Active Pharmaceutical Ingredients - Good Manufacturing Practices - Questions and Answers

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As stated in the Notice to Stakeholders - Amended Food and Drugs Regulations for Active Ingredients - Coming into force on November 8, 2013, Questions and Answers related to Good Manufacturing Practices for active pharmaceutical ingredients (API GMP Q&As) have been created to provide additional guidance regarding inspections and GMPs specific to APIs.

This Q&A list will be updated on a regular basis.

Please note that separate Questions & Answers pertaining to the GMP for APIs Pilot Project for Selected Consumer Health Products will be available on the Health Canada website early in 2014.

Table of contents

• General Questions
• Good Manufacturing Practices
• Importation / Foreign Buildings / Foreign Building Table (referenced in Part B Section 5.1 of FRM-0033

General Questions

1. What is an active ingredient? What is the difference between an active ingredient, an active pharmaceutical ingredient, and a bulk process intermediate?

   Active ingredients are the substances in drugs that are responsible for the beneficial health effects experienced by consumers. The active ingredient in a pharmaceutical drug is called an active pharmaceutical ingredient (API). An example of an API is the acetaminophen contained in a pain relief tablet. The active ingredient in a biological drug is called a bulk process intermediate (BPI). An example of a BPI is the insulin contained in an insulin pen cartridge, for use by diabetics.

2. Why regulate active ingredients?

   The quality of active ingredients in a drug has a direct effect on the safety and efficacy of that drug. Poorly manufactured and contaminated active ingredients have been associated with negative health outcomes, including death, in a number of incidents over the past decades.  For this reason, most countries around the world are now regulating active ingredients.

   Regulating active ingredients in Canada will help increase the quality and safety of drugs for consumers, will strengthen the pharmaceutical drug supply system in Canada, and will bring Canada into line with its international regulatory partners.

3. When will the amended Food and Drug Regulations come into effect?

   The Food and Drug Regulations (Regulations) were amended by extending the requirements of Establishment Licensing and Good Manufacturing Practices to the manufacturing and importation of active pharmaceutical ingredients. The amended Regulations were published in part II of the Canada Gazette on May 8, 2013, and came into force on November 8, 2013.

   As of November 8, 2013, all establishments in Canada that are conducting the licensable activities of fabrication, packaging/labelling, testing and importing of APIs, including finished dosage form fabricators that import APIs for use in manufacturing their own products, are subject to the applicable GMP requirements and are required to submit an Establishment Licence (EL) application form (FRM-0033), and if applicable, signing the attestation to the GMP compliance status of the foreign buildings where fabrication, packaging/labelling and/or testing of APIs occur (Part B, section 5.1 of FRM-0033) and completing the Foreign Building Information Table referenced in Part B Section 5.1 of FRM-0033 before February 08, 2014.

   Importers of finished dosage forms (who are not conducting any API activities in Canada) are subject to the applicable GMP requirements and are required to submit an amendment to their existing EL by signing the attestation to the GMP compliance status of the foreign buildings where fabrication, packaging/labelling and/or testing of APIs occur (Part B, section 5.1 of FRM-0033) and completing the Foreign Building Information Table referenced in Part B Section 5.1 of FRM-0033 to Health Canada before February 8, 2014.

   Importers of finished dosage forms that also import APIs will be required to submit an EL application to Health Canada in order to include the API importation activity on their EL before February 8, 2014.

   Distributors and Wholesalers of APIs in Canada that source APIs within Canada and that perform no other licensable activities are subject to the applicable GMP requirements but are not required to hold an EL for these activities.

   Establishments in Canada that begin to conduct licensable activities related to APIs on or after November 8, 2013 are required to:

   • meet the applicable GMP requirements;
   • submit an EL application form (FRM-0033) and, if applicable, the attestation as well as the completed API Foreign Building Information Table;
   • be inspected and found to be compliant with the applicable Division 2 requirements of the Regulations; and
   • have a EL issued by Health Canada prior to starting licensable activities.

   Finished Dosage Form Fabricators that source APIs within Canada (i.e., do not conduct API licensable activities in Canada) are subject to the applicable GMP requirements but are not required to amend their existing EL. Finished Dosage form fabricator can only use APIs that were fabricated, packaged/labelled and tested by a Canadian or foreign building that met GMP requirements. Furthermore, the finished dosage form fabricator can only source APIs from a Canadian company that meets GMP requirements for importing APIs.

   For additional information please refer to the Notice to Stakeholders - Amended Food and Drugs Regulations for Active Ingredients - Coming into force on November 8, 2013 available on the Health Canada website.

