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Good manufacturing practices guide for natural health products (GUI-0158): NHP GMP guidance, sections 52 to 62

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Stability period (section 52)

Section 52

Every manufacturer and every importer shall determine the period of time during which, after being packaged for sale, the natural health product will maintain its purity and physical characteristics and its medicinal ingredients will maintain their quantity per dosage unit and their potency when

  1. it is stored under its recommended storage conditions; or
  2. if it does not have recommended storage conditions, it is stored at room temperature.

Intent

A written stability program is used to:

Examples of environmental factors that can affect a product's shelf life during storage include:

A product's shelf life may also be affected by a product's:

Environmental factors and product characteristics may cause a product to degrade, lose medicinal ingredient strength or show an increase in microbial contamination.

Manufacturer, importer requirements

Manufacturers and importers must put written procedures (SOPs) and practices in place for product stability studies to ensure that finished products comply with approved specifications.

You must:

You are responsible for obtaining, maintaining and reviewing up-to-date records on the stability program. It does not matter if you or the product licence holder, foreign manufacturer, distributor or other responsible person performs the stability testing.

For imported products, stability studies from foreign sites may be accepted. As the importer, you must:

Stability program written procedure

To implement an effective stability program, you must have a stability program written procedure (SOP). The SOP should include details on the following:

You may be able to reduce the number of stability studies for products with multiple package types by using bracketing or matrixing. For more information on using bracketing and matrixing, consult:

Although NHPs are not within the scope of ICH guidelines, such references are helpful to the NHP industry and other stakeholders. The guidelines may help you gain a better understanding of GMP concepts and processes that also apply to NHPs.

Assigning the initial expiry date

Each finished NHP sold in Canada must have a lot number and an expiry date on the label. To determine the initial expiry date, use known data to predict the product's shelf life, such as:

While accelerated testing generates preliminary shelf-life data in a relatively short timeframe, it may be unreliable when used to assign an expiry date. You will need to determine if it's appropriate to use accelerated stability studies, especially for products that can easily separate, melt, soften, crack or degrade under high temperatures and humidity. Use real-time stability testing to confirm data from accelerated testing.

When using stability data from similar products, maintain evidence of their manufacturing and packaging process (for example, a batch record) to thoroughly evaluate and document any differences between the products that might affect stability. Maintain the stability study results from any similar products used to support your product's initial shelf life.

In general, similar products would be those with similar formulations and manufacturing and packaging processes (premises and equipment):

Differences in raw materials and finished products can change the product's properties, including the material in which they are packaged, how the package is sealed and package size. Interactions between ingredients, added preservatives and the manufacturing process must also be considered.

Conducting real-time stability studies

Real-time stability studies must be conducted and used to verify any shelf life that was proposed based on extrapolation. Use the data collected through real-time studies to ensure that each finished product meets its label claims at the expiry date (when stored according to its labelled storage conditions).

Real-time stability studies must follow an established stability protocol. This means the:

A product held in bulk before it's packaged or any time throughout its manufacture could affect stability studies. You should consider including batches that have been stored at the limits of extended hold times (for example, more than 1 month) in your study. This would represent a worst-case scenario.

The shelf life is established through stability studies (for example, data show that the product is stable for 24 months). The studies are used to assign an expiry date to each lot of packaged product. The expiry date printed on the product packaging must be assigned from the date of original batch manufacture, not the date of packaging. For example, a 24-month shelf life would be indicated by printing an expiry date on the product packaging that is 24 months after the date of manufacturing. This would occur even if the product was held in bulk for 6 months before being packaged.

Stability sample storage areas may include specialized chambers or dedicated rooms. They must be monitored for temperature, humidity and, where applicable, light levels. Storage conditions should be maintained within the ranges specified in the stability protocol and in accordance with the product licence and label. Document and maintain records of the storage conditions.

Tip: The regulations are not prescriptive on the time points required for conducting stability testing on NHPs. However, additional test time points can help manufacturers, importers and product licence holders gather useful information and compile trending data on the product over its shelf life.

