Good manufacturing practices guide for natural health products (GUI-0158): NHP GMP guidance, section 51

Quality assurance (section 51)

Section 51

1. Every manufacturer, packager, labeller, importer and distributor shall
   1. have a quality assurance person who
      1. is responsible for assuring the quality of the natural health product before it is made available for sale, and
      2. has training, experience and technical knowledge relating to the activity conducted and the requirements of this Part; and
   2. investigate and record every complaint received in respect of the quality of the natural health product and, if necessary, take corrective action.
2. Every natural health product shall be manufactured, packaged and labelled using only material that, prior to its use in the activity, has been approved for that use by a quality assurance person.
3. Every natural health product shall be manufactured, packaged, labelled and stored using methods and procedures that, prior to their implementation, have been approved by a quality assurance person.
4. Every lot or batch of a natural health product shall be approved by a quality assurance person before it is made available for sale.
5. Every natural health product that is sold and subsequently returned to its manufacturer, packager, labeller, importer or distributor shall be approved by a quality assurance person before that natural health product is made available for further sale.

Intent

QA is the area of GMP concerned with sampling, specifications, testing, documentation and release procedures. The QAP is the person who maintains your quality system and assures that products are suitable for sale.

This regulation ensures that:

• the necessary and relevant tests are carried out
• products are not released for sale until their quality has been determined to be acceptable
  • includes confirming that the product's specifications are met

Manufacturer, packager, labeller, importer, distributor requirements

A comprehensive quality system will help you properly control manufacturing, packaging, labelling, storing, testing and distributing an NHP.

Ensure your quality system is maintained by a quality unit which is independent from where potential or perceived conflicts of interests may arise:

• independent from production, sales and marketing, and all other areas of your company or organization

A quality unit fulfills both QA and QC responsibilities. Depending on the size and structure of your organization, this can be in the form of:

• separate QA and QC units overseen by the QAP or
• a single person (that is, the QAP themselves)

You should have a written job description for the QAP to ensure the individual makes decisions related to GMP requirements independently.

Support your QAP with a QA team to maintain an efficient oversight throughout your operations. This could be due to the size of your company, its business hours or when the extent of the documentation requiring review becomes difficult to manage due to your company's growth.

To maintain an efficient quality system, your QAP will put in place, manage and run various quality system components.

To help you comply with the requirements in section 51 of the regulations, these components are presented as quality subsystems in this guide. We have also provided detailed information on each of the components. You do not have to organize your quality system along these specific quality subsystems but should make sure that those that apply to you are in place.

The components of an efficient quality system include:

• a quality management system for manufacturers, packagers, labellers, importers and distributors, where the QAP is responsible for:
• maintaining and monitoring overall compliance with GMP, procedures and specifications
• handling all review and approval duties
  • such as CC, reprocessing or reworking, batch release, specifications review and reports
• monitoring and investigating product complaints, defects, returns and reprocessed or reworked products
• a laboratory control system for manufacturers, packagers and importers, where the QAP is responsible for:
• implementing a system that controls laboratory testing and laboratory-related activities
  • such as procedures, testing and method development or verification
• ensuring that the testing methods used are suitable for use, such as through preparatory testing (refer to the glossary) or system suitability, when required
• an importation control system for importers, where the QAP is responsible for:
• ensuring that imported NHPs are manufactured, packaged, labelled and stored at sites that meet GMP requirements equivalent to those of the regulations
• confirming that imported products meet their specifications and Canada's regulatory requirements
• controlling products imported in case there are issues with the product's safety, efficacy or quality
• a risk management system for manufacturers, packagers, labellers, importers and distributors, where the QAP is responsible for:
• assessing, controlling, communicating and reviewing the risks about the quality of a product across its lifecycle
  • from raw materials being received at a manufacturing site to expiry
• coordinating risk management across the company's various functions and departments
• managing change and continual process improvements through a documented change control or management process

Quality assurance person training, experience and technical knowledge

Every manufacturer, packager, labeller, importer and distributor must have a QAP. This person is responsible for assuring the quality of an NHP before it's made available for sale. Your QAP must have the training, experience and technical knowledge of the buildings, equipment, procedures and practices used to conduct each activity outlined in the regulations.

