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Drugs and Health Products

Good Manufacturing Practices Guidance Document

Natural and Non-prescription Health Products Directorate
December 1, 2015 - Version 3.0

Table of Contents

1.0 General overview

1.1 Purpose of this guidance document

This guidance document pertains to Part 3 of the Natural Health Product Regulations (the Regulations) and is intended for manufacturers, packagers, labellers, importers, and distributors of natural health products (NHPs) for sale in Canada. It is meant to facilitate compliance with the good manufacturing practices (GMP) requirements outlined in part 3 of the Regulations. In addition, this document is a tool for the Quality Assurance Person (QAP) to implement and maintain GMP and to fulfill their role in assuring the quality of a NHP before and while it is made available for sale.

The Natural and Non-prescription Health Products Directorate (NNHPD) recognizes that there are various ways of meeting the GMP and producing safe and effective NHPs. For example, specific methods to achieve GMP compliance in sanitation may vary with the particular operation. This guidance document sets out GMP requirements; however, they are not regarded as the only interpretation of the Regulations. Alternative means of complying with the Regulations will be considered by the NNHPD when an appropriate rationale or justification is provided.

1.2 Purpose of good manufacturing practices

The GMP requirements are ongoing measures designed to ensure an effective overall approach to product quality control and risk management. They do this by setting appropriate standards and practices for the manufacturing, packaging, labeling, storing, and importing of NHPs intended for sale in Canada.

Though a NHP may pass all of the finished product specification tests, it may have microbial, physical and/or chemical contamination if manufactured or packaged in poor GMP conditions. Therefore, complying with GMP is a mandatory aspect in the Regulations as it assures a higher level of quality and confidence in the product.

Part 3 (sections 43 to 62) of the Regulations sets out the GMP that manufacturers, packagers, labellers, and importers must meet before the NNHPD will issue a site licence for each location where they intend to manufacture, package, label, or import NHPs for sale in Canada. Distributors and storage sites must follow the GMP, as defined in the Regulations; however, they are not required to hold a site licence. The responsibilities of the distributor are identified in this document with respect to the GMP related to storage, distribution and transportation. For more information on site licensing, refer to the Site Licensing guidance document.

Each section under Places, People, Processes and Products, below, begins with a brief explanation of what is outlined by the Regulations. The section entitled “To Meet the Requirements,” in Chapter 2.1.1, explains in more detail how to comply with the Regulations. It is recommended that applicants follow the GMP described in this document; however, the NNHPD will consider alternative means of complying with the Regulations, when acceptable rationale is provided. To conclude this portion, the section “Examples of Evidence to Demonstrate GMP…” provides examples of documentation and records that are acceptable as GMP evidence to support a licence application. Note that all records should be signed/initialed and dated. In addition, the examples may or may not apply, depending on the activities being performed. The examples provided are not an exhaustive list.

1.3 Roles and responsibilities

As per section 27 of the Regulations, manufacturers, packagers, labellers and importers are required to hold a valid site licence. The site licence holder is responsible for ensuring that activities being conducted at the site are being conducted in accordance with GMP, as outlined in Part 3 of the Regulations.

Any person that conducts an activity or sells a NHP in contravention of the Food and Drug Act (FDA) and/or the Regulations may be subjected to compliance and enforcement actions.

Adherence to GMP is the responsibility of everyone involved in the life cycle of a NHP, from the harvesting or manufacturing to its availability for sale to consumers. The site licence holder is responsible to carry out each activity, in which they are authorized to conduct, in accordance with GMP. This includes ensuring that the quality assurance person (QAP) has the relevant training, experience and technical knowledge to carry out all the necessary quality-related functions. The site licence holder must also ensure that all activities or services contracted out are conducted in accordance with Part 3 of the Regulations.

Part 3 of the Regulations begins with section 43, which states that any NHP sold must be manufactured, packaged, labelled, imported, distributed, and stored according to the requirements outlined therein. It is the importer’s responsibility to ensure that imported NHPs are manufactured, packaged, and labelled at sites that meet the Regulations.For additional information related to evidence required from importers with respect to the foreign sites, refer to the Site Licensing guidance document.  

The following table outlines which activities are applicable to each section of the Regulations. A checkmark indicates that the section of the Regulations is applicable to the activity specified. Note that a site license is not required for the activity of distribution.

Table 1: Regulations applicable to activities
Section of the Regulations / Activities Manufacturing Packaging Labelling Importing Distributing

✔ = applicable
* = if applicable
X = not applicable

43. Prohibition
44. Specifications ✔* X ✔*
45. Premises
46. Equipment  ✔* X
47. Personnel
48. Sanitation Program
Operations
49. SOPs  ✔*  ✔*
50. Recall
51. Quality Assurance 
52. Stability X X ✔* X
Records (53-57) ✔* ✔* ✔* ✔* ✔*
58. Records Maintenance
59. Sterile NHPs X X X
60. Ophthalmic Use X X X
61. Lot or Batch Samples X X
62. Recall Reporting X X

2.0 Good manufacturing practices (GMP)

The text that follows divides the GMP into four (4) categories (Places, People, Processes and Products). As a result, the sections of the Regulations do not run in numerical order.

2.1 Places

2.1.1 Premises

Section 45 of the Regulations sets out the requirements for the premises in which NHPs are manufactured, packaged, labeled, and stored.

Part 3: Good Manufacturing Practices
Premises
Section 45

  1. Every natural health product shall be manufactured, packaged, labelled and stored in premises that are designed, constructed and maintained in a manner that permits the activity to be conducted under sanitary conditions, and in particular that
    1. permits the premises to be kept clean and orderly;
    2. permits the effective cleaning of all surfaces in the premises;
    3. permits the natural health product to be stored or processed appropriately;
    4. prevents the contamination of the natural health product; and
    5. prevents the addition of an extraneous substance to the natural health product.
  2. Every natural health product shall be stored under conditions that will maintain the quality and safety of the natural health product.

Intent

The building should be designed and constructed in a manner that permits cleanliness and orderliness, while preventing contamination. Regular maintenance is required to prevent deterioration of the premises. The objective is to ensure products do not become contaminated through unsanitary conditions.

To meet the requirements

Manufacturers, packagers, labellers, importers, and distributors should ensure the following, where applicable. Alternatively, justification with rationale for the exemption of the requirements should be provided.

  1. Ensure that the buildings are of adequate size and are designed and built to facilitate maintenance, cleaning and sanitary operations, prevent entry of insects and other animals, facilitate waste treatment and disposal, and prevent mix-ups and cross-contamination of raw, packaging and product materials. Every site shall:
    • ensure that effective controls are in place to minimize the potential for mix-ups or the adulteration of raw, packaging and in-process materials;
    • designate separate production and non-production areas, as necessary, to prevent cross-contamination. When required, clearly identify and segregate individual manufacturing, packaging, and testing areas;
    • restrict, during production, the use of doors giving direct access from manufacturing and packaging areas to the outdoors (these doors must be adequately sealed to prevent unauthorised persons and pests from entering);
    • ensure that doors, windows, walls, ceilings and floors contain no holes or gaps, except those that are part of the design;
    • ensure that floors, walls and ceilings permit cleaning, and that all surfaces are made of materials that do not shed particles;  
    • seal surfaces and joints to prevent contamination from extraneous materials and to permit effective cleaning;
    • provide adequate ventilation, filtration and lighting;
    • control humidity and temperature, where required, to protect materials and products;
    • take appropriate measures to controlling, removing and preventing pests from entering the premises; and
    • provide explosion proof bulbs and fixtures to avoid glass contamination.
  2. Separate the rest, change, wash-up and toilet facilities from production areas, and ensure that they are sufficiently spacious and well ventilated, and permit good sanitary practices.
  3. Provide plumbing of an appropriate scale and design to avoid adulteration of products or contamination of water supplies or equipment, and identify outlets for liquids and gases used in production.
  4. Ensure water supply is of potable quality for processing and cleaning and shall meet the Canadian Drinking Water Guidelines, World Health Organization (WHO) guidelines for Drinking Water Quality, or other standards specified by the regulatory agency governing the manufacturer. When purified water is required, water purification, storage and distribution equipment must be operated to ensure a reliable source of water of appropriate chemical and biological purity as defined in any standard listed in Next link will take you to another Web site Schedule B to the Food and Drugs Act.
  5. Ensure that floor drains are screened and trapped.
  6. Maintain the grounds around the manufacturing buildings to protect against the contamination of products.
  7. Install refuse receptacles and follow waste disposal practices that protect against contamination or harborage of pests.
  8. Protect raw materials, packaging materials, in-process, and finished products against physical, chemical and microbial contamination, as well as deterioration of the products and the container during storage and temporary storage while in transit (e.g. between the importer and the distributor, or between the manufacturer and the labeller).
  9. Clearly mark physical quarantine areas when used.

The type of GMP evidence for premises may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for premises

  • A detailed floor plan showing production, non-production, quarantine, packaging and/or labeling areas, etc.
  • Ventilation filters change record.
  • Water quality test records (for manufacturers).
  • Daily temperature, relative humidity, and light (as required) control records.
  • Facility maintenance records (wall, floor or ceiling repair, new drain grates etc.).
  • Pest control inspection report (internal program or contractor visit) with trap replacement information, daily pest control logs.
  • Janitorial duty schedule and cleaning completion records (must be for areas related to activities; i.e. manufacturing, packaging, labeling, and/or storage).
  • Relevant standard operating procedures (SOPs) and associated blank record templates, related to maintenance of premises.

2.1.2 Equipment

Section 46 of the Regulations sets out the requirements for the equipment used to manufacture, package, label, and store NHPs, during operation.

Part 3: Good Manufacturing Practices
Equipment
Section 46

Every natural health product shall be manufactured, packaged, labelled and stored using equipment that is designed, constructed, maintained, operated and arranged in a manner that

  1. permits the effective cleaning of its surfaces;
  2. permits it to function in accordance with its intended use;
  3. prevents it from contaminating the natural health product; and
  4. prevents it from adding an extraneous substance to the natural health product.

Intent

The purpose of these requirements is to prevent the contamination of NHPs by other products, by dust, cleaning agents and by foreign materials such as rust, lubricant and particles coming from the equipment. Contamination problems may arise from inadequate cleaning practices, poor maintenance, the misuse of equipment, exceeding the capacity of the equipment and the use of worn-out equipment. Equipment arranged in an orderly manner permits effective cleaning and does not interfere with other processing operations. It also minimizes the circulation of personnel and optimizes the flow of materials.

To meet the requirements

Manufacturers, packagers, labellers, importers and distributors should ensure the following, where applicable. Alternatively, justifications with rationale for the exemption of the requirements should be provided.

  1. Production equipment is designed, constructed, installed, and maintained to facilitate cleaning, sanitizing (where appropriate), and inspection of the equipment and the surrounding areas. Specifically, this means the following:
    • establishing and following procedures for cleaning and maintaining equipment and utensils used to manufacture products;
    • avoiding temporary repairs (e.g. with tape); and
    • clearly labelling defective equipment as such.
  2. Each piece of production equipment is operated according to its SOP.
  3. Protect analytical instruments and associated control systems from vibration, electrical interference and contact with excessive moisture or other external factors.
  4. Production equipment and utensils having direct contact with materials and products are constructed of smooth, non-reactive and non-toxic materials, and are designed to withstand repeated cleaning.
  5. Avoid the possibility of lubricant or other maintenance materials contaminating the products by ensuring proper equipment design (e.g. tanks, chain drives and transmission gears must be enclosed or properly covered).
  6. Control and monitor temperature-sensitive compartments, and keep records.
  7. Properly maintain instruments and controls, including laboratory equipment, to ensure that they remain accurate, and retain records.
  8. Develop a calibration program for critical manufacturing, packaging, and testing equipment, and maintain records.
  9. Maintain records of equipment cleaning.
  10. Maintain equipment usage logs.

