Non-sterile, non-presciption veterinary drugs: Annex 4 to the good manufacturing practices guide for veterinary drugs

The following guidance applies to:

• non-sterile, non-prescription veterinary drugs that have a drug identification number (DIN) and a zero withdrawal period for all approved species
• veterinary drugs that are subject to a published veterinary monograph

This category includes products such as topical creams, udder washes, teat dips, external antiseptics, external parasiticides and oral pastes for horses.

On this page

• Premises
• Equipment
• Personnel
• Sanitation
• Raw material testing
• Manufacturing control
• Quality control department
• Finished product testing
• Stability

Premises

C.02.004

Interpretation 7 in GUI-0001 associated with requirements for the validation master plan and qualification requirements is replaced with the following:

7. In buildings where drugs are fabricated or packaged/labelled, ensure utilities and support systems are adequately designed and appropriately maintained for their intended use. This includes systems such as heating, ventilation, air conditioning and dust collection, as well as supplies of purified water, steam, compressed air and nitrogen.

Equipment

C.02.005

Interpretation 5.c in GUI-0001 associated with requirements for the qualification of equipment is replaced with the following:

5.c Ensure that the equipment used during fabrication, packaging/labelling and testing (including computerized systems) is suitable for its intended purpose.

Personnel

C.02.006

Interpretation 1 in GUI-0001 associated with requirements for the education and experience of personnel is replaced with the following to clarify expectations for veterinary drug importers or distributors:

1. The person in charge of your quality control department (if you are a fabricator, packager/labeller, tester, importer or distributor) and the person in charge of your manufacturing department (if you are a fabricator or packager/labeller):

1. must hold a Canadian university degree or a degree recognized as equivalent by a Canadian university or accreditation body in a science related to the work being carried out and practical experience in their area of responsibility
2. alternatively, in the case of an importer and distributor, must have a diploma, certificate or other evidence of formal qualifications awarded on completion of a course of study from a college or technical institute in a science related to the work being carried out combined with at least 2 years of relevant practical experience
3. directly controls and personally supervises on-site each working shift during which activities under their control are being conducted (for importers and distributors, the person in charge can be off-site in Canada if they are fully accessible to the quality control department and have enough knowledge of on-site operations to fulfill the responsibilities of the position)
4. may delegate duties and responsibility (for example, to cover all shifts) to a person who is qualified, while remaining accountable for those duties and responsibility:
   1. in the case of a fabricator, packager/labeller or tester, must have a diploma, certificate or other evidence of formal qualifications awarded after completion of a course of study at a university, college or technical institute in a science related to the work being carried out, combined with at least 2 years of relevant practical experience
   2. in the case of an importer or distributor, must have necessary academic training and experience

Sanitation

C.02.007

Interpretations 3.a and 3.e in GUI-0001 associated with cleaning validation requirements are replaced with the following:

3.a Clean primary contact surfaces for manufacturing and filling equipment in a way that consistently ensures there are no visible product or cleaning agent residues. Protect all equipment from contamination and keep it clean and dry.

3.e Ensure methods to detect residues or contaminants in evaluating cleaning are proven accurate and consistent.

Raw material testing

C.02.009

Interpretation 3 in GUI-0001 associated with specifications is replaced with the following to clarify when house standards are acceptable for non-medicinal ingredients:

3. Make sure your specifications of APIs comply with current versions of all of the following:

1. the marketing authorization
2. a recognized pharmacopoeia
   1. where appropriate, include other properties or qualities not addressed by the pharmacopoeia (for example, particle size, polymorphs, density) in the specifications
   2. where a recognized pharmacopoeia (Schedule B of the Food and Drugs Act) contains a specification for microbial content, include that requirement

House standard specifications for other raw materials are allowed if those standards comply with the drug's current marketing authorization.

Interpretation 4 in GUI-0001 associated with requirements for purified water is replaced with the following:

4. Ensure any water used in formulating a drug product for which there is a pharmacopoeial monograph (Schedule B of the Food and Drugs Act) meets the requirements of that monograph.

When drug products do not appear in a pharmacopoeial monograph, the water used in their formulation must meet specifications based on sound physical and chemical principles. These specifications must include requirements for total microbial count, which should not exceed 100 colony-forming units (cfu)/ml.