A qualified QAP has appropriate and sufficient training, experience and technical knowledge:

• Training:
  • a demonstrated understanding of the principles of GMP
• Experience and technical knowledge:
  • experience in:
    • applying and working with GMP
    • the ability to monitor good documentation practices
  • ability to:
    • develop, maintain and review written procedures (SOPs)
    • implement an efficient quality system
    • conduct internal GMP audits to proactively identify GMP issues
    • investigate appropriately and successfully different quality and GMP issues identified and initiate the proper follow-up actions
    • implement efficient risk-mitigation strategies
    • review finished product specifications, batch records (as required) and certificates of analysis
    • review raw material or in-process product specifications and certificates of analysis
    • understand and interpret different test results
    • implement an effective pest control program
    • implement, conduct and monitor product recalls
    • understand the elements of a stability study
    • implement an effective chemical handling system (for example, WHMIS) when required
  • technical knowledge in the manufacturing, packaging and labelling of NHPs as it relates to their responsibilities

You must have evidence that your QAP is qualified.

Refer also to the personnel section for additional guidance on the QAP.

Quality management system

The QAP, with the support of their team:

• establishes and follows written procedures (SOPs) to ensure that products conform to specifications and regulatory requirements
• approves or rejects formulations, procedures, specifications, test methods, controls and results that affect the purity, quality and composition of each ingredient and product
  • establish and implement written procedures (SOPs) for this
• approves or rejects raw, packaging and labelling materials, and finished products
  • includes products manufactured by contractors and is based upon conformance or non-conformance to their respective specifications
    • establish and implement written procedures (SOPs) for this
    • companies that only import finished products do not need to have written procedures (SOPs) for approving or rejecting raw, packaging and labelling materials
• reviews and maintains completed batch records
  • manufacturers, packagers and labellers must review batch records for completeness and adherence to good documentation practices
  • importers may have to review batch records in specific instances
    • refer to the importation control system section for more information
• approves or rejects products for release for sale or distribution against the completed certificate of analysis, batch record or other acceptable documentation
  • document the approval using, for example, a product release form
  • a certificate of analysis must be issued for each lot of product and should include as applicable:
    • identifying information, such as name of the NHP or NPN
    • batch or lot number
    • date of manufacture
    • expiry date
    • test type, method or ID number and acceptance criteria
    • numerical results (when appropriate)
    • the certificate of analysis signed and dated by the approver
• approves or rejects product quality deviations and reprocessing or reworking in the manufacture of a product
  • establish and implement written procedures (SOPs) for this
• investigates deviations and OOS results and ensures proper controls are in place
  • establish and implement written procedures (SOPs) for this
  • document all deviations and OOS results
• approves the destruction of returned or quarantined products, unless the QAP determines, by documented assessment or investigation, that the products may be released for sale or resale
  • establish and implement written procedures (SOPs) for this
    • include steps for determining whether further investigation and corrective action is necessary at the manufacturing, packaging or labelling sites

The QAP also:

• maintains records for returned, reprocessed or reworked, and redistributed products, which should include the following:
  • name and description of the product
  • lot number
  • reason for return
  • quantity returned
  • date of return
  • means of final disposition
  • an investigation report that documents the findings and any follow-up action taken, when required
• handles internal product complaints (deviations) and issues identified during manufacturing, packaging, labelling, storing or transportation
  • establish and implement written procedures (SOPs) for this
    • include a step for determining whether further investigation and corrective action are needed
• documents external product complaints and issues
• establish and implement written procedures (SOPs) for this
• include the following:
  • name and description of the product
  • lot number and expiry date
  • source and nature of the complaint
  • any response taken
  • an investigation report that documents the findings and any follow-up action taken, when required
• monitors and maintains appropriate data integrity (refer to the records section for more information)

Evaluate returned products for defects that could lead to changes being made to your company's processes. Product returns can be caused by quality, manufacturing, packaging or labelling problems, which must be fixed.