By tracking stability test results at several time points over the course of the stability study, trends may be observed in the preservative strength, microbial contaminant levels and medicinal ingredient strength. These may lead to OOS test results before the product expires. Results that are out-of-trend (OOT) should be investigated. Remember, OOS test results can lead to product recalls.

When medicinal ingredients in the finished product are quantified by input, they cannot be assayed at expiry. Instead, you may evaluate other observed changes to the product over its shelf life, such as changes in colour or odour, viscosity, disintegration and microbial contamination. These may indicate changes in the product's quality and stability.

We recommend assigning a shorter shelf life for those products where medicinal ingredients cannot be quantified by assay. Remember to make changes to your stability program when new test methods that can be used for your product become available.

You should confirm and adjust the expiry date when required. Base any updates to the shelf life on real-time studies performed on products stored:

Re-evaluate the product shelf life when significant changes are made to the formulation, the manufacturing process, or the packaging. These may affect the product's stability.

Collecting additional stability data

You may choose to gather additional stability data to expand your knowledge of how various factors affect product quality. This would be in addition to assigning the initial expiry date and confirming the shelf life through real-time studies. Gathering additional data can help to:

Reworking means using an alternate manufacturing process for a single batch of an in-process, bulk or finished NHP due to an unexpected failure to meet predetermined specifications.

The regulations do not specifically require expiration dates for bulk products. However, it's valuable to collect data on various hold times to provide assurance that the product remains stable for the intended period of use. Consider including batches that have been stored in bulk at the limits of extended hold times (for example, more than 1 month) in your stability program.

Any rework performed may affect the stability of the finished product. Enrolling reworked lots into the stability program can provide support for releasing these products and assurance that the lots are still of good quality.

Storage conditions for NHPs need to be in accordance with label requirements, unless you have an acceptable scientific rationale that allows for brief deviations (for example, during shipping). Stability data may support planned temperature deviations and worst-case scenarios (frequency and severity) throughout the distribution chain.

The data are also useful in assessing the effects of unplanned deviations. If you conduct studies such as freeze/thaw or high temperature cycling, you should evaluate the early exposure to extreme temperatures, as stability at the end of shelf life may be affected.

NHPs are not within the scope of USP <1079> Risks and mitigation strategies for the storage and transportation of finished drug products. However, the concepts and mitigation strategies presented in that reference may help to guide best practices related to temperature excursions.

Initial shelf life may be extended if real-time stability studies show that the product is stable for longer than anticipated. Carrying out these studies past the current expiry date and evaluating the test results according to your stability protocol may allow you to make changes to your stability period and extend your expiry date for future lots.

The desire to extend expiry dates requires pre-planning in the protocol stage. You need to enrol additional samples in the program and document the additional test time points you will use.

Consumer complaints, such as those dealing with product colour, odour and appearance, may give additional data on the stability of your product. A product that changes in appearance or smell over time may indicate microbial growth or unwanted chemical reactions.

Designing a stability protocol

A stability protocol should be designed to provide data from the study in a form and quantity that permits a realistic analysis. It should be created for each stability study.

Your stability protocol should include, as applicable, the:

The properties selected for testing during a stability study should include those that may be subject to change during storage or could affect the label claims, product safety, efficacy or quality. Although many minerals are known for their stability over time, mineral medicinal ingredients should still be included in stability studies. Ingredients can change over time in unexpected ways. This includes when they are mixed with other ingredients, manufactured into their finished dosage form and packaged in various packaging materials.

For more information on stability specifications for various dosage forms, consult:

Maintaining a stability report

The stability report summarizes the data generated from each stability protocol, including the study's evaluation and conclusions. Include the following in this report, as applicable:

Also include:

The stability study should provide data in a form and quantity (such as number of test time points) that permits scientific evaluation and realistic statistical analysis. Study results should include results from:

Use the data gathered through real-time studies to confirm and adjust the expiry date, as needed.