For oral preparations, ensure the absence of Escherichia coli and Salmonella. For topical preparations, ensure Staphylococcus aureus and Pseudomonas aeruginosa are absent.

Interpretation 7 in GUI-0001 associated with requirements to validate test methods is replaced with the following:

7. Ensure testing methods have been shown to provide accurate and consistent results.

Interpretation 11 in GUI-0001 associated with requirements to test each container of a lot of raw material is replaced with the following:

11. In addition to the testing required in interpretation 9, test each container of a lot of the active pharmaceutical ingredient (API) for the identity of its contents using a specifically discriminating identity test:

1. Instead of testing each container for identity, you may test a composite sample (derived from sampling each container), as long as you meet the following conditions:
   1. a suitable test exists
   2. the number of individual containers for each composite sample does not exceed 10
   3. a potency test is performed on each composite sample
2. Instead of testing each container for identity, you may test only a proportion of the containers, as long as there is evidence to ensure that no single container of API has been incorrectly labelled.
   1. Interpretation 11.b applies to the API coming from a single product fabricator or plant, or directly from a manufacturer (or in the manufacturer’s sealed container) and there is a history of reliability. To demonstrate this, regular audits of the manufacturer’s quality assurance system must be conducted by or on behalf of the purchaser/drug fabricator.
   2. The available evidence should include an on-site audit report of the vendor by a person who meets the requirements of interpretation 1 under section C.02.006 “Personnel.” The audit report should address at least the following:
      • the nature and status of the manufacturer and the supplier, and their understanding of the GMP requirements of the pharmaceutical industry
      • the quality assurance system of the raw material manufacturer
      • the manufacturing conditions under which the API is produced and controlled
   3. Provided that you meet the requirements outlined in interpretations 11.b.i, you may conduct identity testing on representative samples. You should statistically determine the number of samples taken to prepare the representative sample and specify this number in a sampling plan. You should also define the number of individual samples that may be blended to form a composite sample, taking into account the nature of the material, knowledge of the supplier and homogeneity of the composite sample.
   4. Interpretation 11.b does not apply when the API is supplied by intermediaries (such as brokers), where the source of manufacture is not audited.
3. Ensure each container in a batch is sampled and its contents positively identified when the API is handled in any substantial way (for example, repackaged by a third party) after leaving the site of its fabrication.

Manufacturing control

C.02.011

Interpretation 13.b in GUI-0001 associated with validation of changeover procedures for fabricating or packaging/labelling non-medicinal products is replaced with the following:

13.b. In some cases, similar non-medicinal products can be fabricated or packaged/labelled in areas or with equipment that is also used to produce pharmaceutical products. If this happens, changeover procedures must be effective, evaluated and approved before implementation.

The section on validation in GUI-0001 (interpretations 22 to 25) is replaced with the following:

Validation:

22. Ensure production processes produce consistent results. The person in charge of the quality control department must also approve these production processes. To demonstrate consistency, include an evaluation of completed batch documents, in-process controls, finished product test results and additional testing for at least 3 consecutive batches (as appropriate).

23. Prepare, evaluate, approve and maintain a written report that includes the results and conclusions of the evaluation of the production processes.

24. Before implementation, evaluate any changes to the production processes, equipment, materials or suppliers that could affect product quality or process reproducibility.

25. Evaluate critical processes and related procedures periodically to ensure they remain capable of achieving the intended results.

C.02.012

Interpretation 12.b.i in GUI-0001 associated with validation responsibilities for analytical methods and processes in written agreements is replaced with the following:

12.b. The agreement should include the following:

1. a description of who is responsible for:
   • writing and approving raw materials, packaging materials and finished product specifications
   • purchasing, sampling, testing and releasing raw materials and packaging materials
   • writing and approving manufacturing and packaging master formulae
   • undertaking production, quality and in-process controls
   • ensuring testing methods have been shown to provide accurate and consistent results
   • ensuring production processes produce consistent results
   • overseeing the stability program
   • overseeing transport and storage logistics and conditions
   • preparing specific sections of the annual product quality review

Quality control department

C.02.015

Interpretations 8.e and 8.l.iv in GUI-0001 on the validation of test methods are replaced with the following:

8.e. All test methods have been shown to provide accurate and consistent results. A lab that is using a test method where the lab did not perform the original evaluation (for example, the use of a compendial method) should verify the appropriateness of the test method. All testing as described in the marketing authorization should be carried out according to the approved methods.

