Annex 7 to the Good manufacturing practices guide - Selected non-prescription drugs (GUI-0066): Guidance

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• Modified interpretations
• Personnel
• Sanitation
• Raw material testing
• Manufacturing control
• Quality control department
• Finished product testing
• Stability

Modified interpretations

The following interpretations replace those in the Good manufacturing practices guide for drug products (GUI-0001).

Personnel

C.02.006
Interpretations 1(a) and (d) concerning requirements for education and experience of personnel are replaced with (to clarify the expectations for select non-prescription drugs):

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:
      1. 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 — 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
   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 — the person 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 — the person must have necessary academic training and experience

Sanitation

C.02.007
Interpretations 3.a and 3.e concerning cleaning validation requirements are replaced with:

• 3.a Clean primary contact surfaces for manufacturing and filling equipment in a way that consistently ensures there is no visible product or cleaning agent residues. Protect all equipment from contamination and keep it clean and dry. For throat lozenges, mouthwashes and other susceptible products, you should control the level of microbial contamination and ensure there are no objectionable microorganisms.
• 3.e Ensure methods to detect residues or contaminants in evaluating cleaning are proven accurate and consistent. Demonstration of consistency should include a satisfactory analytical evaluation of parameters such as accuracy, precision and linearity for multiple tests of samples with known properties.

Raw material testing

C.02.009
Interpretation 3 concerning specifications is replaced with (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 concerning requirements for purified water is replaced with:

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 pharmacopoeial 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. The 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 concerning requirements to validate test methods is replaced with:

7. Ensure testing methods have been shown to provide accurate and consistent results. Demonstration of consistency should include a satisfactory analytical evaluation of parameters such as accuracy, precision and linearity for multiple tests of samples with known properties.

Interpretation 11 concerning requirements to test each container of a lot of raw material is replaced with:

11. In addition to the testing required in interpretation 9:
    1. Test each container of a lot of API for the identity of its contents using a specifically discriminating identity test.
    2. 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
    3. 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.c 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 raw material is produced and controlled
       3. Provided that you meet the requirements outlined in interpretation 11.c.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.c does not apply when the API is supplied by intermediaries (such as brokers), where the source of manufacture is unknown or not audited.
    4. Ensure each container in a batch is sampled and its contents positively identified when the raw material 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 concerning validation of changeover procedures for fabrication or packaging/labelling of non-medicinal products is replaced with:

• 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.

Interpretations 22 to 24 concerning validation of critical production processes requirement are replaced with:

Process consistency

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

C.02.012
Interpretation 12.b.i concerning validation responsibilities for analytical methods and production processes in written agreements is replaced with:

• 12.b. The agreement should include the following:
  • 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 formula
    • 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 concerning validation of test methods are replaced with:

• 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 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 should 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 an 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 (see additional guidance under C.02.021)

Finished product testing

C.02.018
Interpretation 2 concerning requirements to validate test methods is replaced with:

2. Ensure all test methods have been shown to provide accurate and consistent results according to the marketing authorization. Demonstration of consistency should include a satisfactory analytical evaluation of parameters such as accuracy, precision and linearity for multiple tests of samples with known properties.

C.02.019
In addition to Interpretation 4:

4. Buildings authorized by recognized countries or regions (List of foreign countries or regions and their regulatory authorities for the application of subsection C.02.019(5) of the Food and Drug Regulations):
   1. If you are a distributor or importer of a drug included in column 1 of the List of non-prescription drugs for which the testing requirements set out in subsections C.02.019 (1) and (2) of the Food and Drug Regulations do not apply and that drug is fabricated, packaged/labelled in Canada or a recognized country or region and tested in a recognized country or region, the following applies:
      1. The fabricator, packager/labeller and tester must be identified and listed on your drug establishment licence (DEL). You can find additional information in the guidance How to demonstrate foreign building compliance with drug good manufacturing practices (GUI-0080).
      2. The drug in column 1 must only contain active ingredients set out in column 2 and each corresponding quantity must be set out in column 3 of the List of non-prescription drugs for which the testing requirements set out in subsections C.02.019 (1) and (2) of the Food and Drug Regulations do not apply.
      3. The distributor or importer must retain a copy of the batch certificate for each lot or batch of the drug received to demonstrate that the drug complies with the finished product specifications. An example of an acceptable format is the International Harmonized Requirements for Batch Certification used with our MRA partners, but is also acceptable for the importation of these products.
      4. Re-testing, including identity testing and confirmatory testing, are not required when the drug is fabricated, packaged/labelled and tested in a recognized country or region.

Note: If any licensable activity (for example, fabricating, packaging, labelling or testing) is performed in a non-recognized country or region, the testing expectations once the product is received in Canada automatically revert to those described under the section for buildings in non-MRA countries.

2. You may ship the drugs directly to a person other than an importer or distributor (a retailer, for example) if:
   • you are an importer of drugs listed in column 1 of the List of non-prescription drugs for which the testing requirements set out in subsections C.02.019 (1) and (2) of the Food and Drug Regulations do not apply and
   • the drugs are from a recognized country or region (List of foreign countries or regions and their regulatory authorities for the application of subsection C.02.019(5) of the Food and Drug Regulations)

• You may ship the drugs as long as the following requirements are met before you import:
  1. The importer must receive and review documentation to determine that the drug complies with the specifications and the master production document for that drug prior to the drug being made available for sale by the person the drug is shipped directly to.
  2. The importer should have measures in place to ensure that all requirements of the Food and Drugs Regulations are met. This means identifying roles and responsibilities and having appropriate quality agreements between all parties including the foreign manufacturer, importer and person (the retailer) receiving the product.

For information on quality agreements, please consult section C.02.012.

Stability

C.02.027
Interpretation 1 concerning the requirements to make stability determinations in accordance with Health Canada and International Council on Harmonisation (ICH) guidelines is replaced with:

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. You should make this determination according to Health Canada and ICH guidelines.

Interpretation 9 concerning the requirement for validating analytical test procedures in accordance with ICH guidelines is replaced with:

9. Ensure all test methods used for stability evaluation have been shown to provide accurate and consistent results. Demonstration of consistency should include a satisfactory analytical evaluation of parameters such as accuracy, precision and linearity for multiple tests of samples with known properties.

Assays should indicate stability (that is, be 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.

Interpretations 10 and 12 concerning the requirement for evaluating stability data in accordance with ICH guidelines is replaced with:

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 if 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 concerning bracketing and matrixing in accordance with ICH for the continuing stability program is replaced with:

3. Enroll a minimum of 1 batch of every strength of the drug into your continuing stability program at all times. Consider packaging size in your choice of batches to be enrolled. You may apply the principle of bracketing and matrixing designs if justified.

Note: Minor changes to the formulations (such as adding, deleting or substituting a fragrance, flavour or colour) may be acceptable without new stability data. However, you must conduct ongoing stability studies on the revised formulation to show that the proposed change does not affect the quality of the drug product. You may conduct these studies while you market the modified product.