If you observe OOS, borderline or atypical trends during the study, you must take further action, such as conducting an investigation, additional stability studies, changing the shelf life or recalling the product. Consider also the impact of the stability study on all batches of the product that are on the market.

Review and evaluate the data collected against Canadian requirements. As the manufacturer or importer, you should do this whether you or the product licence holder, distributor, foreign manufacturer or other responsible person did the stability testing. The QAP for the party responsible for the stability of the product in Canada will review, approve, sign and date the stability reports, and address any deficiencies.

Keep a record of how you determined each shelf life for 1 year after the last lot of the NHP to which that stability record relates has expired.

The record must include the:

Note: The regulations do not distinguish between a manufacturer and a contract manufacturer. Both have the same responsibilities for stability and related records:

  • Section 52: Every manufacturer and every importer shall determine the period of time during which, after being packaged for sale, the NHP will maintain its purity and physical characteristics and its medicinal ingredients will maintain their quantity per dosage unit and their potency.
  • Section 53: Every manufacturer who sells a natural health product shall maintain the following records at the site at which the NHP is manufactured: a record of each determination made by the manufacturer in accordance with section 52 and the information that supports that determination.

GMP evidence

You must demonstrate GMP compliance for stability with supporting evidence. The type of GMP evidence for stability may vary. Examples of evidence include:

Records (sections 53 to 58)

Section 53 to 58

53 Every manufacturer who sells a natural health product shall maintain the following records at the site at which the natural health product is manufactured:

  1. the master production document for the natural health product;
  2. a list of all ingredients contained in each lot or batch of the natural health product;
  3. records of any testing conducted in respect of a lot or batch of raw material used in the manufacture of the natural health product;
  4. records of any testing conducted by or for the manufacturer in respect of a lot or batch of the natural health product;
  5. a copy of the specifications for each natural health product that is being manufactured at the site;
  6. records demonstrating that each lot or batch of the natural health product was manufactured in accordance with the requirements of this Part;
  7. a record of each determination made by the manufacturer in accordance with section 52 and the information that supports that determination;
  8. records containing sufficient information to enable the recall of every lot or batch of the natural health product that has been made available for sale;
  9. a list of all natural health products that are being manufactured at the site; and
  10. a copy of the sanitation program in use at the site.

54 Every packager who sells a natural health product shall maintain the following records at the site at which the natural health product is packaged:

  1. records of any testing conducted by or for the packager in respect of the material used to package the natural health product;
  2. records demonstrating that each lot or batch of the natural health product was packaged in accordance with the requirements of this Part;
  3. records containing sufficient information to enable the recall of every lot or batch of the natural health product that has been made available for sale;
  4. a list of all natural health products that are being packaged at the site; and
  5. a copy of the sanitation program in use at the site.

55 Every labeller who sells a natural health product shall maintain the following records at the site at which the natural health product is labelled:

  1. records demonstrating that each lot or batch of the natural health product was labelled in accordance with the requirements of this Part;
  2. records containing sufficient information to enable the recall of every lot or batch of the natural health product that has been made available for sale;
  3. a list of all natural health products that are being labelled at the site; and
  4. a copy of the sanitation program in use at the site.

56 Every importer who sells a natural health product shall maintain the following records:

  1. the master production document for the natural health product;
  2. a list of all ingredients contained in each lot or batch of the natural health product;
  3. records of any testing conducted by or for the importer in respect of a lot or batch of the natural health product;
  4. a copy of the specifications for the natural health product;
  5. a record of each determination made by the importer in accordance with section 52 and the information that supports that determination;
  6. records containing sufficient information to enable the recall of every lot or batch of the natural health product that has been made available for sale; and
  7. a copy of the sanitation program in use by the importer.

57 Every distributor shall maintain the following records at the site at which the natural health product is stored:

  1. records containing sufficient information to enable the recall of every lot or batch of the natural health product that has been made available for sale;
  2. a list of all natural health products that are being stored at the site; and
  3. a copy of the sanitation program in use at the site.