The type of GMP evidence for equipment may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for equipment:

  • Preventative maintenance schedule for equipment.
  • Equipment cleaning and maintenance logs.
  • Equipment usage logs.
  • Calibration records for essential equipment.
  • Relevant SOPs and associated blank record templates.

2.2 People

2.2.1 Personnel

Section 47 of the Regulations requires NHPs to be manufactured, packaged, labelled, and stored by personnel who are qualified by education, training or experience to perform their respective tasks.

Part 3 Good Manufacturing Practices
Personnel
Section 47

Every natural health product shall be manufactured, packaged, labelled and stored by personnel who are qualified by education, training or experience to perform their respective tasks.

Intent

People are the most important element in performing any authorized activity. The appropriate personnel with sufficient training are necessary to manufacture, package, label, import, or store NHPs of high quality.

It is essential that qualified personnel be employed to supervise the manufacturing, packaging, labeling, importing and storage of NHPs. The operations involved in the handling of NHPs require constant monitoring, attention to details and a high degree of competence on the part of employees. Inadequate qualification or training of personnel may lead to the failure of an NHP to meet its specifications and its quality requirements.

To meet the requirements

Manufacturers, packagers, labellers, importers, and distributors should ensure the following, where applicable:

  1. Individuals in charge of manufacturing and quality assurance have adequate education, training, and/or practical experience to control and/or supervise the activities.
  2. All personnel have appropriate education (including on-going GMP or other training) and/or have the practical experience necessary to perform their assigned duties.  It is important to maintain records of education and training and update when needed.

The type of GMP evidence for personnel may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance of personnel:

  • Job descriptions.
  • Resume, C.V., or copy of educational degrees (shows the person meets their job description).
  • Employee training schedule and/or attendance records (demonstrating on-going relevant training).
  • Certificates of completion (i.e. GMP).
  • Relevant SOPs and associated blank record templates related to personnel.

2.2.2 Quality assurance

Section 51 of the Regulations sets out the requirements and responsibilities of the QAP.

Part 3: Good Manufacturing Practices
Quality Assurance
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 the 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, as the case may be, shall be approved by a quality assurance person before that natural health product may be made available for resale.

Intent

Quality assurance is the area of GMP concerned with sampling, specifications, testing; including documentation, and release procedures. The QAP bears the responsibility of assuring each product is suitable for sale. This regulation ensures that the necessary and relevant tests are carried out and that products are not released for sale, until their quality has been determined to be satisfactory by confirming that products specifications are met.

To meet the requirements

Manufacturers, packagers, labellers, importers, and distributors should ensure, where applicable that they have a QAP who is responsible to do the following:

  1. Establish and follow written procedures to ensure that products conform to specifications and regulatory requirements. 
  2. Establish and follow written procedures for sampling, inspecting and testing raw and/or packaging materials, in-process and finished products.
  3. Approve or reject all formulations, procedures, specifications, test methods, controls and results that affect the purity, quality and composition of each ingredient and product. Written procedures shall be established and implemented.
  4. Approve or reject all raw materials, packaging materials and finished products, including products manufactured by contractors, based upon conformance/nonconformance to respective specifications. Written procedures shall be established and implemented.
  5. Review and maintain completed batch records. 
  6. Approve or reject the product for distribution against the completed certificate of analysis, batch record, or other acceptable documentation. 
  7. Approve or reject product quality deviations and product reprocessing in the manufacture of a product. Written procedures shall be established and implemented.
  8. Destroy returned products unless he or she determines, by assessment or other investigation, that they may be released for resale. Written procedure shall be established and implemented.
  9. Maintain records with respect to returned, reprocessed and redistributed products and include the name and description of the product, lot number, reason for return, quantity returned and date and means of final disposition.
  10. Ensure that laboratories (in-house and contract) are capable of performing all of the tasks and responsibilities assigned to them.
  11. Maintain laboratory records of tests and investigations, or have access to these records when required.
  12. Set up and follow written procedures for handling product complaints. These procedures must include determining whether further investigation and corrective action are required.
  13. Document all complaints with the following information (when applicable): the name and description of the product, the lot number, the source and nature of the complaint, and any response. When an investigation is conducted, include in the written record the findings and any follow-up action taken.

It is good practice for manufacturers, packagers, labellers, importers, and distributors to provide a written job description to the QAP to avoid a conflict of interest with duties versus the requirements outlined in Section 51 of the Regulations.

The type of GMP evidence for a quality assurance may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for quality assurance:

  • Job Descriptions.
  • QAP resume, C.V., educational degrees (to demonstrate the person meets their job description).
  • Approved finished product specification for products manufactured, packaged, labelled and stored the site.
  • Master production documents and batch records.
  • Finished product specification change control log.
  • Certificates of analysis for all raw materials (medicinal and non-medicinal ingredients).
  • Raw material release records.
  • Complete finished product testing against approved specification (Certificate of Analysis)
  • Records for Out of Specification (OOS) results, including investigations into route causes.
  • Finished product release record.
  • Product complaint investigation reports and corrective/preventative actions.
  • Logs for complaint, returned products, product disposition, distribution and disposal.
  • Relevant SOPs and associated blank record templates related to quality assurance.
  • Organization structure which clearly demonstrates independence of function (e.g. from activities such as manufacturing).

2.3 Processes

2.3.1 Sanitation program

Section 48 of the Regulations sets out the sanitation requirements for the premises and the health and hygiene of personnel.

Part 3: Good Manufacturing Practices
Sanitation Program
Section 48

Every natural health product shall be manufactured, packaged, labelled and stored in accordance with a sanitation program that sets out

  1. procedures for effectively cleaning the premises in which the activity is conducted;
  2. procedures for effectively cleaning the equipment used in the activity;
  3. procedures for handling any substance used in the activity; and
  4. all requirements, in respect of the health, the hygienic behaviour and the clothing of the personnel who are involved in the activity, that are necessary to ensure that the activity is conducted in sanitary conditions.

Intent

Sanitation of a building, as well as employee hygiene, influences the quality of NHPs. The GMP requirements indicate that activities be performed in areas that are free from environmental contamination and free from contamination by another product.

A written sanitation program informs employees of the expectation as well as the necessary steps to ensure sanitation is maintained. It also provides some assurance that levels of cleanliness in the plant are maintained.

To meet the requirements

Manufacturers, packagers and labellers shall have a facility sanitation program and a health and hygiene program in place, as detailed below. Importers and distributors shall meet, where applicable, the appropriate requirements with respect to storage.

Facility Sanitation Program

  1. Develop a sanitation program adequate to prevent contamination of product.
  2. Develop a written sanitation program that includes the following elements:
    • cleaning procedures for facilities and processing equipment;
    • a list of cleaning/sanitizing agents, pesticide chemicals shall be identified, used and stored in such a manner to prevent the contamination of raw, packaging materials and process equipment;
    • procedures for cleaning frequencies and cleaning lines between the production of different products;
    • provisions for storing cleaned equipment to avoid recontamination;
    • clear identification of dirty/clean equipment and utensils; and
    • procedures for the destruction and disposal of waste materials and debris.
  3. Contain or ventilate dusty operations to prevent contamination of other areas.

Health and Hygiene Program

All personnel having direct contact with raw and/or packaging materials, in-process materials and any unpackaged products, as well as personnel, who use processing equipment, must follow appropriate practices to protect products against contamination. This health and hygiene program must be in writing and should include the following requirements:

  • wearing outer garments, including shoe coverings, that protect against contamination of products and equipment, when applicable;
  • removing all unsecured jewellery and hand jewellery, or covering hand jewellery that cannot be removed, when applicable;
  • using intact, clean and sanitary gloves;
  • wearing hairnets, caps, beard covers or other effective hair restraints;
  • maintaining personal cleanliness;
  • washing hands thoroughly before starting work and at any other time when hands may have become soiled or contaminated;
  • storing clothing or other personal effects outside of processing areas;
  • refraining from consuming food and drink, as well as chewing products or smoking, in manufacturing, packaging, storage, and testing areas;
  • periodically conducting eye examinations of personnel responsible for visual inspection;
  • reporting to supervisors any health conditions of personnel that could adversely affect products;
  • respecting quarantine times imposed by public health authorities; and
  • removing from the manufacturing facility any person who has, or appears to have, an illness that could be a possible source of product contamination, until the disease or hygienic condition is no longer a risk for possible product contamination.

The type of GMP evidence for sanitation may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for a sanitation program:

  • Facility cleaning schedule and cleaning completion logs.
  • Microbiological surface swab test results.
  • Personnel hygiene training log.
  • Relevant SOPs and associated blank record templates related to sanitation.

2.3.2 Operations

Section 49 of the Regulations requires every NHP to be manufactured, packaged, labelled, and stored in accordance with SOPs designed to ensure that the activity is conducted in accordance with the Regulations.

Part 3: Good Manufacturing Practices
Operations
Section 49

Every natural health product shall be manufactured, packaged, labelled and stored in accordance with standard operating procedures that are designed to ensure that the activity is conducted in accordance with the requirements of this Part.

Part 3: Good Manufacturing Practices
Operations
Section 50

Every manufacturer, packager, labeller, importer and distributor shall establish and maintain a system of control that permits the rapid and complete recall of every lot or batch of the natural health product that has been made available for sale.

Intent

The Regulations requires that measures be taken to maintain the integrity of a NHP from when raw materials enter the plant to the time the finished dosage form is released for sale and distributed.

To meet the requirements

Manufacturers, packagers, labellers, importers, and distributors shall ensure, where applicable, that practices and procedures are in place for material control, process control, the inspection program for contractors, and product recall, where applicable. Alternatively justifications with rationale for the exemption of the requirements should be provided.

