Post-Notice of Compliance (NOC) Changes: Guidance for quality of veterinary drugs: Documentation

On this page

• Introduction
• Supporting data
• Clinical data
• Comparative in vitro studies
• Stability testing
• Pharmaceutical development and quality by design
• Multiple changes

Introduction

This section provides general information on documentation, including supporting data common to each reporting category. For other specific documentation requirements, refer to the post-NOC change examples sections (for drug substance or drug product). They include recommendations on the supporting data for a given change, either to be submitted to Health Canada or maintained by the sponsor. An adequate rationale is required when supporting data cannot be provided.

Supporting data

Certified Product Information Document

The Certified Product Information Document (CPID) provides an accurate record of technical data in the drug submission at the time the NOC is issued. It is intended to serve as an official reference document during the course of post-approval inspections and post-approval change evaluations as performed by Health Canada. The document helps expedite the review process and facilitate the management of future post-approval changes. Refer to the VDD's Certified Product Information Document (CPID) template for the following scenarios and provide the required document(s) as outlined:

1. When proposing changes to products with a currently approved CPID

   Provide an electronic copy (Microsoft Word document with tracked changes) of the revised CPID with the updated sections affected with the proposed change.

2. When proposing changes to products with no approved CPID

   Provide an electronic copy of the CPID in Microsoft Word format. Use tracked changes for the sections affected with the newly proposed changes that have not been previously approved by Health Canada. Include a statement under the administrative summary table on the title page to confirm that the information on the CPID is accurate, complete, and consistent with the quality information approved for the product.

   A complete CPID should be submitted at the filing of Level I or Level II changes. Should you have any questions or concerns, contact the assigned Regulatory Project Managers (RPMs) or SKMD at vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca.

Level I and Level II changes

Provie all data recommended to support the change with the submission. Submit data as indicated below.

Provide a detailed rationale when you cannot submit recommended supporting data.

Supporting data common to Level I and Level II changes

Where applicable, include in the submission package for Level I and Level II Quality changes:

• a covering letter that includes a brief narrative description and rationale of the change(s)
• a list of changes describing each in sufficient detail to allow for a quick assessment as to whether the appropriate reporting category has been used along with a table outlining the currently approved and the proposed information
• an electronic copy (Microsoft Word document with tracked changes) of:
  • Package Insert
  • a sample of the inner and outer labels to reflect any proposed changes and
  • the relevant Certified Product Information Document (CPID)

Recommendations are also included in Post-NOC Change Examples sections outlining the specific information to support the various quality changes. Noted that common information is not repeated for the various change examples provided in this guidance document.

When cross-references are made to previously submitted information, details on the cross-referenced information should be indicated in the covering letter. For example:

• brand name of the drug product
• manufacturer or sponsor's name
• submission type
• control number
• date approved

Certificate of Suitability (CEP)

We encourage the use of Certificates of Suitability to the monographs of the European Pharmacopoeia (CEPs) issued by the European Directorate for the Quality of Medicines and Healthcare of the Council of Europe (EDQM) to support changes to the drug substance used in pharmaceuticals for veterinary use. Also, the use of Transmissible Spongiform Encephalopathy (TSE) CEPs may be provided to support raw materials, auxiliary materials and reagents at risk of transmitting BSE/TSE agents. Contact the Veterinary Drugs Directorate for further guidance.

With respect to the Health Canada Guidance Document Use of Certificates of Suitability as supporting information in Drug Submissions (2017/08/21) , sponsors should note:

• The term Master File (MF) used in Section 4 is synonymous with the term Active Substance Master File (ASMF).
• If the company has a current valid Certificate of Suitability (CEP), and they can provide all the attestations as per the guidance document (Section 2.1), they are encouraged to submit a CEP in support of the information for the drug substance. The minimum information required is described in Section 2.2 of the guidance document.
• The ASMF should be provided in all cases mentioned under Section 2.3 of the guidance document.

Level III changes

Sponsors should not submit any data generated in support of a Level III change with the Post-Notice of Compliance Changes (Level III) Form. Health Canada can request this data, which sponsors must make available within 30 calendar days.

Any Level III changes that have been implemented should be annotated in the affected documents. Dates of implementation should be:

• clearly identified (for example, Package Insert and CPID)
• filed with the next Level I - Supplement or Level II - Notifiable Change that necessitates a label or quality change as well

Level III changes submitted annually during the sponsor's Annual Drug Notification period should include:

• All Level III changes implemented for each new drug that has received a NOC and that have occurred in the preceding 12 months should be compiled using the Post‐Notice of Compliance (NOC) Changes: Level III form
• A completed Post‐Notice of Compliance (NOC) Changes: Level III form for each drug that has received a NOC

Only submit a copy of the revised annotated labels, Package Insert and/or CPID with the filing of the next Level I ‐ Supplement or Level II - NC that necessitates a label change or quality change as well. Clearly identify the dates of implementation for these Level III changes.

Level IV changes

The quality changes included in this category should:

• be retained as part of the product's record by either the sponsor or the manufacturer
• comply with Good Manufacturing Practices (GMP) requirements of Division 2 of the Regulations

Annotate these changes in the affected documents (such as Package Insert and CPID) with the filing of the next submission that necessitates a label or quality change as well.