58 Every person required under this Part to maintain a record that relates to a lot or batch of a natural health product shall maintain that record for a period of 1 year following the expiry date of the natural health product to which that record relates.

Intent

Good documentation is a key part of a quality system. It promotes and supports compliance with GMP requirements. Documentation may be paper-based, electronic or photographic media.

Your quality system should define the various types of documents and media that you are using. The documentation system's main objective is to establish, control, monitor and record all activities, especially those that directly or indirectly impact the quality of your product. This includes information from all stages of the product lifecycle and all records on product quality.

Records must be reliable, complete, consistent and accurate.

Your company, QAP and employees must view documentation and record-keeping as a fundamental element of GMP and of your quality system.

Manufacturer, packager, labeller, importer, distributor requirements

You must have a documentation control system that properly documents, records and tracks all stages of manufacturing, packaging, labelling, storage, testing and distribution.

Table 2 lists the minimum record-keeping requirements for manufacturers, packagers, labellers, importers and distributors.

Table 2: Record-keeping requirements for various activities
Record Manufacturer Packager Labeller Importer Distributor
Master production document Maintain None None Maintain None
Batch record Maintain Maintain Maintain AccessFootnote 1 None
Test results: raw materials Maintain None None AccessFootnote 2 None
Test results: packaging materials None Maintain None Access None
Test results: finished product Maintain NoneFootnote 3 None Maintain None
Specifications: raw materials Maintain None None Access None
Specifications: packaging materials None Maintain None Access None
Specifications: finished product Maintain NoneFootnote 3 None Maintain None
Stability Maintain None None Maintain None
Ingredients list Maintain None None Maintain None
Products list Maintain
Complaints Maintain
Recall Maintain
Sanitation program Maintain

Maintain: Indicates the party will keep and make readily available such records.
Access: Indicates the party does not need to keep these records but will have ready access to them.
None: Indicates the party does not need to have such records.

Tip: As an importer you may want to maintain copies of product licences and of product labels to confirm, during the release process, that products meet their label requirements.

You must:

You must also maintain, as applicable:

Note: When the manufacturer is located outside of Canada, specific parts of a master production document may be a trade secret or confidential. They may be held on behalf of the Canadian importer by an independent party in Canada.

  • The importer and independent party will ensure that Health Canada can access the data in a timely manner.
  • The master production document will describe in general terms what, if anything, was redacted.

Specific requirements:

You must also:

Good documentation practices

Good documentation practices is a term used to describe standards that one follows to create and maintain documents. These common standards support GMP.

For more information about good documentation practices principles, consult the pharmacopoeial references on this topic (for example, USP <1029> Good documentation guideline).

Not following good documentation practices may lead to unreliable, incomplete, inconsistent or inaccurate documentation and cause multiple GMP-related failures. Good documentation practices are an essential part of a comprehensive GMP training program.

Good documentation practices generally include the following elements:

Other good documentation practices:

Electronic signatures and records

Sections 84 and 85 of the regulations on electronic signatures and electronic records state:

If you keep your records in an electronic format (instead of paper), be sure those records are reliable and can be accessed.

You must:

You must also ensure that:

Most PDF editing software have an electronic signature identification system that would be an acceptable alternative to handwritten signatures. These systems have been:

Data integrity

The general principles of good documentation practices apply to the management of a record throughout its lifecycle. This is from the time that data is first generated to any modifications made after, regardless of format (including paper records and electronic records).

Establish a data governance system to ensure data integrity is maintained for all GMP records.

Make sure to:

Translating records into English or French

All documents requested by Health Canada (for example, during an inspection or a site licence application review) must be provided in English or French. Any document written in another language must be translated into either of these official languages. Keep a copy of the document in its original language along with the translated version.

Documents that are already in English or French do not have to be translated into the other official language. For example, records completed in French may be accompanied by another document in English. A translation of the English document is not required.