1. The transfer of test methodology from 1 lab to another should include an assessment to verify that the test method(s) complies with the marketing authorization. A gap analysis should be performed and documented to identify aspects to be verified before starting a technical transfer process.
2. The transfer of test methodology should be described in a written protocol. This should include (but is not limited to) the following parameters:
   • the relevant test method(s) undergoing transfer
   • additional training requirements
   • standards and samples to be tested by both labs
   • any special processing, transport and storage conditions for test items
   • the testing to be performed
   • the acceptance criteria
3. Deviations from the protocol should be investigated before closing the technical transfer process. The technical transfer report should document the comparative outcome of the process and identify areas requiring further test method re-evaluation.

8.l.iv Technical aspects of the agreement must be drawn up by qualified personnel suitably knowledgeable in the relevant lab testing and GMP. The agreement must:

1. permit audit of the external lab's facilities and operations
2. clearly describe (at a minimum) who is responsible for:
   1. overseeing collection, transportation and storage conditions of samples before testing
   2. keeping stability samples at predetermined temperatures and humidity, if applicable
   3. testing methods to be used, limits and test method evaluation for accuracy and consistency
   4. retaining analytical results and supporting documentation (refer to the additional guidance under C.02.021)

Finished product testing

C.02.018

Interpretation 2 in GUI-0001 associated with requirements to validate test methods is replaced with the following:

2. Ensure all test methods have been shown to provide accurate and consistent results according to the marketing authorization.

Stability

C.02.027

Interpretation 1 in GUI-0001 associated with requirements to make stability determinations in accordance with the guidelines of Health Canada and the International Council on Harmonisation (ICH) or International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) is replaced with the following:

1. Determine the stability of a drug before any marketing takes place. Its stability should also be determined before making any significant changes to formulation, fabrication procedures or packaging materials that may affect the drug's shelf life. Store stability samples according to the intended label storage conditions.

Interpretation 9 in GUI-0001 associated with the requirement for validating analytical test procedures in accordance with ICH or VICH guidelines is replaced with the following:

9. Ensure all test methods used for stability evaluation have been shown to provide accurate and consistent results.

Assays should be stability indicating (for example, specific enough to detect and quantify degradation products and to distinguish between degraded and non-degraded materials). Ensure limits for individual specified, unspecified and total degradation products comply with the marketing authorization.

Interpretation 10 and 12 in GUI-0001 associated with the requirement for evaluation of stability data in accordance with ICH or VICH guidelines is replaced with the following:

10. Ensure shelf life is assigned according to an appropriate statistical evaluation of stability data. Verify shelf life using additional long-term stability data, as these data become available.

12. For imported products, stability studies from foreign sites are acceptable if the data meet Health Canada guidelines for stability and the site can show GMP compliance. The importer/distributor's responsible quality function should ensure study protocols comply with the marketing authorization. They must also review, update and maintain the stability results.

C.02.028

Interpretation 3 in GUI-0001 associated with bracketing and matrixing in accordance with ICH or VICH for the continuing stability program is replaced with:

3. Enroll a minimum of 1 batch of every drug strength and container closure system into your continuing stability program each year the drug is produced. Consider packaging size in your choice of batches to be enrolled. You may apply the principle of bracketing and matrixing designs if justified.

Interpretation 5 in GUI-0001 associated with 5 time points in continuing stability programs is supplemented with the following information to provide further clarity.

5. For drugs with an established shelf life and consistent historical stability profile, conduct testing at least every year, with a minimum of 5 time points (including the initial and final time points) unless otherwise approved in the marketing authorization.

Note: You should conduct your continuing stability program in a manner that allows you to detect changes and provide you with sufficient data to support statistical analysis. A minimum of 5 time points will help you in fulfilling requirements. You may also reduce the number of time points in line with the provisions of VICH GL3 stability testing of new veterinary drug substances and medicinal products (for example, bracketing and matrixing).

For veterinary drugs that have a well-established history with a stability profile demonstrating absence of significant change, you may be able to justify testing once per year in your continuing stability program.