Veterinary drug premixes: Annex 4 to the good manufacturing practices guide for veterinary drugs

The following interpretations apply to veterinary drug premixes.

On this page

• Premises
• Equipment
• Personnel
• Sanitation
• Raw material testing
• Manufacturing control
• Packaging material testing
• Stability

Premises

C.02.004

Interpretation 3 in GUI-0001 associated with measures to prevent contamination is replaced with the following:

3. To prevent contamination, consider the following for all areas where raw materials, in-process drug premixes, primary packaging materials or drug premixes are exposed:

1. Ensure floors, walls and ceilings allow cleaning, and avoid surface materials that shed particles.
2. Ensure floors, walls, ceilings and other surfaces are made of hard, smooth materials and free of sharp corners where extraneous material can collect.
3. Ensure joints between walls, ceilings and floors are designed to avoid accumulation of extraneous materials.
4. Ensure pipes, light fittings, ventilation points and other services do not create surfaces that cannot be cleaned.
5. Screen and trap floor drains (as needed) or seal them when they are not in use.
6. Maintain air quality through dust control and by checking and replacing air filters periodically. Air handling systems must provide adequate control of airborne dust. Check them on a regular basis to ensure they remain compliant with their design specifications and keep records of this verification. Ensure cross-contamination is avoided.

Interpretation 7 in GUI-0001 associated with requirements for validation master plans 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.

Interpretation 11.b in GUI-0001 associated with requirements for self-contained facilities does not apply.

Interpretation 11.c in GUI-0001 associated with requirements to ensure external contamination with drug product residues does not exceed established limits does not apply.

Equipment

C.02.005

Interpretation 3.d in GUI-0001 associated with the area in which equipment is located to ensure compatibility and prevent cross-contamination is replaced with the following:

3.d Locate equipment to allow for compatible production operations that prevent cross-contamination. Physically separate equipment used to produce or store drug premixes or components from equipment used to manufacture or store fertilizers, herbicides, insecticides, fungicides, rodenticides and other pesticides. Do not use the same equipment for both purposes.

Interpretation 5.c in GUI-0001 associated with requirements for installation, operational and performance qualification is replaced with the following:

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

Personnel

C.02.006

Interpretation 1 in GUI-0001 associated with requirements for 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 Canadian 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 or 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

Interpretation 3.f in GUI-0001 associated with campaign production is replaced with the following:

3.f In certain cases, campaign production can be accepted on a product-by-product basis. This is allowed if you can provide proper justification, conduct validation and ensure validated controls and monitoring are in place to minimize the risk of cross-contamination.

In facilities where other veterinary drugs are produced, campaign production of drug premixes containing penicillin is considered acceptable if:

• non-penicillin drug products for human use are not fabricated, packaged/labelled or stored in the same facility and
• the risk of cross-contamination is minimized with validated decontamination and cleaning procedures

Interpretation 5 in GUI-0001 associated with containing operations that generate dust and unit or portable dust collectors is replaced with the following:

5. Conduct the manufacture of drug premixes in segregated areas. If possible, these segregated areas should not be part of a main manufacturing plant. If this is not possible, surround these areas with a buffer zone to minimize the risk of contamination between manufacturing areas.
Contain operations that generate dust. Avoid using unit or portable dust collectors in fabrication areas, especially in dispensing. If you do use them, ensure the effectiveness of their exhaust filtration is demonstrated and the units are regularly maintained according to written approved procedures.

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 active pharmaceutical ingredients (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 should include requirements for total microbial count, which should not exceed 100 cfu/ml. For oral preparations, ensure Escherichia coli and Salmonella are absent. 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 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 API coming from a single product fabricator or plant. It also applies if it comes directly from a manufacturer (or in the manufacturer's sealed container) and there is a history of reliability. In this case, 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 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.

C.02.010

Interpretation 2 in GUI-0001 associated with identity testing is replaced with the following:

2. Conduct identity testing on all lots of any raw materials received on the premises of the person that formulates the raw material into drug premixes. With the exception of feed ingredients (where only non-specific identity tests may exist), this test should be specific. This identity testing should be performed according to interpretations 9 to 11 of C.02.009.

Interpretation 6 in GUI-0001 associated with testing subsequent batches of a received raw material is replaced with the following:

6. If the same batch of raw material is received later on, you must also consider this batch as separate for the purposes of sampling, testing and release. Feed ingredients are the only exception to this requirement.

However, full testing to specifications may not be needed if all these conditions are met:

1. a specifically discriminating identity test is conducted
2. the raw material has not been repackaged or re-labelled
3. the raw material is within the vendor's re-test date
4. evidence is available to show that all pre-established transportation and storage conditions have been maintained

Manufacturing control

C.02.011

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

13.b In some cases, you may fabricate or package/label non-medicinal products in areas or with equipment that is also used to produce pharmaceutical products. If this is done, you must evaluate and approve changeover procedures before implementation.

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

Validation:

Validate all processes that affect content uniformity and potency.

Packaging material testing

C.02.016

Interpretation 2 in GUI-0001 associated with specifications complying with current versions of the marketing authorization and a recognized pharmacopoeia and the adequacy of test or examination methods is replaced with:

2. Ensure specifications comply with current versions of the marketing authorization. The adequacy of test or examination methods must be established and documented.

Stability

C.02.028

Interpretation 3 in GUI-0001 associated with the requirement to enroll 1 batch of every drug strength and container closure system into your continuing stability program has been replaced with the following:

3. Ensure at least 1 batch of each strength and container closure system of a drug premix is enrolled in the continuing stability program at all times. Consider packaging size in your choice of batches to be enrolled. You may apply bracketing and matrixing designs as long as they align with VICH GL3 stability testing of new veterinary drug substances and medicinal products and VICH GL8 stability testing for medicated premixes.

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 to fulfill the requirements. You may also reduce the number of time points in line with 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.