Deviations

A deviation is the departure from an established or approved procedure, process, work instruction or form, or an accepted standard. An example would be an OOS result.

Some deviations are not planned (for example, when a manufacturing process is not followed because equipment failed during production).

Some deviations are planned (for example, when a piece of equipment not listed in the master production documents is used instead).

Investigating deviations under your quality system shows that your company:

• notices problems as they arise
• has investigative and control processes in place to deal with them

Note that deviations are not always a negative occurrence.

As well as identifying the deviation as planned or unplanned, the QAP should rate its scope and severity (critical, major or minor) by evaluating its potential impact on the following:

• product safety, efficacy and quality
• previous batches or lots that could be affected
• trends relating to similar products, including similar causes or issues on other products
• materials and equipment implicated
• testing processes

Types of deviations:

• Minor deviation: will probably not affect the finished product's safety, efficacy and quality
  • Example: a short temperature deviation on a product meant to be stored at room temperature
• Major deviation: will probably affect a product's safety, efficacy and quality
  • Example: not adding an ingredient during manufacturing
• Critical deviation: will lead to hazardous or unsafe products
  • Example: a machine leaking oil into or onto a product, or when there are product cross-contamination incidents

Document, investigate and resolve any deviation from established procedures and standards as quickly as possible. Major and critical deviations may lead to:

• CC put in place
• CAPA plans
• recalls

To investigate deviations efficiently, we suggest defining a reasonable timeline for this based on the deviation rating. For example, investigations into critical, major and minor deviations could be completed within 10, 20 and 30 working days, respectively. You should not release a product on the market before you confirm that the deviation did not affect the product's safety, efficacy or quality.

Out-of-specifications

An OOS is a specific type of deviation. An OOS occurs when:

• a material or product fails to meet an established specification
• things like machinery or monitoring equipment perform or are used outside established conditions or parameters
  • for example, mixing speed is too high or too low or a temperature excursion is recorded

Section 44 of the regulations states that every NHP available for sale must comply with the specifications submitted during the product licensing process. Thus, releasing OOS products for sale without following an approved written procedure (SOP) for investigating OOS results and correcting the root cause is a serious GMP error and a non-compliance with the regulations.

When investigating an OOS, the QAP, with the support of their team, is responsible for:

• placing the OOS material or product in a quarantine area until the issue is resolved appropriately
• analyzing the data related to the OOS
• evaluating the impact on product safety, efficacy and quality
• revisiting previous batches or lots that could be affected and looking at related trends
• evaluating the materials, equipment and testing processes implicated
  • refer to the laboratory control system section for more information
• considering similar causes or issues on other materials or products
• developing a corrective action plan
• ensuring that any resampling or retesting are performed properly, according to a written procedure (SOP)
• ensuring the OOS material or product is appropriately disposed of (such as raw materials being returned to the supplier), as required
• initiating a recall of batches or lots that were distributed in the Canadian market, when required

As the QAP, ensure that OOS test results are investigated in accordance with a written procedure (SOP). This procedure should include the following aspects:

• an investigation (or requesting an investigation from the testing laboratory) to determine the cause of the OOS result
• When caused by a clearly identified laboratory error: You can invalidate the original results, then repeat the test and report the results. Record an explanation, including the source of the error and the corrective actions to prevent recurrence.
• When not caused by a clearly identifiable laboratory error: The investigation should focus on a review of the manufacturing processes and any other factors that could have impacted the results.
• any retesting or resampling must be approved in advance by the QAP with the number of retests to be performed
• The original sample should be sufficiently large to accommodate a retest. Include a justification if a resampling is performed.
• testing your hypothesis may be required to demonstrate the presumptive root cause

OOS results may require you to implement CAPA. Refer also to the CAPA process section of this guide.

Remember that repeated testing or sampling until a passing result is obtained to invalidate the OOS is not an acceptable practice. This is commonly referred to as “testing into compliance”.

• Report all valid test results (both passing and suspect) and fully consider them in batch release decisions.
• Averaging compliant and OOS results is not appropriate.