  • Material control
    • 1. Set up and follow written procedures for the transportation, receipt, identification, examination, handling, sampling, testing and approval, rejection and disposal of raw and/or packaging materials. Updating the procedures as required.
    • 2. Identify each lot of raw and/or packaging materials with a distinctive lot number for traceability.
    • 3. Inspect containers of raw and/or packaging materials upon receipt for closure and physical integrity.
    • 4. Assess each lot of raw and/or packaging materials against specifications, such as species identity, detectable foreign matter and the integrity (appropriate characteristics) and quality of species material or extracts.
    • 5. Retest raw and/or packaging materials after any exposure to conditions likely to adversely affect their purity, quality or composition.
    • 6. Identify and control each lot of raw and/or packaging materials according to its quality status (e.g. quarantined, approved or rejected).
    • 7. Store raw materials, in-process materials and reprocessed materials in appropriate conditions, including temperature and humidity, to protect against quality deterioration and contamination.
    • 8. Set a time limit beyond which raw materials that are subject to deterioration may not be used in production without additional testing. When appropriate, use the oldest approved stock of raw and/or packaging materials first (follow the first in, first out system).
    • 9. Ensure that the QAP approves and releases materials prior to their use.
    • 10. Establish appropriate systems and controls to ensure that water used in the production of products is of potable quality and shall meet the guidelines and standards specified by the regulatory agency governing the manufacturer.
    • 11. Destroy outdated or obsolete printed packaging materials and record the disposal.
  • Process control
    • 12. Formulate the product to ensure that it adheres to regulatory requirements and claims stated on the label.
    • 13. Prepare a master production document for the manufacture of each product, and have the QAP review and approve the document.
    • 14. Prepare and follow batch records for each batch of product. These records must be an accurate representation of the master production document and include documentation that each significant step in the manufacturing process was completed.
    • 15. Allocate and track each batch of manufactured product by an individual control number.
    • 16. Record and evaluate any deviations from written and approved manufacturing processes, standards and test methods, with final approval by the QAP.
    • 17. Conduct manufacturing, packaging, and storage operations according to written procedures and appropriate sanitation principles, in a manner that protects against adulteration and in conditions that minimize the potential for contamination.
    • 18. Identify all materials, products, samples, containers, processing lines, and major equipment at all times to indicate their contents and/or status.
    • 19. Ensure adequate procedures are in place to prevent extraneous materials from being included in the products and finished package.
    • 20. Ensure adequate procedures are in place to identify, store and dispose of rejected or contaminated/adulterated products.
    • 21. Establish written procedures for reprocessing batches that do not conform to finished product specifications.
    • 22. Securely store labels to prevent mix-ups (e.g. stored and withdrawn against a labelling order and reconciled at the end of every run). Specifically, this means the following:
      • not returning sample labels taken from the processing areas;
      • labelling the product as quickly as possible after filling and sealing (when labelling is delayed, follow procedures to ensure that no mislabelling occurs); and
      • prior to release, investigating and accounting for any significant or unusual discrepancies observed during reconciliation of the product or labels.
    • prior to release, investigating and accounting for any significant or unusual discrepancies observed during reconciliation of the product or labels.
    • 23. Prevent cross-contamination and mislabelling by establishing procedures for removing all raw and/or packaging materials and finished products from previous runs (i.e. written line clearance procedures and appropriate area to record completion).
    • 24. Set up and follow written procedures to ensure that the correct labels and packaging materials are issued and used.
    • 25. Identify each package with a lot number and expiry date that permits determination of the history of the manufacture and control of the lot.
    • 26. Restrict the access to production areas to authorized personnel.
  • Inspection program for contractors
    • 27. Manufacturers, packagers, labellers, and importers must ensure that activities contracted out to other sites meet the GMP requirements, which can be demonstrated by an inspection and/or an evaluation of the contractor. This inspection program of contracted activities verifies that Part 3 of the Regulations is met by all parties at all times. It is essential to clearly establish and document the roles and responsibilities of each party involved in the contracted operations. See the records section 2.4.4 for information related to contractors and required documentation.

The type of GMP evidence for operations may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for operations:

  • Approved finished product specification for products manufactured, packaged, labelled and stored at the site.
  • Master production documents and batch records.
  • Finished Product specification change control log.
  • Certificates of analysis for all raw materials (medicinal and non-medicinal ingredients).
  • Raw material release records.
  • Complete finished product testing against approved specification (Certificate of Analysis).
  • Records for Out of specification (OOS) results, including investigations into root causes.
  • Finished product release records.
  • Product complaint log and resulting action.
  • Product disposition, distribution and disposal logs and records.
  • List and copies of all SOPs in use for the production run/importation.
  • Records indicating samples from the product run/importation have been secured.
  • Audit reports or completed records of pre-evaluation for approved contractors.
  • Relevant SOPs and associated blank record templates related to operations.

2.4 Products

2.4.1 Specifications

Section 44 of the Regulations describes the requirements related to product specifications.

Part 3: Good Manufacturing Practices
Specifications
Section 44

  1. Every natural health product available for sale shall comply with the specifications submitted in respect of that natural health product under paragraph 5(i) and with every change to those specifications made by the product licence holder.
  2. The specifications shall contain the following information:
    1. detailed information respecting the purity of the natural health product, including statements indicating its purity tolerances;
    2. for each medicinal ingredient of the natural health product, detailed information respecting its quantity per dosage unit and its identity, including statements indicating its quantity and identity tolerances;
    3. if a representation relating to the potency of a medicinal ingredient is to be shown on a label of the natural health product, detailed information respecting the potency of the medicinal ingredient, including statements indicating its potency tolerances; and
    4. a description of the methods used for testing or examining the natural health product.
  3. The specifications and every change to those specifications shall be approved by a quality assurance person.

Intent

Ensuring that a product meets its specifications has two aspects. The first is that product specifications are established and the second is that the manufacturer has a quality system in place that ensures the product consistently meets the established specifications. Finished product tests complement the controls employed during the manufacturing and importing processes. It is the responsibility of each manufacturer and importer to have accurate specifications, adequate quality systems in place, and appropriate test methods that will help ensure that each NHP sold meets the product specifications.

To meet the requirements

The manufacturer, importer and, if applicable, packager, and distributor, shall ensure the following, where applicable. Alternatively, justifications with rationale for the exemption of the requirements should be provided. 

  1. Develop and implement written specifications for all finished products pertaining to identity, purity, quantity, potency, and tolerances as per the Quality of Natural Health Products Guide.
  2. Ensure specifications are maintained and every change is approved by the QAP prior to use. Changes to specifications as per section 11(i) of the Regulations requires an amendment to the product licence.
  3. Set up and follow written procedures that describe tests to be conducted to ensure the identity, purity, and quantity of finished products. When applicable, these procedures should include potency testing.
  4. Verify that all test methods provide accurate and consistent results.
  5. Assess each lot for compliance with specifications prior to release.

Importers are required to review a supplier’s certificate of analysis (CoA) submitted with each lot received to ensure the product meets specifications. This review should cover verification that all required testing is performed and that specifications are met.

For all testing methods and requirements, please refer to the Quality of Natural Health Products Guide.

The type of GMP evidence for specifications may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for specifications:

  • Product specifications for all products to be manufactured, packaged, labeled or imported to the site.
  • Approval of finished product specifications by the QAP.
  • Record of approval from the QAP regarding any changes to the finished product specification.
  • Relevant SOPs related to finished product testing and associated blank record templates related to specification.
  • CoA for each lot of finished product demonstrating the product meets its specifications according to the requirements outlined in the Quality of Natural Health Products Guide.
  • Evidence that testing against specifications adheres to GMP or other comparable quality audit standard.

Confirmatory testing

A confirmatory testing program, independent of the manufacturer, is encouraged and provides added assurance of a product’s quality when it is manufactured by a supplier. The following outlines an example for a confirmatory testing program:

  1. fully test against specifications, the first lot of product received from each supplier for each product;
  2. each subsequent lot received thereafter will:
    • undergo a review of the certificate of analysis showing actual test results and verify that the product meets its specifications prior to release; and
    • take precautions to ensure that transportation and storage conditions do not adversely affect product potency, purity or physical characteristics;
  3. conduct complete confirmatory testing against specifications on at least one lot per dosage form per supplier per year.

Exemptions

An exemption to microbiological contaminants testing would be acceptable if the manufacturer is able to demonstrate any of the following, (using valid test methods, on multiple batches and throughout shelf-life):

  1. low water activity;
  2. antimicrobial properties;
  3. historical testing showing low microbial load;
  4. proposed frequency of microbial testing to be performed on subsequent batches (e.g. every 10th batch to be tested to a minimum of 1 batch per annum).

An exemption to the various chemical contaminants’ testing would be acceptable if the manufacturer is able to demonstrate the following:

  1. pesticide testing if all ingredients are organic and evidence of organic certification is provided;
  2. pesticide testing if all ingredients are tested for pesticides individually and/or the ingredients are synthetic;
  3. solvent testing if solvents are not used in the manufacturing process (and the raw materials have been tested for or are not manufactured with solvents); and/or
  4. heavy metal testing if raw materials (medicinal and non-medical ingredients) are tested and the raw material suppliers’ test results are verified and/or the ingredients are of synthetic origin or of pharmacopeial grade.  

An exemption to medicinal ingredient assay testing of the finished product would be acceptable if the manufacturer is able to demonstrate all of the following:

  1. justification for using quantification by input rather than assaying the final product using an appropriate method;
  2. certificates of analysis for raw material for all the medicinal ingredients to be quantified by input; and
  3. a batch record as objective evidence that these medicinal ingredients were added to the final product. The manufacturing documents should indicate the target quantity for the medicinal ingredient (i.e. 100% of the label claim) and an acceptable range of variation for addition of the ingredient during manufacturing; 
  4. Weight variation is performed on the finished dosage form as part of the finished product testing as per industry standards.

2.4.2 Stability

Section 52 of the Regulations sets out the requirements for product stability.

Part 3: Good Manufacturing Practices
Stability
Section 52

Every manufacturer and every importer shall determine the period of time that, after being packaged for sale, the natural health product will continue to comply with its specifications 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

The purpose of a stability program is to determine how long the NHP can be expected to remain within approved specifications under recommended storage conditions.

To meet the requirements

Manufacturers and importers of finished NHPs shall ensure the following where applicable:

  1. Use data from accelerated or real-time stability studies or from similar product formulations to make an initial determination of the expiry date.
  2. Provide data and rationale to reasonably ensure that each finished product meets its label claims at the expiry date.
  3. Confirm and adjust the expiry date, when required, on the basis of real-time studies on product stored in the conditions noted on the label, for the period of time indicated by the expiry date.
  4. Display the lot number and expiry date on the label of each finished product.
  5. Ensure that all packaging and labelling requirements are met, and that the product will remain free from contamination until the expiry date (e.g. deterioration of packaging material and labelling).
  6. Establish the shelf life from the date of original batch fabrication.
  7. Re-evaluate the product shelf life when significant changes are made to the formulation, manufacturing process or package that may affect the product’s stability.
  8. Carry out testing appropriate to each product.

The type of GMP evidence for stability may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for stability:

  • The CoA demonstrating that every product meets specifications at expiry. Please note that chemical contaminants do not need to be tested to support stability (i.e. heavy metals, pesticides, solvent residues, etc.).
  • Stability testing protocol for a product manufactured at or imported to the site, including actions to be taken when a product fails stability, stability failure investigations and recalls, and details for establishing a longer shelf life.
  • The corresponding testing results as indicated in the stability testing protocol (i.e. T=0, T=6 months, T=1 year, etc.).
  • Relevant SOPs and associated blank record templates related to stability data.

2.4.3 Samples

Section 61 of the Regulations indicates that the NNHPD may ask a manufacturer, importer, or distributor to submit samples of a lot or batch of a product if a concern arises regarding the safety of that product.

Part 3: Good Manufacturing Practices
Lot or Batch Samples
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 one year has elapsed since the expiry date of that natural health product.

Intent

Samples (in their final packaging) are maintained as evidence of product quality should an investigation ensue from a customer complaint, product recall, etc. Samples are to be maintained in an environment that would mimic regular storage requirements to ensure the sample is equivalent to products available for sale.

To meet the requirements

Manufacturers, importers and distributors shall ensure the following, where applicable:

  1. Retain an adequate number of samples of each lot of a finished product. Importers and distributors may have the manufacturer or a designated third party keep samples for them, provided the samples are readily available upon request.
  2. Retain samples in their final trade packages or in containers of the same material and construction.
  3. Store samples in the environmental conditions listed on the label.
  4. Ensure that finished product samples are of sufficient size to permit complete testing according to specifications.
  5. Maintain samples for at least one year after the product expiry date.

Importers are responsible to notify the NNHPD when making alternative arrangements for retaining samples. The alternate site must commit to retaining the samples in the same containers as those marketed in Canada.

Contract manufacturers for bulk or intermediates ingredients might be exempted to meet this requirement as they might not have the finished product in its final packaging. The onus will be on the product manufacturer to retain samples once they are in their final packaging.

The type of GMP evidence for lot or batch samples may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for sampling:

  • List of all samples being held, including product name and lot number.
  • Description, SOP, or record confirming that the samples are held and maintained for at least one year past the product expiration date.
  • Approved sampling protocol.

2.4.4 Records

Sections 53 to 58 of the Regulations set out the record-keeping requirements for manufacturers, packagers, labellers, importers, and distributors.

Part 3: Good Manufacturing Practices
Manufacturers
Section 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 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.

Part 3: Good Manufacturing Practices
Packagers
Section 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 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.