Clinical data

A number of changes outlined in this guidance document include recommendations for supporting clinical or comparative bioavailability data.

The nature of a change and the related conditions fulfilled for that change, as well as the type of product and its characteristics would generally dictate the need for clinical data. Product characteristics can include:

• indications
• formulation
• dosage form
• pharmacokinetic profile
• physicochemical properties

In certain situations, where specific criteria are met, sponsors may submit a request for a waiver of in vivo (clinical) studies. This is also known as biowaiver.

Clinical data may take the form (or be a combination) of:

• palatability studies
• pharmacovigilance data
• in vivo laboratory studies
• field safety or efficacy trial data
• comparative bioavailability studies
• published articles from literature, as deemed appropriate to support a particular change

Clinical data may be required for each major species included in the indications when a veterinary drug product is intended for use in more than one animal species if the change and/or the product is not eligible for a biowaiver.

Sponsors should consult the Veterinary Drugs Directorate for specific questions, alternatives, or for additional information on biowaivers and in vivo bioavailability/bioequivalence studies.

Comparative in vitro studies

Several changes outlined in this guidance document include recommendations for supporting comparative in vitro studies (such as comparative dissolution studies). Where an in vitro comparison is recommended to support a Post-NOC Change, compare the product manufactured according to the same formulation and manufacturing process used in the pivotal clinical and/or comparative bioavailability studies approved for the original drug submission. For example, including batch formula or manufacturing process. This is called the "approved product" in this guidance document.

Alternative approaches to this recommendation may be acceptable if scientifically justified. For example, a comparison to a sponsor's marketed product (rather than the product used in the pivotal clinical and/or comparative bioavailability studies) could be justified if a significant body of information has been established for the marketed drug product. For the purposes of this document, a significant body of information for the marketed drug product is likely to exist after a reasonable number of batches of the drug product will be marketed during the specified period of time (for example, a minimum of 10 batches).

Sponsors should refer to the General Chapters available in the current Schedule B pharmacopoeia for general dissolution and drug release specifications. For example, United States Pharmacopeia (USP) <711>, USP <724>, European Pharmacopeia (Ph.Eur.) 2.9.3.

Appendix 1 also outlines recommendations for conducting and assessing comparative dissolution profiles (such as conditions or similarity).

Stability testing

If stability studies are recommended to support a change, these studies should be conducted in accordance with applicable VICH and Health Canada guidance documents, for example:

• VICH GL3 - Stability testing of new veterinary drug substances and medicinal products
• VICH GL8 - Stability testing for medicated premixes
• VICH GL5 - Stability Testing: Photostability Testing of New Drug Substances and Products
• VICH GL4 - Stability Testing: Requirements for New Dosage Forms
• VICH GL45 - Quality: Bracketing and matrixing designs for stability testing of new veterinary drug substances and medicinal products
• VICH GL51 - Quality: Statistical evaluation of stability data
• VICH GL58 - Stability Testing of New Veterinary Drug Substances and Medicinal Products in Climatic Zones III and IV

In case where accelerated stability studies are not routinely performed due to the nature of the product, provide a rationale.

Pharmaceutical development and quality by design

The International Council for Harmonisation (ICH) has developed the Q8 guideline: Pharmaceutical Development and Q8 Annex. They describe respectively the suggested contents for the 3.2.S.2.2 to 3.2.S.2.6 sections and for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the Common Technical Document (CTD) format.

The pharmaceutical development section is intended to provide a comprehensive understanding of the product and manufacturing process for reviewers and inspectors. Provide the pharmaceutical development information for a veterinary drug submission as outlined in section 6.4.2 of Guidance for Industry: Preparation of Veterinary New Drug Submissions.

The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support establishing the design space, specifications, and manufacturing controls.

The applicant proposes the design space, which is subject to regulatory assessment and approval. Working within the design space is not considered as a change that would require prior approval but should be documented with the requisite Change Controls where necessary. Movement outside of the design space is considered to be a change and would normally initiate a regulatory post approval change process.

For example, some of the Post-NOC Changes that are listed in this guidance document as Level I or Level II may not require approval prior to implementation if they are within the approved design space.

A sponsor may also establish a new design space for an existing product. Once approved, this would provide the advantage of limiting the necessity to file future submissions for changes within the ranges of the design space.

If proposed and approved, record the details of the design space in the Certified Product Information Document (CPID). We encourage sponsors to discuss with Health Canada when considering the establishment of a design space.

Multiple changes

Multiple Level II (Quality) changes to the same drug product may be filed in a single submission provided those changes are related or supported by the same information. If the changes are related, the sponsor should indicate the association between the proposed changes. The sponsor should ensure that the documentation for each change complies with the requirements of the corresponding section of the guidance. For submissions that include multiple changes, the sponsor should clearly specify which supporting data supports which change.

If there are too many changes filed within the same submission or major issues are identified with a change which would require extensive time to review, Health Canada may divide the changes into separate submissions.

If the same change is applicable to multiple drugs, the same supporting data package may be used but a separate submission is required for each drug product.