Laboratory control system

A laboratory control system may differ greatly from one organization to another. It will depend on how a manufacturer, packager or importer decides to test (analyze) their material or product to ensure specifications are met prior to sale. Companies may completely outsource product testing or do it entirely in-house. Some may do a limited subset of simple analysis (such as brix, density or pH) and outsource the rest.

Testing is fundamentally linked to sections 44 and 51 of the regulations. Although testing is not a licensable activity under Part 2 of the regulations, manufacturers, packagers and importers must have a laboratory control system. The breadth and depth of this system will depend on whether you have an in-house laboratory or use a third-party laboratory.

Third-party laboratory testing

If your company outsources testing to a third party, your QAP must still be involved in maintaining the laboratory control system. The QAP, with the support of their team, ensures that:

• any third-party laboratory can do all the tasks and responsibilities assigned to them and that they apply acceptable laboratory practices
• ideally, you should use an accredited laboratory
  • refer to the Standards Council of Canada to identify laboratories
  • laboratories holding a Health Canada drug establishment licence (DEL) for testing
  • laboratories meeting the ISO/IEC 17025:2017 General requirements for the competence of testing and calibration laboratories
• if not, your QAP should confirm that the third-party laboratory is acceptable, such as by:
  • performing a virtual or in-person audit of the laboratory
  • reviewing the laboratory credentials
• all testing methods used:
• are suitable for use
• are applicable to the product being analyzed
• yield valid test results
• testing is done according to pharmacopoeial (such as the USP) or other acceptable methods
• refer to the Quality of natural health products guide for more information on test methods
• product sampling is performed properly, according to a written and approved procedure
• microbial contamination testing is done at the finished product stage
• if done prior to packaging, a manufacturer or importer should maintain an acceptable scientific rationale, supported by efficient process controls and risk management strategies
• manufacturers and packagers keep records of material or in-process testing
• manufacturers and importers keep records of all finished product testing
• importers must keep the certificate of analysis from the manufacturer as well as other additional testing they had performed
  • refer to the importation control system section for more information

Regardless of who conducts the testing, the Canadian manufacturer or importer must make sure that:

• products comply with their specifications before they are released for sale
• records of finished product test results are maintained in accordance with sections 51, 53 and 56 of the regulations

In-house laboratory testing

In addition to what is needed for third-party laboratory controls, the role of the QAP expands when testing is done in-house. The QAP is typically supported by personnel who have the appropriate scientific background to do testing.

The QAP, with the support of their team, ensures that:

• the in-house laboratory can do all the tasks and responsibilities assigned to them and is following acceptable laboratory procedures
• laboratory procedures, testing, method development and verification are properly controlled by qualified personnel
• procedures to handle and prepare the reagents or standards are implemented
• sampling and retesting are performed properly, according to a written procedure (SOP)
• laboratory records of tests, including test results, and investigations are maintained
• laboratory operations training records of staff implicated in the laboratory are maintained
• staff follow proper hygiene practices
• water used in the laboratory's operations is appropriate to the methods used
  • such as USP grade, purified or potable

Importation control system

The importer is the final party responsible for products imported into Canada and thus plays a critical role in ensuring that the products are safe, effective and of high quality. Part of this role is monitoring foreign manufacturers, packagers and labellers to ensure that imported NHPs meet appropriate standards and have been manufactured in a GMP environment. Refer to the operations section for more information.

When you import products, the QAP, with the support of their team:

• confirms that the imported products meet their specifications and Canada's regulatory requirements
  • establish and implement written procedures (SOPs) for this
• controls the products imported in case of safety, efficacy or quality issues (such as by doing additional tests or initiating recalls when needed)
• approves or rejects finished products manufactured by foreign sites based on conformance or non-conformance to their respective specifications
  • establish and implement written procedures (SOPs) for this
• approves or rejects test methods, controls and results done on behalf of the foreign site if the site does not completely test the product specifications, especially those that affect the product's purity, quality and composition
  • establish and implement written procedures (SOPs) for this
• reviews and maintains completed batch records when applicable
  • a certificate of manufacture for a product manufactured in a non-MRA or PIC/S inspected facility may be an acceptable alternative to a batch record when the process in place meets the following:
    • the content of the certificate meets the definition of a certificate of manufacture in this guide (refer to the glossary)
    • the master production document has been reviewed and approved by the importer's QAP
    • periodic review of batch records is conducted (for example, at least once a year)
    • complete batch documentation is available upon request
    • the product's medicinal ingredients have not been quantified by input
    • the product's medicinal ingredients are not on a rotational testing schedule
    • the batch has not been reworked or reprocessed
  • refer to the specifications section for more information on importing from buildings inspected by a regulatory authority under an MRA or PIC/S
• approves or rejects the product for release and distribution against the completed certificate of analysis, batch record or other acceptable documentation
  • document this approval (for example, use a product release form)
  • importer (or a third-party laboratory contracted by the importer) must conduct any tests required by the specifications but not completed by the foreign site before releasing the product
  • importer must maintain documentation that includes the following:
    • identifying information, such as name of the NHP or NPN
    • batch or lot number
    • date of manufacture
    • expiry date
    • test type, method or ID number and acceptance criteria
    • numerical results (when appropriate)
    • quantity of product released
    • reference to any applicable deviation reports
• investigates OOS results and ensures proper controls are in place at the foreign and importing sites
  • establish and implement written procedures (SOPs) for this
  • document and investigate all OOS results from imported products
• approves the destruction of returned or quarantined imported products unless the QAP determines, by assessment or other investigation, that they may be released for sale or resale
  • establish and implement written procedures (SOPs) for this
• handles complaints for imported products
  • establish and implement written procedures (SOPs) for this
    • include steps for determining whether further investigation and corrective action is necessary at the manufacturing, packaging, labelling or importing sites
• monitors issues related to importation, such as transportation:
  • establish and implement written procedures (SOPs) for this
  • include steps for determining whether further investigation and corrective action is necessary

Risk management system

Risk management involves assessing, controlling, communicating and reviewing risks that could affect the quality of an NHP across its lifecycle. A quality risk management process can help a company comply with GMP requirements. Refer to the quality risk management section for more information.

A risk management system for quality involves CC and CAPA. It also includes internal audits (self-inspections) to proactively identify potential issues.

For examples of quality risk management processes and applications, consult the ICH's guideline, adopted by Health Canada:

• Q9: Quality risk management

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.

Change control

A CC process will help you:

• monitor changes that could affect the manufacturing, packaging, labelling, importing, distributing and quality of your NHPs
• ensure that premises, equipment, methods or product-related changes are made in a controlled and efficient manner
• reduce the possibility of process disruptions or the introduction of faults, errors or problems during the implementation of a change

Establish and implement written procedures (SOPs) to support your CC process. When implementing a CC process, the QAP, with the support of their team:

• identifies and supports a qualified team to lead the change
  • such as the production team or laboratory analysts
• analyzes the potential impacts of the planned changes on:
  • product quality
  • manufacturing, packaging, labelling, importing or distributing processes, as applicable
• monitors the process and signs off on the implementation of the planned CC
• documents, reviews and approves changes
  • process should describe measures made to ensure that all documents affected by the change are revised appropriately
• includes a classification system based on the nature and scope of the change (critical, major or minor) and identifies its impact on the process using clear terminology
  • the classification system will help determine the appropriate level of effort and documentation required to justify the change (such as testing, validation and support)
• evaluates the impact and effectiveness of the change
• signs off on and closes the CC record once the change is fully implemented

Corrective and preventive actions

CAPA are taken to eliminate the cause of a detected non-conformity or undesirable situation. Always have in place a process for CAPA so that personnel can correct an undesired, unacceptable or improper issue or practice. This will also help to prevent it from happening again. An efficient CAPA process supports a company's ongoing and long-term GMP and QA standards.