Part 3: Good Manufacturing Practices
Labellers
Section 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.

Part 3 Good Manufacturing Practices
Importers
Section 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 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.

Part 3: Good Manufacturing Practices
Distributors
Section 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.

Part 3: Good Manufacturing Practices
Record Maintenance
Section 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 one year following the expiry date of the natural health product to which that record relates.

Intent

Records are maintained as evidence of product production and quality should an investigation ensue from a customer complaint, product recall, etc.

To meet the requirements

  1. Manufacturers, packagers, labellers, importers and distributors shall meet the minimum record-keeping requirements set out in Appendix 2.

  2. Records must demonstrate that each batch has been manufactured, packaged and labelled according to the procedures described in the master production document. For importers, a certificate of manufacture is an acceptable alternative to lot or batch documents. However, complete batch documentation must be made available upon request.

    When the manufacturer is located outside Canada, specific parts of the master production document considered to be a trade secret or confidential may be held on behalf of the Canadian importer by an independent party in Canada; however, the importer or independent party must ensure that the NNHPD can access the data in a timely manner. The master production document must describe in general terms what, if anything, has been deleted.

  3. Records must demonstrate that each lot of product has been manufactured, packaged, labelled, and imported according to the requirements of Part 3 of the Regulations:

    1. when a product is manufactured, packaged, and/or labelled within Canada and/or imported, it is recommended that the site licence holder:
      1. maintain a copy of the contractor’s site licence, when applicable;
      2. document and maintain records of all tasks carried out by the contractor; and
      3. establish and maintain a document or written technical agreement covering the arranged manufacturing, packaging, labelling, importing, storage, or distribution in accordance with Part 3 of the Regulations. All arrangements for contracting, including any proposed changes to technical arrangements, should be in accordance with the GMP as well as the marketing authorization for the product concerned. 

      Note: The technical agreement or relevant parts thereof should be made available to the NNHPD upon request in the event that further assessment and clarification is needed.

    2. when the product is manufactured, packaged and/or labelled outside of Canada, importers must ensure that records can be accessed in a timely manner.

  4. Manufacturers and importers must maintain evidence establishing the expiry date of each product.

  5. Manufacturers must maintain evidence or records of raw material testing conducted with respect to a lot or batch of raw material used in the manufacture of the NHP.

  6. Packagers must maintain evidence or records of packaging material testing conducted with respect to the material used to package the NHP.

  7. Maintain evidence showing compliance of each finished product with specifications.

  8. Other record-keeping practices may include the following.

    • retain authorized written procedures for all sections of these requirements for reference and inspection. Review written procedures regularly and have authorized employees keep them up to date. Document the reasons for revising the procedures, and establish a system to ensure that only current procedures are in use;
    • have authorized employees approve, sign and date all relevant documents related to GMP, such as records of actions taken or conclusions reached, and procedures. Ensure that any alteration of a document is signed and dated and that the alteration permits reading of the original information. Do not alter documents without authorization;
    • records may be maintained by authorized person(s) in electronic format provided that there is adequate back-up. Such electronic data must be printable and all alteration must be tracked. Manufacturers, packagers, labellers, importers and distributors must be able to access their electronic records and documents at least one year after the product’s expiry date; and
    • electronic signatures are acceptable as an alternative to handwritten signatures. The electronic signature identification system must be tested and evaluated for security, validity and reliability. The electronic signature identification system must be secured from abuse, and include electronic protection against willful or accidental damage. All stages of development of electronic signature identification systems must be documented.
  9. Manufacturers, packagers, labellers, importers, and distributors must maintain at their premises in Canada distribution records that contain sufficient information to enable the recall of every lot that has been made available for sale. Please refer to the recall reporting section of this guidance document for further information.

  10. Manufacturing, testing, and distribution records must be retained for at least one year after the lot expiry date.

The type of GMP evidence for records maintenance may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for records maintenance:

  • Master Production Documents and/or batch records.
  • A list of all contract manufacturers, packagers and labellers used.
  • For each contract manufacturers, packagers and labeller used, a signed Quality Technical Agreement, clearly demonstrating who is responsible for each section of Part 3 of the Regulations.
  • Stability data and testing records for each product.
  • Records of all raw materials testing for each product.
  • Relevant SOPs for all activities and products.
  • List of all NHPs that are manufactured, packaged, labelled, imported or stored at the site.

2.4.5 Recall and recall reporting

Section 50 of the Regulations requires that every manufacturer, packager, labeller, and distributor must establish and maintain a system for recall. Section 62 of the Regulations outlines what information manufacturers, importers, and distributors must provide to Health Canada when a product recall is initiated.

Part 3: Good Manufacturing Practices
Recall Reporting
Section 62

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

  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 each manufacturer, importer and distributor of the natural health product;
  6. the reasons for commencing the recall;
  7. the quantity manufactured or imported into Canada;
  8. the quantity that was distributed in Canada;
  9. the quantity remaining in the possession of each manufacturer, importer and distributor of the natural health product; and
  10. a description of any other action that the manufacturer, importer or distributor, as the case may be, is taking in respect of the recall.

Intent

The requirements for recall system and recall reporting are to ensure that the manufacturer, packager, labeller, and/or importer may execute a product recall successfully, ensuring that all the pertinent information is available and all products on the market are given the correct disposition.

To meet the requirements

  1. Establish written procedures that define controls to ensure the effective recall of a product, including notification of Health Canada's Health Products and Food Branch Inspectorate (HPFBI) Regional Operational Centres. Specifically, this means the following:
    • identifying individual(s) to be responsible for initiating and coordinating recall activities;
    • ensuring that the recall procedure can be put into operation at any time, during and outside normal working hours;
    • ensuring that the recall procedure outlines the steps for implementing a recall (e.g. determining extent of recall and means of notifying affected parties);
    • maintaining distribution records to enable tracing of each lot;
    • identifying and storing recalled products separately in a secure area until further action is determined;
    • assessing at intervals and recording in writing, the progress and efficacy of the recall, and issue a final report, including a final reconciliation; and
    • notifying all Canadian and foreign sites involved in the manufacture, import, or distribution of the recalled products.
  2. Manufacturers, importers, and/or distributors who recall a NHP must submit product recall information to the appropriate Health Canada's HPFBI Regional Operational Centre within three days of initiating the recall. The following information is required to be provided:
    • the proper name and the common name of each medicinal ingredient that it contains;
    • each brand name under which it is sold;
    • its product number (NPN);
    • the number of each lot or batch recalled;
    • the name and address of each manufacturer, importer, and distributor of the NHP;
    • the reasons for commencing the recall;
    • the quantity manufactured or imported into Canada;
    • the quantity that was distributed in Canada;
    • the quantity remaining in the possession of each manufacturer, importer, and distributor of the NHP; and
    • a description of any other action that the manufacturer, importer, or distributor, as the case may be, is taking in respect of the recall.

The type of GMP evidence for a recall reporting may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of acceptable evidence that would be expected to demonstrate GMP compliance for recall reporting:

  • Listing of all previous recalls and reasons for the recalls.
  • Recall record or recall report from within the last 12 months.
  • Product distribution records from within the last 12 months.
  • Mock recall report from within the last 12 months.
  • All recall information (recall notice, communication and final report) and product disposition.
  • SOP related to recall information required to be provided (indicated above) to Health Canada in the event of a recall as well as the contact information for the appropriate HPFBI Regional Operational Centre.

2.4.6 Sterile products

Sections 59 and 60 of the Regulations set out the requirements for manufacturing and packaging of sterile products.

Part 3: Good Manufacturing Practices
Sterile Natural Health Products
Section 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.

Part 3: Good Manufacturing Practices
Ophthalmic Use
Section 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

This regulation requires that proper GMP are implemented to ensure the product meets the definition of a sterile product, whether through manufacturing or terminal sterilization.

To meet the requirements

  1. Manufacturers, packagers, labellers, importers and distributors shall treat all sterile (ophthalmic) NHPs in the same manner as any other sterile health product. Follow the guidance for sterile products provided in the Health Products and Food Branch Inspectorate’s Good Manufacturing Practices Guidelines as it is amended time to time. The guidelines for sterile products apply in addition to the non-sterile requirements outlined in this document.

The type of GMP evidence for sterile manufacturing may vary; however, it is expected that all requirements stated above are supported by evidence. Examples of evidence that would be expected to demonstrate GMP compliance for sterile manufacturing:

  • Batch records.
  • In-process and finished product testing results.
  • Validation process /sterilization and environmental monitoring records.
  • QAP and product support staff qualifications.
  • Records related to specialized training in microbiology.
  • SOP and associated records related to clean room maintenance, laminar flow maintenance and product sterilization

3.0 References

4.0 Glossary

The definitions given below apply to the terms used in this guidance document. Certain terms may have different meanings in other contexts.

