide – Veterinary drugs (GUI-0012) for a 5 month stakeholder consultation period from February 19, 2020 to July 19, 2020.

This revised guidance document contained new information.

This guide is an annex to the Good manufacturing practices guide for drug products (GUI-0001). You must read the two documents together to understand all relevant guidelines. These guides will help you understand and comply with Part C, Division 2 of the Food and Drug Regulations (the Regulations), which is about good manufacturing practices (GMP).

The key changes proposed are listed below.

Overview of Key Changes

Formatting changes

The format of GUI-0012 was improved. Key changes included:

• conforming with the new template for guides and policies
• adding visual call-out boxes for important and reference information

Language changes

GUI-0012 was rewritten in plain language. Key changes included:

• changing regulatory interpretations from passive to active voice
• using plain language where possible, excluding for technical terms or those related to regulatory content
• shortening sentences and paragraphs where appropriate
• converting some passages to bulleted lists

Regulatory and technical language was left intact, particularly in the Glossary.

Technical changes

General

The title was shortened from the original Guidance Document Annex 4 to the Current Edition of the Good Manufacturing Practices Guidelines - Veterinary Drugs to Annex 4 to the Good manufacturing practices guide – Veterinary drugs. This helps in alignment with other newly revised Annexes.

In keeping with the current layout for Health Canada guides, the section titled "Introduction" was renamed "About this document." In addition, the "Purpose" and "Scope" sections were moved to come before the material contained in the previous "Introduction" section.

An information box was added to the scope to direct readers to the correct reference material for establishment licensing and active pharmaceutical ingredients.

"Appendix B – References" was added to reflect the list of veterinary references not available in the main GUI-0001.

Introduction

The introduction was updated to align with language applied in Health Canada's Good manufacturing practices guide for drug products (GUI-0001). Clarity was provided as to the section of the guide that applies to veterinary drugs that are subject to a published veterinary monograph on Canada.ca.

Section 4 – All veterinary drugs

Clarity was provided that this section of the guide does not apply to veterinary drugs that are subject to a published veterinary monograph on Canada.ca.

Section 4 — All veterinary drugs — Premises – C.02.004 & Sanitation – C.02.007

Content associated with the previous interpretation 11.1 for acceptance of campaign production in the Premises section was moved to the Sanitation section under 3.f to align with revised structure in GUI-0001.

Section 5 — Non-sterile, non-prescription veterinary drugs

Clarity was provided that this section of the guide also applies to veterinary drugs that are subject to a published veterinary monograph on Canada.ca.

Section 5 — Non-sterile, non-prescription veterinary drugs — Equipment – C.02.005

Interpretation #5.c (previously interpretation 5.3) was changed to remove the word "critical" as equipment needs to be suitable for its intended purpose in all cases.

Section 5 — Non-sterile, non-prescription veterinary drugs — Personnel – C.02.006

The text has changed significantly to improve readability when read with the revised version of GUI-0001. Expectations remain consistent with the previous version.

Section 5 — Non-sterile, non-prescription veterinary drugs — Sanitation – C.02.008

Provisions associated with health examinations were removed from this Annex. The requirement now defaults to the requirements in GUI-0001. As such, the requirement to have periodic medical examinations now applies. This period can be defined with appropriate risk management principles.

Section 5 — Non-sterile, non-prescription veterinary drugs — Raw Material Testing – C.02.009

The text has changed significantly to improve readability when read with the revised version of GUI-0001. The expectation remains the same in that the requirement to test each container for identity applies to that of the active pharmaceutical ingredient. The requirement to test other raw materials received for identity without evaluating each container — unless handled in a substantial way (e.g. repackaged by a third party) — remains consistent with the previous version.

Section 5 — Non-sterile, non-prescription veterinary drugs —Manufacturing Control — C.02.011

The word "Validate" has been introduced as a header in advance of interpretations #22-25 with expectations remaining the same. This addition helps facilitate use of language relating to validation in GUI-0001 that can be found in sections related to annual product quality reviews, reworking, and reprocessing.

Interpretation #22 (previously interpretation 2) was changed from "All critical production processes have been shown to produce consistent results…" to "ensure production processes produce consistent results". This change is not expected to have significant burden on stakeholders as data available should demonstrate consistency in the process.

Interpretation #24 (previously interpretation 4) which was associated with evaluating changes to production processes, equipment, or materials has been expanded to include suppliers to align with new content in GUI-0001.