Key terms related to CAPA:

• Immediate correction: to immediately correct or contain a GMP deficiency or product issue
• these corrections usually do not fully address the issue
• Corrective actions: to control a current event
• Preventive actions: to avoid an event from happening again

The key steps of a strong CAPA process are:

1. Identify a GMP deficiency or product issue
2. Document and record
3. Assemble a team of subject matter experts to review and investigate
4. Use immediate correction measures to contain the problem
5. Identify the root cause
6. Evaluate the impact
7. Implement a CAPA plan
8. Monitor the effectiveness of the plan
9. Close the CAPA with QAP approval

Refer to the CAPA process section of this guide for more information.

The following events may trigger the need to initiate a CAPA process:

• deviations
• complaints
• investigations
• internal findings
• external findings

Your QAP is responsible for establishing, monitoring and maintaining a CAPA process, which includes:

• a tracking system for events (such as deviations, OOS results) and actions taken (CAPA and CC)
• a team of appropriate subject matter experts (such as QA, QC, manufacturing) to:
  • determine and document the root cause of the problem
  • plan, develop and implement appropriate CAPA
  • undertake the following steps if the issues are product-related and the products are available on the Canadian market:
    • evaluate and mitigate the issues identified that are related to product safety, efficacy and quality
    • revisit previous batches or lots that could be affected and look at related trends
    • evaluate if similar causes or issues could apply to other products
    • determine if amendments to regulatory submissions are necessary
    • initiate a recall for batches or lots already distributed in Canada, when required
  • describe and document short- and long-term CAPA
  • determine a reasonable timeline to correct issues and plan for CAPA implementation, when required
• revisiting the CAPA within a specified timeline to monitor and evaluate their effectiveness
• signing and closing the CAPA when complete

Your CAPA process may lead you to identify or consider that the issue may affect other products or processes. Your CAPA investigation should include those products or processes.

Importers are responsible for the products they import into Canada. Also note:

• products imported must be manufactured, packaged, labelled, imported, distributed and stored with equivalent GMP to Canadian GMP for NHPs
  • section 43 of the regulations
• products must meet their specifications and be approved by the QAP before they are for sale (before release)
  • sections 44 and 51 of the regulations
• the importer or Canadian manufacturer is responsible for establishing and maintaining data on product shelf life
  • section 52 of the regulations

When product-related issues are identified, the importer must develop and implement a strong CAPA plan. Although this plan may leverage the foreign manufacturing, packaging or labelling sites, the importer must ensure that processes and controls are in place to prevent the event from occurring again.

You should do periodic self-inspections to monitor GMP and proactively correct issues. During the self-inspection, ensure to cover all GMP that apply to your activities. For more information, consult the self-inspection chapter in the PIC/S's Guide to good manufacturing practice for medicinal products, part I🔗.

GMP evidence

Your QAP must be qualified. You must have evidence to support this and the responsibilities of this position. Examples of evidence include:

• relevant written procedures (SOPs) and associated blank record templates outlining responsibilities and activities, such as:
  • QAP job description that outlines roles and responsibilities, required training, experience and technical knowledge
  • review and approval of methods, procedures and systems used to manufacture, process, label and import NHPs
  • approval of raw, packaging and labelling materials
  • finished product release, including:
    • direction on how to assess each lot for compliance with its Canadian specifications and the product licence after testing has been performed
    • direction on how to confirm the lot number and expiry date on the label
    • a description of what conditions would stop the release of a product
  • disposition, distribution and disposal of products, including returns released for re-sale
  • complaint investigation and resolution
  • corrective actions addressing deviations, non-conformities and OOS results
• approved finished product specifications for products manufactured, packaged, labelled and stored at the site, including confirmation that:
  • the medicinal ingredients, including quantity and potency (if applicable) amounts, are the same as on the product licence
  • all required test results, test methods and acceptance criteria are within Health Canada requirements
• approved finished product release records that include:
  • product identification, NPN and lot number
  • date of manufacture, packaging and labelling, and expiry
  • quantity of product manufactured or imported and released
  • results of the finished product testing and the product status (released or rejected)
• QAP's resumé (C.V.), including education, that demonstrate the person meets their job description
• QAP's training record that demonstrates ongoing and relevant training
• organizational structure or chart that clearly demonstrates that the QAP operates independently