Using a certified translator: Use a certified translator for your translation needs. A certified translator will have a certification that can be confirmed by a seal or stamp. This will show the translator's membership number from a professional translation association, either in Canada or abroad. All stamps and seals that are not in English or French must also be translated.

If the translation is not done by a certified translator, have a certified translator confirm its accuracy (provided as a signed attestation). In other words, you could do the translation in-house and then have it checked by a certified translator.

When translation is done in Canada: Use a translator who is in good standing with their provincial or territorial organization (who represents translators and interpreters) and is certified to translate documents.

When translation is done outside of Canada: Use an accredited translator who is officially recognized or authorized in the country where the translation is being completed.

Using an affidavit: If the translation cannot be provided or checked by a certified translator, rely on an affidavit to support an uncertified translator. The translator attests to their language proficiency and that their translation accurately represents the contents of the original documents or records. This is done in front of a commissioner authorized to administer oaths in the country where they live. The commissioner or notary public must be proficient in English or French to administer the oath. All stamps and seals that are not in English or French must also be translated.

Who can take an affidavit:

In Canada:

Outside of Canada:

Affidavits must not be prepared by you or by members of your family (even if a member is a lawyer, notary or certified translator).

Documents without translations: We do not accept documents that are not accurately translated into English or French. This includes those that are evidence to demonstrate GMP compliance or those that are required to be maintained under the regulations.

Translated documents that have expired: A translation is valid indefinitely unless the original document has changed or has expired. The signature of a certified translator or notary that has expired does not invalidate the translation. As long as the translator's certification was valid at the time of signature, the translation is valid.

The only time a new translation is required is if you change the original document.

GMP evidence

Maintain records and have evidence to show that your records maintenance system demonstrates GMP compliance for records. Examples of evidence include:

Sterile NHPs (section 59) and ophthalmic use (section 60)

Sections 59 and 60

59 Every natural health product that is intended to be sterile shall be manufactured and packaged

  1. in a separate and enclosed area;
  2. under the supervision of a person trained in microbiology; and
  3. using a method scientifically proven to ensure its sterility.

60 (1) Section C.01.064 of the Food and Drug Regulations applies in respect of natural health products except that it shall be read without reference to the words “or parenteral”.
     (2) Section C.01.065 of the Food and Drug Regulations applies in respect of natural health products except that it shall be read without reference to

  1. the words “or parenteral”; and
  2. the words “or to its common name if there is no proper name”.

Intent

The regulations require that proper GMP be implemented to ensure a product meets the definition of a sterile product. This is achieved either through manufacturing processes or terminal sterilization.

Manufacturer, packager requirements

The manufacturing of sterile products is subject to special requirements to minimize the risk of microbial and particulate contamination. Success depends on the skill, training and attitudes of the personnel involved. QA is very important, as this type of manufacturing must adhere to carefully established and validated or suitable methods of preparation and procedure. Do not rely only on a terminal process, finished product test for sterility or other quality aspects to ensure sterility.

Health Canada is an active member of PIC/S. We have adopted the PIC/S guidance on the manufacture of sterile medicinal products.

For more information on how to manufacture sterile products in compliance with the regulatory requirements, consult:

Treat all sterile NHPs as any other sterile health product. Be sure to:

Importer requirements

In addition to the records listed in Table 2 for non-sterile NHPs, you should maintain summaries of the:

You should also ensure you have access to copies of complete protocols and related studies for all validation activities.

GMP evidence

You must demonstrate GMP compliance for sterility with supporting evidence. The type of GMP evidence for sterility may vary. Examples of evidence include:

Note that GMP evidence for sterility is in addition to all of the GMP evidence expectations that apply to non-sterile NHPs.