Attenuation
Attenuations are prepared by dissolving one part of the soluble basic substance in a sufficient quantity of purified water or other appropriate menstruum, specified in the recognized monograph, to produce (x) parts by volume of liquid attenuation (e.g. 1X, 1CH).
Batch
A quantity of product in the processing stage, homogeneous within specified limits, produced according to a single manufacturing order and as attested by the signatories to the order. In the case of continuous manufacture, the batch corresponds to a defined fraction of the production, characterized by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.
Batch number
A distinctive combination of numbers and/or letters that specifically identifies a product batch, and appears on documents such as the batch record, certificate of analysis.
Batch record
Production document that captures the quantity and lot number of all materials used, as well as production steps, in the manufacturing of a single batch of a natural health product in dosage form.
Bulk natural health product
Unpackaged dosage form, usually in quantities larger than the largest commercially available package size.
Bulk preparation
Unpackaged homeopathic preparation, usually in quantities larger than the largest commercially available package size.
Certificate
A legally authenticated written declaration issued by a recognized institution to a person completing a course of study.
Certificate of Analysis
A document signed by a qualified analyst that includes the product name, ingredient listing, lot number of the product, test conducted, test method and results, conclusion of the test (satisfactory or unsatisfactory), name and position of the analyst, and date of issuance.
Certificate of Manufacture
A document issued by a vendor to a distributor or importer that attests that a specific lot of product has been produced according to its master production document. Such certificates include a summary of the current batch documentation, with reference to respective dates of revision, manufacture and packaging, and are signed and dated by the vendor’s authorized quality assurance person.
Compliance
The state of conformity of a regulated party (including a corporation, institution, individual or other legal entity) or a product with a legislative or regulatory requirement, or a recognized standard.
Contract Manufacturer
A firm (business) that manufactures, packages, and/or labels a natural health product, or performs any other activity or operation in respect of a natural health product, under the terms of an agreement with another party. Additional terms of reference may include: contract manufacturing organization, contractor, contract acceptor.
Critical process
A process that may cause significant variation in the quality of the finished product.
Diploma
A document issued by an educational institution, such as a university, college, or technical institute, vouching that the recipient has earned a degree or successfully completed a particular course of study.
Distributor
A person who sells a natural health product to another person for the purpose of further sale by that other person.
Dosage form
  The final physical form of the natural health product which may be used by the consumer without requiring any further manufacturing.
Education
The act or process of imparting or acquiring knowledge or skills; the learning of information by instruction, training, or study can be testified to by a degree, certificate or diploma.
Experience
Active participation in events or activities leading to the acquisition of knowledge or skills; the knowledge or skills retained from personally observing, encountering, or undergoing something.
Filling
Transferring and enclosing a bulk product into its final container.
Finished product
A product that has undergone all stages of production, including packaging in its final container and labelling.
Formulate
To prepare components and combine raw materials into a bulk natural health product.
Hazard Analysis and Critical Control Points (HACCP)
An internationally recognized system of food safety methods. It is a systematic approach to the identification, evaluation, and control of food safety hazards.
Homeopathic Medicines
Medicines that are manufactured from or contain as medicinal ingredients only those substances or sources referenced in The Homeopathic Pharmacopoeia of the United States (HPUS), the Homöopathische Arzneibuch (HAB), the Pharmacopée Française (PhF) or the European Pharmacopoeia, as amended from time to time, and that are prepared in accordance with these pharmacopoeias.
Import
To bring into Canada a natural health product for the purpose of sale.
Importer
A person who imports a natural health product into Canada, for the purpose of sale. This would include bulk natural health products.
In-process control
Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the finished product conforms to its specifications. The control of the production environment or equipment may also be regarded as a part of in-process control.
In-process product
Any materials or mixture of materials that must, to become a product in dosage form, undergo further processing.
In-process testing
The examination or testing of any materials or mixture of materials during the manufacturing process.
ISO (International Organization for Standardization)
A worldwide organization of national standards bodies; ISO is a non-governmental organization that maintains a group of global standards.
Label (n)
Includes any legend, word or mark attached to, included in, belonging to or accompanying any food, drug, cosmetic, device or package. Natural health products are included.
Label (v)
To affix the inner or outer label of the natural health product.
Lot
A quantity of any natural health product in dosage form, a raw material or a packaging material, homogeneous within specified limits, constituting all or part of a single batch and identified by a distinctive lot number which appears on the label of the finished product.
Lot number
Any combination of letters, figures or both, by which any natural health product can be traced in manufacture and identified in distribution.
Maceration
Processing method using unheated solvent (cold or room temperature water, alcohol, or other organic solvent) to extract medicinal properties from a raw material.
Manufacture
To fabricate or process a product for the purpose of sale.
Manufacturer
A person who fabricates or processes a natural health product for the purpose of sale, but does not include a pharmacist or other health care practitioner who, at the request of the patient, compounds a natural health product for the purpose of sale to that patient.
Manufacturing order
Instructions that outline in detail the materials and procedures required to manufacture prepare and preserve a single batch of a natural health product in dosage form.
Master formula
A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed description of the procedures and precautions required to produce a specified quantity of a finished product.
Master production document
A document that includes specifications (raw material, packaging material, packaged dosage form), master formula, sampling procedures and critical processing related standard operating procedures, whether or not these procedures are specifically referenced in the master formula. It also includes a complete list of raw materials used in the manufacture of the product, designated by names or codes; the amount of each raw material required for the theoretical product formulation; manufacturing and process control instructions and in-process testing requirements (e.g. checks on materials, pre-treatments, sequence of adding materials, mixing time and temperatures); a statement of the principal equipment to be used; a statement of the theoretical weight or measure of the manufactured product and the acceptable limits beyond which an investigation is required; a description of the finished product containers, closures and packaging labels; any special precautions to be observed; and dates and times (if applicable) of commencement and completion of significant intermediate stages, such as blending or heating, and of completion of production.
Mother tincture
A relatively concentrated aqueous alcoholic extract from which subsequent attenuations are prepared. Synonyms: mother liquor, stock solution, starting solution.
Natural health product
A substance set out in Schedule 1 of the Regulationsor a combination of substances in which all the medicinal ingredients are substances set out in Schedule 1, a homeopathic medicine or a traditional medicine that is manufactured, sold or represented for use in
  1. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans;
  2. restoring or correcting organic functions in humans; or
  3. modifying organic functions in humans, such as modifying those functions in a manner that maintains or promotes health.
However, a natural health product does not include a substance set out in Schedule 2 of the Regulationsor any combination of substances that includes a substance set out in Schedule 2.
Nosodes
Attenuations of pathological organs or tissues; causative agents such as bacteria, fungi, ova, parasites, virus particles, and yeast; disease products; excretions or secretions.
Observation
A deviation or deficiency of good manufacturing practice
Package (n)
Includes immediate container in which any food, drug, cosmetic or device is wholly or partly contained, placed or packed.
Package (v)
To put a product in its immediate container.
Packaging material
Labels, printed packaging materials and those components in direct contact with the dosage form.
Packaging order
Instructions that outline in detail the materials and special procedures required to package and label a single lot of a product in dosage form.
Percolation
A method used for the extraction of dried substances that have been reduced to the proper degree of fineness.
Potency
The amount per dosage unit of the standardized component(s) which further characterizes the quantity of the ingredient. It is required only when a claim on the potency is to be on the label, or it is required for a specific product (e.g. when literature supports the product with that standardized component). In Supplementary Good Manufacturing Practices for Homeopathic Medicines, “potency” refers to the degree of dilution of a homeopathic medicine.
Production
All operations involved in the preparation of a finished product, from receipt of materials, through processing and packaging, to completion of the finished product, including storage.
Purity
The extent to which a raw material or a product in dosage form is free from undesirable or adulterating chemical, biological or physical entities as defined by specification.
Qualification
To make competent or eligible for an office, position, or task by having the proper or necessary skills, knowledge, credentials, accomplishments or qualities.
Quality assurance
All the planned and systematic activities applied within the quality system to provide adequate confidence that the predetermined standards for quality and safety will be met.
Quality assurance person
The person who is responsible for assuring the quality of the natural health product before it is made available for sale. This person has the training, experience and technical knowledge relating to the specific activity conducted (i.e. manufacturing, packaging, labelling, importing, and distributing) and the requirements of Part 3 of the Regulations.
Quality assurance Report
A report prepared by a quality assurance person who meets the requirements with respect to education, training, and experience according to section 51 (1)(a)(ii) of the Regulations. This report is based on the assessment against the regulations and requirements set out in the Good Manufacturing Practices (GMP)guidance document. It is considered a self-assessment document and evidence of GMP compliance.
Quantity
The amount of medicinal ingredient(s) per dosage unit. It is always required for a product, as it is the amount of medicinal ingredient in the product.
Quarantine
Effective restriction of the availability of material or product for use (physically or by system), until released by the quality assurance person.
Raw material
Any substance, other than in-process product or packaging material, intended to be used in the manufacture of products, including those that appear in the master formula but that do not appear in the product such as solvents and processing aids.
Recognized institution
A post-secondary educational facility (e.g. a university, college or professional institute) generally approved for having a secure reputation; credible, reputable, and authoritative.
Reconciliation
A comparison, making due allowance for normal variation, between the amount of product or materials theoretically produced or used and the amount actually produced or used.
Reprocessing
Subjecting all or part of a batch or lot of an in-process product or finished product to a previous step or alternate manufacturing process due to failure to meet predetermined specifications.
Returned product
Bulk or finished product sent back to the manufacturer, distributor, or importer.
Sampling
Collection of a number of units that comprises representative sample from a designated lot or batch of product.
Sample Size
In determining the size of sample to be maintained, it is to be kept in mind that Health Canada needs at least enough of the product to carry out tests to determine whether the natural health product complies with its specifications. The manufacturer or importer may also wish to test the product in the event of a complaint; the sample should therefore be at least double the amount needed to complete all required tests.
Secondary Package (n)
A container in which an NHP is wholly or partly contained without direct contact with the NHP itself.
Secondary Packaging (v)
To place an NHP in its immediate package/container into a secondary package/container.
Sell
(section 2 of the Food and Drugs Act). “Sell” includes offer for sale, expose for sale, have in possession for sale and distribute, regardless of whether the distribution is made for consideration.
Site
A place of or for an activity specified under the Regulations.
Standard operating procedure
An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning, cleaning of premises and environmental control, sampling and inspection). Certain standard operating procedures may be used to supplement product-specific master production documents.
Sterile dosage form
A dosage form that is free from microbial contamination.
Storage
A site, also called a warehouse, whose main purpose is to hold natural health products.
Technical agreement
A formal written document between two or more parties outlining the technical portions of a contract and the specific duties of each party involved with respect to Part 3 of the Regulations. A technical agreement is mutually understood and signed by each party.
Trituration
Attenuations of solid substances are prepared by trituration of the crude substance with lactose.
Voucher Specimen
A representative specimen preserved to permit independent verification of identity and to allow further examination (e.g. pressed plants, non-human animal material in preserving fluids).

Appendix 1: Supplementary GMP for homeopathic medicines

To be considered a homeopathic medicine, a product must meet two criteria. It must be:

  1. Manufactured from, or contain as medicinal ingredients, only substances referenced in a homeopathic monograph in one of the following homeopathic pharmacopoeias, as they are amended from time to time:
    • Homeopathic Pharmacopeia of the United States (HPUS).
    • Homöopathisches ArzneiBuch (HAB) or German Homeopathic Pharmacopoeia (GHP).
    • Pharmacopée française or French Pharmacopoeia (PhF).
    • European Pharmacopoeia (Ph.Eur.).
    • Encyclopedia of Homeopathic Pharmacopoeia (EHP).
  2. Prepared in accordance with the methods outlined in one of the homeopathic pharmacopoeias listed above, as they are amended from time to time.

Homeopathic medicines are made from a wide range of materials such as plants, animals, chemicals and minerals many of which are highly toxic in the raw material form. Nosodes are another type of homeopathic medicines, which are preparations of pathological tissues, excretions or secretions. Due to these factors, manufacturers must ensure the critical processes (i.e. raw material identification, raw material handling, attenuations, etc.) are carried out under controlled conditions.

Manufacturers, packagers, labellers of homeopathic medicines, in addition to meeting the requirements in Chapter 2, must meet the supplementary requirements of this appendix. The sections in Chapter 2 on equipment, quality assurance, samples, records, recall reporting and sterile products fully address the requirements for homeopathic medicines, and therefore are not repeated here. 

The Evidence for Homeopathic Medicines guidance document outlines product requirements. Also note, in this chapter, potency refers to the degree of dilution of a homeopathic medicine.

1.0 Places

1.1 Premises

To meet the requirements

Due to the infinitesimal dose of active ingredients, homeopathic medicines must be prepared in a manner that eliminates the possibility of cross-contamination and/or outside contamination.

  1. Manufacturers, packagers, labellers must design their premises so that the homeopathic attenuations are prepared in rooms or workstations that have appropriate environmental controls (e.g. a room with filtered air under positive pressure or in a laminar airflow workstation) and must be distinctly separate from products which are volatile or have permeating odours.

  2. Manufacturers, packagers, labellers must design their premises to accommodate hazardous raw material storage and processing requirements.  These requirements include, but are not limited to, the following:

    • Isolating toxic or infectious raw materials from other materials; and
    • Handling raw materials in segregated areas with appropriate environmental controls suitable for each material.

    Note: A list of raw materials that should be “Stored with care” and “Stored with great care” are listed in the German Homeopathic Pharmacopoeia (GHP).

  3. Equipment and utensils used must be exclusive to homeopathic preparations. In addition:

    • Must be made of materials that do not shed particles;
    • The cleaning and maintenance products used (e.g. lubricants) must not lead to contamination; and
    • Standard operating procedures include the cleaning of vessels and containers employed in successive attenuations or triturations.

2.0 People

2.1 Personnel

To meet the requirements

  1. Manufacturers, packagers, labellers must provide training specific to the attenuation and/or trituration of homeopathic medicines. Supporting documents would provide details of training content and completion dates.
  2. Restricting the entry of untrained or unnecessary personnel in processing areas designated for attenuation and trituration.

3.0 Processes

3.1 Sanitation

To meet the requirements

  1. Manufacturers, packagers, labellers must ensure that the sanitation program does not contaminate the homeopathic product with chemical or particulate matter:
    • cleaning, microbial and environmental monitoring requirements for all processing areas, with emphasis on areas designated for attenuation and trituration;
    • methods  ensure cleaning products do not contaminate product; and
    • methods are adequate to ensure there is no cross contamination of product.

3.2 Operations

To meet the requirements

Homeopathic products must be made according to the preparation methods in one of the five (5) accepted homeopathic pharmacopoeias as described above.