Section 5 — Non-sterile, non-prescription veterinary drugs —Manufacturing Control — C.02.012

A new interpretation has been added replacing Interpretation #12 b.i in GUI-0001. This provides clarity in the expectations for written agreements to include a description of who is responsible for:

• ensuring testing methods have been shown to provide accurate and consistent results
• ensuring production processes produce consistent results

Section 5 — Non-sterile, non-prescription veterinary drugs —Quality Control Department — C.02.015

Two new interpretations have been added replacing Interpretation #8.e and 8.l.iv in GUI-0001. These provide clarity on aspects associated with ensuring testing methods have been shown to provide accurate and consistent results.

Section 5 — Non-sterile, non-prescription veterinary drugs — Finished Product Testing – C.02.018

A note was removed that previously provided an allowance to test physical characteristics (e.g. specific gravity or viscosity) of certain topical non-Schedule products (for example, hoof ointment) that contain only ingredients such as oils, tars and other emollients. The removal of this note will help industry better align with regulatory requirements to confirm identity for which gravity or viscosity based testing is not sufficient.

Section 5 — Non-sterile, non-prescription veterinary drugs —Stability Testing – C.02.027

The previous interpretation to establish stability based on one commercial-scale batch was removed. As such, provisions for 3 batches as specified in GUI-0001 will apply. This will facilitate alignment with drug submission requirements described in Health Canada's Guidance for Industry Preparation of Veterinary New Drug Submissions.

You should note the removal of the interpretation that previously specified "The assignment of the expiry date may be initially based on accelerated data and data from similar formulations, and is supported by long term testing." This has been removed because the previous and current interpretation in this Annex already details a similar expectation in that stability data be based on samples stored according to the intended label storage conditions (see Interpretation #1).

A new interpretation #12 has been added to replace the same interpretation in GUI-0001 that makes reference to ICH and VICH stability guidelines.

Section 5 — Non-sterile, non-prescription veterinary drugs —Stability Testing – C.02.028

The previous interpretation under C.02.028 which specified that a minimum of one batch of every strength of the drug premix is enrolled in the continuing stability program at all times has been modified. This requirement now specifies enrollment of each strength and container closure system. Provisions for bracketing and matrixing continue to be permitted.

The interpretation associated with minor changes of minor excipients was removed to avoid duplication or conflict with Health Canada's Post-Notice of Compliance (NOC) Changes: Quality Document.

Section 6 Premixes

Section 6 — Premixes — Premises — C.02.004 & Sanitation — C.02.007

Content associated with the previous interpretation 11.1 for acceptance of campaign production was moved to the Sanitation section under 3.f to align with revised structure in GUI-0001.

Section 6 — Premixes — Equipment – C.02.005

Interpretation #5.c (previously interpretation 5.3) was changed to remove the word "critical" as equipment needs to be suitable for its intended purpose in all cases.

Section 6 — Premixes — Personnel — C.02.006

The text has changed significantly to improve readability when read with the revised version of GUI-0001. Expectations remain consistent with the previous version.

Section 6 — Premixes — Sanitation — C.02.008

Provisions associated with health examinations were removed from this Annex. The requirement now defaults to the requirements in GUI-0001. As such, the requirement to have periodic medical examinations now applies. This period can be defined with appropriate risk management principles.

Section 6 — Premixes — Raw Material Testing – C.02.009

No new changes were made to this section. The text has changed significantly to improve readability when read with the revised version of GUI-0001. The expectation remains the same in that the requirement to test each container for identity applies to active pharmaceutical ingredients. The requirement to sample and test API when handled in a substantial way (e.g. repackaged by a third party) remains consistent with the previous version.

Section 6 — Premixes — Stability Testing — C.02.027

The previous interpretation under C.02.027 which detailed requirements for analytical test procedures to provide accurate and consistent results was removed. As such, the provisions for method validation as specified in GUI-0001 will apply. This change was proposed as finished product testing method validation was already a requirement for veterinary premixes under C.02.018 interpretation #2.

Section 6 — Premixes — Stability Testing — C.02.028

The previous interpretation under C.02.028 which specified that a minimum of one batch of every strength of the drug premix is enrolled in the continuing stability program at all times has been modified. This requirement now specifies enrollment of each strength and container closure system. Provisions for bracketing and matrixing continue to be permitted.