Lot or batch samples (section 61)

Section 61
  1. Subject to subsection (3), if the Minister has reasonable grounds to believe that a lot or batch of a natural health product made available for sale may result in injury to the health of a purchaser or consumer, the Minister may require the manufacturer, importer or distributor to provide a sample of that lot or batch.
  2. The sample shall be of sufficient quantity to enable a determination of whether the lot or batch of the natural health product complies with the specifications for that natural health product.
  3. The Minister shall not require a sample of a lot or batch referred to in subsection (1) to be provided if more than 1 year has elapsed since the expiry date of that natural health product.

Intent

Samples of units from a batch of finished product must be kept for:

The retention samples also serve as a record of the batch of finished product and can be assessed if there is:

You may also choose to keep samples of raw materials and packaging materials, to help you when conducting thorough investigations in the case of quality defects or OOS tests.

Manufacturer, importer, distributor requirements

You must:

Health Canada may request a sample. The sample must be large enough to complete full finished product testing in duplicate. Some companies keep retention samples in triplicate, to use for their own investigation. Retention samples that are stored in optimal storage conditions may be used as comparison samples. They may be useful when investigating product quality complaints where storage conditions are the suspected root cause.

You must also:

Retention samples and stability samples are not the same. When collecting samples to complete stability testing from a particular lot, keep a separate set of retention samples of that same lot. Refer to the glossary for more information.

GMP evidence

You must demonstrate GMP compliance for lot or batch samples with supporting evidence. The type of GMP evidence for lot or batch samples may vary. Examples of evidence include:

Recall reporting (section 62)

Section 62

Every manufacturer, importer or distributor who commences a recall of a natural health product shall, within 3 days after the day on which the recall is commenced, provide the Minister with the following information in respect of the natural health product:

  1. the proper name and the common name of each medicinal ingredient that it contains;
  2. each brand name under which it is sold;
  3. its product number;
  4. the number of each lot or batch recalled;
  5. the name and address of the manufacturer, importer or distributor who commenced the recall;
  6. the reasons for commencing the recall;
  7. the name and address of each person to whom the recalled product was sold by the manufacturer, importer or distributor who commenced the recall;
  8. the quantity of the recalled product that was sold by the manufacturer, importer or distributor who commenced the recall;
  9. the quantity of the recalled product remaining in the possession of the manufacturer, importer or distributor who commenced the recall;
  10. if the recall was commenced by a manufacturer, the quantity of the recalled product that they manufactured;
  11. if the recall was commenced by an importer, the quantity of the recalled product that they imported and the name and address of each person that sold it to them;
  12. if the recall was commenced by a distributor, the quantity of the recalled product that was sold to them and the name and address of each person that sold it to them; and
  13. a description of any other action, in respect of the recall, that the manufacturer, importer or distributor who commenced the recall is taking.

Note that section 25 of the regulations states that every licensee who recalls a NHP must provide the Minister with the information referred to in section 62 within 3 days after the start of the recall.

Intent

The requirements for recall reporting are in place to ensure a product is recalled successfully. The manufacturer, importer and distributor must ensure that all the pertinent information is available and all products on the market are given the correct disposition.

Manufacturer, importer, distributor requirements

You must:

Even if no health risk is identified, a product may still need to be recalled if it contravenes the regulations (for example, when there is an error in the NPN on the product label).

When recalling an NHP, follow your recall written procedure (SOP) as outlined in section 50, and submit product recall information to the appropriate Health Canada regional office within 3 days of initiating the recall.

Refer to section 62 of the regulations for the list of information that you must provide.

Note: Section 62 does not specifically apply to packagers and labellers. However, many recalls are the result of product packaging and labelling issues. Packagers and labellers must have appropriate systems in place in case they are affected by a recall.

You must also consult:

These documents contain guidance on the following:

As with all your written procedures (SOPs), you should review your recall SOPs periodically to ensure your procedures and contact information for reporting recalls are up to date.

Mock recalls

A mock recall program may help you comply with the sections of the regulations on recalls. Be sure to include all departments that may be involved in the recall.

Mock recalls should:

GMP evidence

You must demonstrate GMP compliance for recall reporting with supporting evidence. The type of GMP evidence for recall reporting may vary. Examples of evidence include:

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