Manufacturers, packagers, labellers shall maintain separate written procedures for homeopathic products and do the following critical production processes:

  1. Raw materials are harvested or produced as per the pharmacopoeias. The identity of all raw materials must be verified and recorded. Raw materials that are toxic or potentially infections must be labelled as to their safety status (e.g. allergen, toxic) or MSDS equivalent.
  2. Mother tincture batch records must contain sufficient information, such as: the duration of maceration and/or percolation, trituration duration and intensity for each type and size of apparatus, particle size of the raw materials in the triturate matrix, quality specifications and QA release, ensuring sterility of nosodes, such as heat processing of the first attenuation in the preparation, etc.
  3. In-process attenuations or triturations are the most critical steps in the production of homeopathic medicines and every effort must be made to ensure the process is consistent, reliable and contaminant-free. Include the following information in the master formula and batch record: 
    • the system for the particular attenuation series (e.g. Hahnemannian, Korsakovian);
    • SOPs, or reference to SOPs, to be followed at each processing stage;
    • number of succussions during each attenuation;
    • duration of trituration, where applicable;
    • disposal of unused intermediate homeopathic potencies;
    • technique for impregnation, where final dosage forms are manufactured;
    • in-process controls with specifications;
    • a reference number unique to a particular series, different from the batch number assigned to the product;
    • the attenuation or trituration number at the particular stage of preparation (e.g. this could be designated by potency);
    • the name, dosage form, batch number and batch size of the preparation for which it is intended;
    • the composition or reference to the master formula;
    • the internal code and analytical control number of each raw material or mother tincture used;
    • precautions to be adopted during handling, when applicable; and
    • Schedule manufacturing to ensure continuity within the attenuation or trituration series and avoid prolonged storage of intermediate homeopathic potencies.
  4. For the manufacturing of impregnated pellets from medicating potencies made by a separate company, the following is required:
    • Raw material identity testing and the batch record demonstrating that the raw material was added during the manufacturing process;
    • Studies demonstrating that impregnation procedure is adequate;
    • the SOPs, or reference to SOPs, for washing, drying and, when applicable, sterilizing packaging materials; and
    • Stability studies or challenge studies from your site demonstrating that the procedures and materials used adequately ensure there is no microbiological contamination until expiry.

4.0 Products

4.1 Specifications

To meet the requirements

Manufacturers, packagers and labellers shall maintain written specifications that describe the homeopathic medicine and the required test methods. For specifications pertaining to identity, purity, quantity, potency and tolerances, see the Evidence for Homeopathic Medicines Guidance Document. Specifications must meet pharmacopoeial (e.g. The Homeopathic Pharmacopoeia of the United States, the Pharmacopée Française, the Homöopathische Arzneimittel or the European Pharmacopoeia) requirements.

Manufacturers must also follow conventional testing protocols for the dosage form (e.g. for tablets, uniformity of weight, hardness and disintegration; for liquid, alcohol type and percentage; for ointments/syrups, viscosity or rheology; etc.).

4.2 Stability

To meet the requirements

Manufacturers, packagers and labelers shall establish a period of time that the product meets its specifications:

  • develop and maintain standard operating procedures that ensure the stability of the homeopathic medicines;
  • maintain records of ongoing purity testing as outlined in the Evidence for Homeopathic Medicines Guidance Document. Note: Due to the unique quality of homeopathic medicines, the evidence of stability would focus on microbiological contamination (i.e. in products of <50% alcohol) and the non-medicinal ingredients (e.g. concentration of alcohol remains consistent, granules/tablets hardness and disintegration are consistent); and
  • packaging materials testing, such as bottles and caps, demonstrating that they do not contaminate product; and demonstrating that the labels do not fade or come away from the packaging.

Appendix 2: Records

Sections 53 to 58 of the Regulations set out the record-keeping requirements for manufacturers, packagers, labellers, importers, and distributors.

In this chart, “maintain” indicates that records must be retained and readily available by that party while the term “access” refers only to the need to make sure that records are available in timely manner. “None” would be for any records that are not required to be kept.

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 Access None
Test results: raw material Maintain None None Maintain None
Test results: packaging material None Maintain None Access None
Test results: finished product Maintain None None Maintain None
Specifications: raw material Maintain None None Access None
Specifications: packaging material None Maintain None Access None
Specifications: finished product Maintain None None Maintain None
Stability Maintain None None Maintain None
Ingredients list Maintain None None Maintain None
Products list Maintain Maintain Maintain Maintain Maintain
Complaints Maintain Maintain Maintain Maintain Maintain
Recall Maintain Maintain Maintain Maintain Maintain
Sanitation program Maintain Maintain Maintain Maintain Maintain

Appendix 3: Good documentation practices

Below are the generally recognized elements that define Good Documentation Practices.

  1. Documentation creation:
    • Completed at the same time as the event they describe;
    • not handwritten (except for handwritten entries thereon);
    • when electronically produced, the documentation must be checked for accuracy;
    • free from errors; and
    • in a format that permits trend evaluation, when applicable.
  2. Document approval:
    • approved, signed, and dated by appropriate authorized personnel.
  3. Handwritten entries:
    • adequate space is provided for expected handwritten entries;
    • handwritten entries are in indelible ink;
    • critical entries must be independently checked (SPV, or second person verified);
    • no spaces for handwritten entries are left blank - if unused, they are crossed out or "N/A" (or similar text) entered;
    • ditto marks or continuation lines are not acceptable; and
    • a stamp, in lieu of a handwritten signature, is not acceptable.
  4. Copies of documents:
    • clear, legible; and
    • errors are not introduced.
  5. Document maintenance:
    • regularly reviewed and kept current;
    • retained and available for appropriate duration;
    • electronic document management systems are validated; and
    • electronic records are backed up.
  6. Document modification:
    • handwritten modifications are signed and dated;
    • altered text is not obscured (e.g. no Wite-Out);
    • where appropriate, the reason for alteration must be noted ("E.E." is a common abbreviated reason, indicating "Entry Error");
    • controls exist to prevent the inadvertent use of superseded documents;
    • electronic versions can only be modified by authorized personnel;
    • access to electronic versions must be controlled by password or other means; and
    • a history (audit trail) must be maintained of changes and deletions to electronic versions.

Regarding the Good Documentation Practices interpretation from the guidance above, additional expectations or allowances can be inferred by extension. Among these are:

  1. prohibition against removing pages - the removal of a page would obscure the data that were present, so this is not permissible;
  2. page numbering - the addition of page numbers, particularly in "Page x of y" format, allows a reviewer to ensure that there are no missing pages;
  3. stamped signatures  - the culture of certain Asian countries, and the controls they employ, are such that their use of a stamp in lieu of handwritten signatures has been accepted;
  4. date and time formats - dates may be written in a variety of formats that can be confusing if read by personnel with a different cultural background. In the context where different cultures interact, a date such as "07-05-10" can have numerous different meanings and therefore, by Good Documentation Practices standards above, violates the requirement for being clear. The date and time format used should be consistent and well communicated amongst all parties involved to avoid ambiguity;
  5. transcription - a transcription of data, where the original document is not retained, effectively obscures the original data and would be prohibited. Transcription may be helpful where the original is of poor quality writing or is physically damaged, but it should be clearly marked as a transcription and the original retained nevertheless;
  6. scrap paper, post-it notes - intentionally recording raw data on non-official records is a set-up for transcription and is therefore prohibited; and
  7. avoiding asterisks as part of the notation of a hand-change - Where insufficient white space permits a fully notated hand change, a common practice is to use an asterisk (or other mark) near the correction, and elsewhere record the same mark and the notation. The risk is that additional changes are made by another person who uses the same mark, and now the notation can be interpreted to apply to all changes with the mark. Some will therefore advise against the use of the asterisk. Others will accept it, if the notation clearly includes the number of changes that it applies to, such as, "* Three entries changed above due to entry errors. KAM 13-Jan-2011".

Appendix 4: Standard operating procedure

Standard operating procedures (SOPs) aim to systemize your processes and document them; they play a major role in the quality assurance system of a company. When followed, SOPs create efficiency, consistency and reliability in activities performed; they help generate fewer errors and a healthy and safe environment.

What is a SOP?

A SOP is a procedure specific to your operation that describes the steps necessary to complete tasks in accordance with regulations and/ or your own standards. Format, structure and level of detail may vary, however, it should provide adequate information to keep performance consistent from one person to another. They are also used to train employees and should be available to all. SOPs are of limited value, if written incorrectly. It is recommended that each SOP is specific to a given task, activity or process. 

SOP Development

It is highly recommended that SOP contain the following (if applicable):

  1. Header section with the SOP’s title, number, and version. Footer section with SOP’ author name, page number, creation, and approval dates.
  2. Scope: describe the purpose and to what activity the SOP is related, as well as to whom or which department it applies.
  3. Responsibilities: mention all job position that should follow this SOP as part of their task.
  4. Material: list all materials, equipment or devices that will be needed to perform this activity.
  5. Safety: this section could be added when it applies, to raise awareness on any safety issues regarding a specific task (e.g. wearing a mask).
  6. Procedure: describe step by step how to perform the activity in a consistent and repeatable fashion.
  7. Records: states where to annotate and keep records related to the activity.
  8. List of attachments: a SOP can have attachments or annexes that are forms to be completed when an activity is executed (e.g. cleaning of equipment log, that will be used to track the dates at which a certain equipment was cleaned, the person who performed the task, the signature and any other comments if necessary).
  9. History: track the dates of revision and the change that were made to the SOP.
  10. Approval: should show the name of the author, process owner, reviewer, and approval by the QAP. This must appear in the document either at the beginning or the end.

Additional sections can be added to a SOP if needed, especially if it improves the quality of the document. It is recommended to maintain style and consistency across documents to assist in their readability.

Illustrations or pictures can be used to ease understanding and cross references to other SOPs can be made.

Control of SOP

A SOP should be:

  1. reviewed by one or more individuals. The final version should be approved and dated by the Quality Assurance Person;
  2. updated and re-approved whenever procedures are changed;
  3. systematically reviewed on a periodic basis to ensure that procedures remain current and appropriate; and
  4. a controlled document with a numbering system to systematically identify and label them. Each page of a SOP should have control documentation notation. The revision number and date are very useful in identifying the SOP in use when reviewing historical data and is critical when the need for evidentiary records is involved and when the activity is being reviewed. When the number of pages is indicated, the user can quickly check if the SOP is complete.

A list of all SOPs should be maintained and updated. Codes can be used when assigning them a number and can be related to the department that owns the SOP. For example, the SOP for the warehouse cleaning can be identified as WA-01-V0: Warehouse Cleaning, where:

  1. WA will be the code for all procedures related to the warehouse;
  2. 01 will be for procedure # 1;
  3. V0 will be for Version 0, (if changes are made to this procedure, the updated SOP will be WA-01-V1); and
  4. The code if followed by the title of the SOP.

Appendix 5: Risk classification of natural health products GMP Observations

Purpose

Risk Classification of Natural Health Products Good Manufacturing Practices Observations is a useful tool intended to describe the risk classification of Good Manufacturing Practices (GMP) observations which can be noted during such activities as a natural health product (NHP) site licence assessment (new application, amendment or renewal), inspection or audit.

This document can also be used by a company’s QAP when conducting a GMP self-inspection.

Furthermore, this document aims to help inform regulated parties, stakeholders and the public regarding the practices that are considered unacceptable, which may result in non-compliance with GMP and the subsequent suspension, cancellation or refusal to issue, amend or renew a NHP site licence.

Background

The risk classification of GMP observations was a component of the Revised Approach to NHP Site Licensing. Due to stakeholder feedback this section has since been updated and added to the current version of the Good Manufacturing Practices guidance documentfor NHPs.

As part of the NNHPD’s continuous improvement initiative, this document was revised to ensure a transparent and consistent approach to evaluate GMP compliance.

Scope

This tool is based on the Regulations and the current edition of the Good Manufacturing Practices guidance document for NHPs and applies to all manufacturers, packagers, labellers, importers and distributors of NHPs, who are required to meet the requirements of Part 3 of the Regulations. (Distributors must follow the GMP as defined in the Regulations; however, they are not required to hold a NHP site licence.)

It is recognized that GMP deviations can result in a NHP that is harmful to the consumer. Therefore, the evaluation of a company’s overall compliance with GMP will take into account the nature and extent of the deviation(s).

Note that the list of GMP observations presented in this document is not exhaustive and, therefore, additional observations may be added where appropriate.

Definitions

The definition of terms used in this appendix can be found in the part 4 glossary terms.  

Risk classification guide

If any observations are noted, quality assurance personnel are responsible to document and take appropriate corrective and preventive actions as required to eliminate the cause and prevent future problems. It is the responsibility of manufacturers, packagers, labellers, importers and distributors to ensure that appropriate GMP are followed.

The risk classification categories are defined below, and lists of the observations, although not exhaustive, are provided for the various GMP categories as outlined in the Good Manufacturing Practices guidance document (Places, People, Processes, and Products). In addition to this document, other relevant documents and information may be used to examine the compliance history of a company, where necessary, to aid in the determination of risk classification and compliance and enforcement measures.

Note that not all of the observations listed below may be applicable for all types of activities. The observations below are a non-exhaustive list, intended to provide examples of various types of observations that may be noted and their corresponding level of risk.

Risk categories

GMP observations are classified into one of three (3) risk categories: Risk 1, 2 and 3, based on the nature of the deviation from GMP, as well as the number and extent of occurrences.

Risk 1 (critical observation)

A GMP deviation that results in or is likely to result in a non-compliant product or an immediate or latent health risk. This includes, but is not limited to, an observation of fraud, product adulteration, misrepresentation and/or falsification of data, or widespread cross-contamination, infestation or unsanitary conditions.

Risk 2 (major observation)

A GMP deviation that may result in a product that does not consistently meet its marketing authorization; and/or results in a failure to follow procedures to approve batches of products prior to sale; and/or failure of the QAP to fulfil his/her responsibilities. Certain Risk 2 observations may be upgraded to a Risk 1 and are identified with an arrow (↑) indicating that the site does not control its processes and operations effectively.

Risk 3 (other observations)

A GMP deviation that does not meet Risk 1 or Risk 2 criteria but is a departure from the GMP. Certain Risk 3 observations may be upgraded to a Risk 2 and are identified with an arrow (↑).
Note: Repeated deviations or unresolved deviations from a previous assessment may result in a higher classification.

Assignment of the overall GMP compliance rating

As part of the NHP site licensing process, GMP observations will be assigned a corresponding risk category followed by an overall GMP compliance rating, either Compliant (C) or Non-Compliant (NC). This rating is a determining factor in the site licensing decision by the NNHPD.

Non-Compliant (NC) rating

In general, a Risk 1 observation will result in a NC rating. As a result, the NNHPD may suspend, cancel, or refuse to issue, amend or renew the site licence. When the resulting products present a significant health hazard, appropriate enforcement actions may be initiated such as product recall, detention or seizure. Upon discovery of a Risk 1 observation, Health Canada may provide the company with the opportunity to take immediate corrective actions.

A NC rating may also be assigned in the following situations:

  • When numerous Risk 2 observations are identified indicating that the site does not control its processes and operations effectively ; or
  • Repeated Risk 2 observations noted previously, indicating that the company did not implement the required corrective actions following the previous assessment.

When several Risk 2 observations result in a NC rating, the applicant/site licence holder has the opportunity to resolve the situation and achieve a C rating, by immediately implementing all the necessary corrective actions required to resolve the causes of the observations that led to the NC rating and provide sufficient evidence demonstrating that the situation will not recur. Failure to do so will result in a suspension or cancellation.

Compliant (C) rating

In situations where no observations or only Risk 3 observations are observed, a C rating will be assigned. In addition, if only a few Risk 2 observations are observed, a C rating may be assigned.

Risk classification of GMP observations

The following lists the observations related to each category of risk within each GMP category (Places, People, Processes and Products).

1.0 Places

1.1 Premises

Section 45 of the Regulations.

Risk 1 (critical) observations

  • Inadequate segregation of raw material dispensing, manufacturing, storage or testing areas to prevent cross-contamination, with evidence of cross-contamination.
  • Inadequate building maintenance, resulting in premises in poor condition (e.g. major structural defects or damages such as holes, cracks or peeling paint) with evidence of product contamination or direct exposure to contaminant.
  • Inadequate pest management, resulting in premises with evidence of contaminated product, extraneous pest matter or visible signs of infestations.

Risk 2 (major) observations

  • Inadequate segregation of raw material dispensing, manufacturing, storage or testing areas to prevent cross-contamination, with no evidence of cross contamination.
  • Malfunctioning of the ventilation or filtration system resulting in possible localized or occasional cross-contamination.
  • Outlets for liquids and gases or accessory supplies (e.g. steam, air, nitrogen, dust collection) not properly installed or identified.
  • Maintenance (such as air filter replacement), periodic verification, and monitoring of pressure differentials not performed, when applicable.
  • Temperature and humidity not controlled or monitored where necessary (e.g. storage not in accordance with labelling requirements of the product). (↑)
  • Damage (e.g. holes, cracks or peeling paint) to walls, ceilings and floors immediately adjacent to or above manufacturing areas or equipment where the product is exposed.
  • Accumulation of dust, powder or other contaminants on hard-to-clean pipes, fixtures or ducts directly above products or manufacturing equipment.
  • Surface finishes (floors, walls and ceilings) do not permit effective cleaning.
  • Unsealed porous finishes (e.g. on floors, walls and ceiling) in manufacturing areas that may lead to contamination (mildew, mould, powder from previous productions, etc.). (↑)
  • Insufficient manufacturing, packaging, labelling and storage space that could lead to mix-ups.
  • Quarantine area accessible to unauthorized personnel; quarantine area not clearly marked.
  • Insufficient precautions to prevent contamination or cross-contamination of the materials and product.
  • Grounds around manufacturing buildings not suitably maintained.
  • Inadequate refuse receptacles and improper waste disposal practices that may lead to contamination of the product or harbourage of pests. (↑)
  • Doors giving direct access to exterior from manufacturing and packaging areas used by personnel during production.
  • Inadequate measures to prevent pests from entering the premises and contaminating products.

Risk 3 (other) observations

  • Unscreened and unstrapped floor drains.
  • Damage to surfaces not directly adjacent or above exposed products.
  • Non-production activities performed in production areas.
  • Inadequate rest, change, wash-up and toilet facilities.
  • Insufficient lighting in production and inspection areas.
  • Untidy conditions that do not permit effective cleaning.

1.2 Equipment

Section 46 of the Regulations.

Risk 1 (critical) observations

  • Critical equipment, such as equipment used for complex manufacturing operations, not operating within specifications, or evidence of malfunctioning that could affect the quality or safety of the final product.
  • For shared equipment, no cleaning performed between production runs of different products.

Risk 2 (major) observations

  • Evidence of contamination of product by foreign materials (e.g. grease, oil, rust, leaking gaskets particles) from the equipment due to inadequate equipment maintenance, installation, use, etc. (↑)
  • Non-critical equipment not operating within its specifications.
  • Clean-In-Place equipment not consistently operating within established limits.
  • No or inadequate provisions in place for storing/protecting clean equipment to avoid contamination.
  • Production equipment and utensils in direct contact with materials (raw, in-process, or finished product), made of porous, reactive or toxic materials, and not designed to withstand repeated cleaning.
  • No covers for tanks, hoppers or similar manufacturing equipment.
  • Equipment location may lead to cross-contamination or possible mix-ups, (for operations performed in a common area).
  • Water system not maintained or operated to provide water of adequate quality. (↑)
  • Leaking gaskets, may lead to contamination of product.
  • No calibration program for automatic, mechanical, electronic or measuring equipment and no records maintained.
  • No equipment usage logs.
  • Temperature-sensitive compartments are not controlled and inadequate records maintained. (↑)

Risk 3 (other) observations

  • Insufficient distance between equipment and walls to permit proper cleaning. (↑)
  • Base of immovable equipment not adequately sealed at points of contact.
  • Temporary means for repairs (e.g. tape, cardboard).
  • Defective or unused equipment not removed or appropriately labelled.

2.0 People

2.1 Personnel

Section 47 of the Regulations.

Risk 1 (critical) observations

  • Individual or team responsible for manufacturing, packaging, labelling and/or importing has no GMP knowledge or training.

Risk 2 (major) observations

  • Individual or team responsible for manufacturing, packaging, labelling and importing not qualified by education, training or experience to perform their respective tasks. (↑)
  • Insufficient training (initial and/or ongoing) for personnel responsible for quality assurance and manufacturing operations resulting in related GMP deviations.
  • Insufficient personnel with the necessary qualifications for quality assurance and manufacturing operations resulting in a high probability of error (with evidence of error) (↑)
  • Use of outdated or unapproved written procedures.

Risk 3 (other) observations

  • Inadequate training records.
  • Insufficient written training program.

2.2 Quality assurance

Section 51 of the Regulations.

Risk 1 (critical) observations

  • No quality assurance person who is responsible for assuring the quality of the product before it is released (made available) for sale.
  • Individual or team responsible for quality assurance not qualified by training, experience and technical knowledge relating to the activities conducted and GMP.
  • Quality Assurance is not a distinct and independent function/unit, with evidence that quality assurance decisions are overruled by production department or management.
  • No testing of finished products.
  • Test results that suggested a negative impact on product quality were not documented, reported or investigated.
  • Misrepresented or fabricated analytical samples, tests results or raw data.
  • Deleted tests results or raw data used to support release.

Risk 2 (major) observations

  • Inadequate testing of finished product (not according to finished product specifications). (↑)
  • Use of materials in manufacturing, packaging, labelling or storage without prior assessment and approval by the quality assurance person. (↑)
  • Products made available for sale or resale without assessment and approval by the quality assurance person. (↑)
  • Batch or lot records not reviewed as part of the determination to reject or approve product for distribution by the manufacturer. (↑)
  • Lack of or inadequate system for complaint handling and returned goods.
  • No or inadequate written procedures available for sampling, inspecting and testing of materials (raw, packaging, in-process or finished product), where applicable.
  • Out of specification test results, deviations and/or borderline conformance not properly investigated and documented, according to a written procedure.
  • Reprocessing done without prior approval of quality assurance person.
  • Decisions made by quality assurance person are not recorded, signed and dated.
  • Returned products unsuitable for resale are not identified, segregated and/or destroyed.
  • No or inadequate records maintained for returned, reprocessed and redistributed products.
  • No or inadequate written procedures for handling product complaints.

Risk 3 (other) observations

  • Written procedures for manufacturing, packaging, labelling and storage of products are not approved by the quality assurance person.
  • Incomplete or missing documentation for a written complaint.
  • Failure to provide a written job description of the quality assurance person.

3.0 Processes

3.1 Sanitation program

Section 48 of the Regulations.

Risk 1 (critical) observations

  • Evidence of widespread accumulation of residues, extraneous matter and/or gross infestation, indicative of inadequate cleaning.
  • No or inadequate written sanitation program in place for premises and/or equipment, coupled with unclean/unsanitary manufacturing, packaging, labelling or storage areas.

Risk 2 (major) observations

  • Personnel with illnesses that could affect the safety and/or quality of a product are permitted to work around or near production materials or products. (↑)
  • No or incomplete written sanitation program, but premises in acceptable state of cleanliness.
  • No or incomplete written health and hygiene procedures.
  • Personnel having direct contact with materials or using processing equipment and not following appropriate hygienic practices to protect product against contamination. (↑)
  • No written procedures and inadequate equipment cleaning.
  • No or inadequate procedures for cleaning frequencies and cleaning lines between the production of different products. (↑)

Risk 3 (other) observations

  • Incomplete equipment and facility cleaning records.
  • No list of cleaning and sanitizing agents.
  • Personnel responsible for cleaning not identified.
  • Sporadic dust, powder or residue observed in some manufacturing areas or on equipment. (↑)
  • No or inadequate procedures for the destruction and disposal of waste materials and debris.

3.2 Operations

Sections 49 and 50 of the Regulations.

Risk 1 (critical) observations

  • Contracting out manufacturing, packaging, labelling, or storage services from a site that does not comply with the applicable GMP and/or does not hold a site licence.
  • No written procedures in place for the critical activities conducted at the site.

Material control

  • Evidence of material (raw, in-process, bulk or finished) adulteration or contamination.
  • Unsuitable treatment of raw agricultural materials that contain soil or other contaminants.
  • Materials (raw, packaging, in-process or finished) stored under inappropriate conditions with evidence of quality deterioration or cross-contamination.
  • Raw materials improperly identified or labelled (e.g. failure to include appropriate name, description, lot number, expiry date, quality status and potency, as required) leading to the risk of mix-ups.
  • Presence of material not authorized for use in NHPs (e.g. prescription drug, controlled drug), unless permitted under a separate licence.
  • Use of raw materials that are subject to deterioration beyond their shelf-life without approval from the quality assurance person.

Process control

  • No written master formula or master production document.
  • Master formula or manufacturing order showing gross deviations or significant calculation errors.
  • Inappropriate control of labels with evidence of mix-ups.
  • No investigations and corrective action plans pertaining to deviations and/or out of specification testing results.
  • Insufficient controls in place to ensure that records cannot be deleted
  • Insufficient controls in place to ensure that changes made to data are tracked and justified

Risk 2 (major) observations

  • Evidence that approved procedures are not followed by the personnel. (↑)
  • Absence of a recall procedure that would permit an adequate recall.

Material control

  • Upon receipt, bulk and in-process raw and/or packaging materials not held in quarantine until released by the quality assurance person.
  • Inadequate or inaccurate labelling of bulk and in-process raw and/or packaging materials.
  • No time limit established for raw materials.
  • Production personnel do not respect the quarantine status of raw and/or packaging materials.
  • No written procedures for conditions of transportation and storage.
  • Water used in manufacturing or processing not of acceptable quality. (↑)
  • Successive attenuations completed in area other than laminar airflow workstation (applicable to Homeopathic Medicines).
  • Failure to destroy outdated or obsolete printed packaging materials and record the disposal.
  • Certificate of analysis shows incomplete testing results. (↑)

Process control

  • Complex production processes not controlled.          
  • Deviations from instructions during production not documented and not approved by the quality assurance person.
  • Lack of proper identification of in-process materials resulting in a high probability of mix-ups.
  • Inaccurate or incomplete information in manufacturing and packaging orders.
  • Significant or unusual discrepancies observed during reconciliation of bulk product, printed packaging materials and/or labels not investigated by qualified personnel prior to release.
  • Failure to record duration (such as efficiency of maceration, percolation) and other critical manufacturing steps as specified in the procedure, when applicable.
  • No signed quality technical agreement(s) with the contractor(s).
  • Activities performed were not attributable to the person who performed them
  • Activities were not documented at the time they were performed

Risk 3 (other) observations

Material controls

  • Incomplete written procedures for handling non-critical materials.

Process controls

  • Access to production areas not restricted to authorized personnel.
  • Incomplete recall procedure.
  • No inspection program for contractors. (↑)

4.0 Products

4.1 Specifications

Section 44 of the Regulations.

Risk 1 (critical) observations

  • Products not assessed or tested according to their finished product specifications (including testing methods and limits).
  • Finished products that do not comply with their specifications are distributed or released for sale.
  • Addition of adulterants (e.g. ingredients listed in the Prescription Drug List/Schedule F to the
    Food and Drug Regulations, narcotic substances and any other prescription drugs), or fraudulent replacement or mixing of medicinal and non-medicinal ingredients.
  • Modifications to testing records were not documented.

Risk 2 (major) observations

  • Inadequate/incomplete finished product specifications available for products.
  • Reduced testing program applied by importer without a certificate of analysis for each lot received.
  • No identity testing, as described in the finished product specification conducted upon receipt of the NHP in Canada to support a reduced testing program for the importer.
  • Evidence that specifications and any changes made to the specifications are not approved by the quality assurance person.

4.2 Stability

Section 52 of the Regulations.

Risk 1 (critical) observations

  • No data, scientific rationale or program available to establish a product shelf life.

Risk 2 (major) observations

  • Insufficient data (e.g. real time or accelerated, number of lots) to establish shelf life.
  • No action taken when data shows that product does not meet its specifications prior to the expiry date. (↑)
  • Lack of or inadequate stability program.
  • No stability studies pertaining to changes in manufacturing and packaging materials, if applicable.
  • Samples retained for stability studies are not stored under recommended storage conditions.

Risk 3 (other) observations

  • Incomplete testing of parameters.
  • Insufficient quantities retained for complete testing.
  • Failure to follow stability procedure.

4.3 Samples

Section 61 of the Regulations.

Risk 2 (major) observations

  • Failure to retain and store samples of each lot of product in its original container or in containers of the same material and construction for a period of one year past the expiry date of the NHP, as part of an established sample retention program.
  • Failure to provide retained samples of finished products.
  • Retained sample not stored under appropriate environmental conditions (as listed on the product label).

Risk 3 (other) observations

  • Samples of insufficient size for finished product testing retained.

4.4 Records

Sections 53-58 of the Regulations.

Risk 1 (critical) observations

  • Evidence of falsification or misrepresentation of records (e.g. release and stability testing results, manufacturing documents, sales documents).

Risk 2 (major) observations

  • Documentation not readily available from site licence holder. (Unable to access records from products that are manufactured, packaged and or labelled outside of Canada in a timely manner.)       
  • Failure to maintain master production documents at the manufacturing site.
  • Failure to maintain a listing of all ingredients contained in each lot or batch of the NHP.
  • Failure to maintain testing records in respect of a lot or batch of raw or packaging material used in the manufacturing and/or packaging of the NHP.
  • Failure to maintain testing records in respect of a lot or batch of the NHP by the manufacturer or importer.
  • Failure to maintain a copy of the specifications for each NHP that is being manufactured or imported at the site.
  • Failure to maintain general records demonstrating that each lot or batch of the NHP was manufactured in accordance with GMP.
  • Failure to maintain stability data to establish the expiry date of each NHP.
  • Failure to maintain records containing sufficient information to enable the recall of every lot or batch of the NHP that has been made available for sale (manufacturing, testing and distribution records).
  • Failure to maintain a list of all the NHPs that are being manufactured, packaged and labelled at the site.
  • Failure to maintain a copy of the sanitation program that is in use at the site.
  • Records not signed.
  • Incomplete records, records not dated.
  • Failure to maintain records for one year following the expiry date of the NHP.
  • Records required to be maintained were not retained in a readable and readily accessible format for their required period.
  • Records were not named and organized in a manner that allowed for adequate traceability.

Risk 3 (other) observations

  • Illegible records.

4.5 Recall reporting

Section 62 of the Regulations.

Risk 2 (major) observations

  • Failure to notify Health Canada within three days of commencing the recall and provide the information as outlined in section 62 of the Regulations.
  • Recalled products are not identified appropriately and placed in quarantine until disposition is determined.

4.6 Sterile products

Sections 59 and 60 of the Regulations and Chapter 1.4.6 of the Good Manufacturing Practices guidance document.

Risk classification for Sterile NHPs are the same as the ones detailed in the current edition of the HPFBI’s Risk Classification of GMP Observations (GUI-0023), and are as follows:

Risk 1 (critical) observations

  • Lack of or inadequate validation of critical sterilization cycles.
  • Water for Injection (WFI) systems not validated with evidence of problems such as microbial/endotoxin counts not within specifications.
  • No media fills performed to demonstrate the validity of aseptic filling operations.
  • No environmental controls/No monitoring for viable microorganisms during filling for aseptically filled products.
  • Aseptic filling operations continued following unsatisfactory media fill results obtained.
  • Batches failing initial sterility test released for sale on the basis of a second test without proper investigation.
  • Inadequate environmental conditions for aseptic operations.
  • Absence of leak test for ampules.

Risk 2 (major) observations

  • Aqueous-based products not subject to terminal steam sterilization without proper justification
  • Inadequate room classification for processing/filling operations. (↑)
  • Aseptic manufacturing suites under negative pressure compared to clean areas (C-D). Clean areas (C-D) under negative pressure to unclassified areas. (↑)
  • Insufficient number of samples taken for environmental monitoring/inadequate sampling methods. (↑)
  • Insufficient environmental controls/Insufficient monitoring for viable microorganisms during filling for aseptically filled products. (↑)
  • Premises and equipment not designed or maintained to minimize contamination/generation of particles. (↑)
  • Inadequate maintenance of purified water and WFI systems.
  • Inadequate re-validation of purified water and WFI systems after maintenance, upgrading, out-of-specs trends.
  • Inadequate training of personnel.
  • Personnel involved in aseptic filling prior to completing successful media fill.
  • Inadequate gowning practices for clean and aseptic areas.
  • Inadequate sanitation/disinfection program.
  • Inadequate practices/precautions to minimize contamination or prevent mix-ups.
  • Non-validated time lapse between cleaning, sterilization, and use of components, containers and equipment.
  • No consideration given to bioburden prior to sterilization.
  • Non-validated time lapse between start of manufacturing and sterilization or filtration.
  • Inadequate program for media fill.
  • Capability of media to grow a wide spectrum of microorganisms not demonstrated.
  • Misinterpretation of results for media fills.
  • Samples for sterility testing insufficient in number or not representative of the entire production run.
  • Each sterilizer load not considered as a separate lot for sterility testing.
  • Purified water is not used as the feed water for the WFI system and the clean steam generator.
  • Inadequate testing program for WFI. (↑)
  • The WFI used for the final rinsing of containers and components used for parenteral drugs is not tested for endotoxins when those containers and components are not depyrogenated subsequently.
  • Inappropriate environment/controls for crimping following aseptic filling.
  • Inadequate inspection for particles and defects. (↑)
  • Gases used to purge solutions or blanket products not passed through a sterilizing filter. (↑)
  • Inadequate integrity testing of sterilizing or vent filters. (↑)

Risk 3 (other) observations

  • Steam used for sterilization not monitored to assure suitable quality.
  • Inadequate control on the maximum number of personnel present in clean and aseptic areas.

Compliance and enforcement

Compliance and enforcement measures by the HPFBI will be based on the nature of the deviation(s) from GMP and the risks to health and safety that these represent.
Enforcement activities may include the following:

  • request for recall for one or more NHPs;
  • public advisor (ies);
  • request for voluntary detention, export or voluntary disposal of one or more NHPs;
  • seizure of one or more NHPs;
  • cancellation, refusal or suspension of a product licence;
  • cancellation, refusal or suspension of a site licence;
  • stop sale request from Health Canada;
  • injunction preventing firms from selling one or more NHPs;
  • prosecution and
  • refusal by Canada Customs of entry of one or more NHP into Canada

For more information on compliance and enforcement activities, consult the HPFBI’s Compliance and Enforcement Policy (POL-0001).