4. Do the amended Food and Drug Regulations apply to active ingredients used in pharmaceutical drugs? in biological drugs? in over-the-counter drugs? in veterinary drugs? in natural health products? in disinfectants?

   The decision to modify the Food and Drug Regulations was made after a number of consultations with different industries.

   The amended Food and Drug Regulations apply to active ingredients in pharmaceutical drugs for human use. Pharmaceutical drugs include both prescription and over-the-counter drugs.

   The amended Food and Drug Regulations do not apply to active ingredients used solely in drugs for veterinary use or in natural health products.

   The active ingredients in biological drugs (also known as bulk process intermediates) were subject to the establishment licensing and Good Manufacturing Practices requirements of the Food and Drug Regulations prior to the amendment which came into force on November 8, 2013. The amended Food and Drug Regulations continue to apply to the active ingredients in biological drugs.

   Until the new Blood Regulations are made, existing requirements, as they read immediately before the coming into force of the Regulations Amending the Food and Drug Regulations (1475 -- Good Manufacturing Practices), will continue to apply to whole blood and blood components.

   Active ingredients used in the fabrication of hard surface disinfectants (also known as antimicrobial agents) that are exempt from the requirements of Division 1A (Establishment licences) and Division 2 (Good Manufacturing Practices) of Part C of the Food and Drug Regulations are not covered under the API regulatory framework. Active ingredients used in the manufacture of disinfectant products, which are not considered as antimicrobial agents (such as antiseptic hand soaps), will be covered by the new Regulations.

5. Do the amended Food and Drug Regulations apply to excipients?

   Excipients are drug ingredients other than the active ingredient that produces health benefits for patients. The amendment does not affect the existing requirements for excipients.

6. Do the amended Food and Drug Regulations apply to medical gases?

   The amendment does not affect the existing requirements for medical gases.

7. Will finished dosage form importers be affected by the amended Food and Drug Regulations for active ingredients?

   Finished dosage form importers will be subject to Establishment Licensing and Good Manufacturing Practices (GMP) requirements for the active ingredients used in the finished dosage form drugs they import, and will be required to demonstrate their compliance with the new requirements during their regular inspection. For additional information please refer to the Notice to Stakeholders - Amended Food and Drugs Regulations for Active Ingredients - Coming into force on November 8, 2013 available on the Health Canada website.

Good Manufacturing Practices

1. What are Good Manufacturing Practices?

   Good Manufacturing Practices are a set of internationally recognized standards which are applied to drug manufacturing to ensure drug quality and safety.

2. What is the ICH Q7 Guideline?

   The ICH Q7 Guideline is a quality standard that governs the manufacturing of active ingredients. The ICH Q7 Guideline was established by an international organization known as the International Conference on Harmonization, which includes several countries, including the United States, Japan and the countries of the European Union.

3. What are the GMP requirements for fabricators, packagers/labellers, testing laboratories, importers, wholesalers and distributors of active ingredients?

   All Canadian fabricators, packagers/labellers, testing laboratories, importers, wholesalers and distributors of active ingredients must meet Good Manufacturing Practices (GMP) regulatory requirements (Part C, Division 2 of the Food and Drug Regulations). Good Manufacturing Practices (GMP) for Active Pharmaceutical Ingredients (APIs) (GUI-0104) is a guide used by companies to understand the requirements and meet Division 2 of the Food and Drug Regulations. This draft guide was available for public consultation in the fall of 2012. The comments received were reviewed and where appropriate, were incorporated into the document. The final version of GUI-0104 was sent via email to stakeholders on December 6, 2013 and will be available on the Health Canada website early in 2014. In the interim, interested stakeholders who wish to obtain this document may send a request for an electronic copy or alternate format of the document to api_questions_ipa@hc-sc.gc.ca

4. Which requirements and guideline should I use for the manufacture of an active ingredient sold as finished dosage form (i.e. an API that does not go through any further manufacturing process before being sold)?

   If the finished product is an active ingredient that is sold as a drug in dosage form, the Good Manufacturing Practices Guidelines, 2009 Edition, Version 2 (GUI-0001) apply.

   All Canadian fabricators, packagers/labellers, testing laboratories, importers, wholesalers and distributors of finished dosage form drugs must meet the Good Manufacturing Practices (GMP) regulatory requirements (Part C, Division 2 of the Food and Drug Regulations). Guidance on the fabrication, packaging/labelling, testing, distribution, wholesaling, and importation of drugs in finished dosage form, is provided in the GUI-0001.

5. Does GUI-0104 apply if the API is purchased from a foreign manufacturer then shipped directly to a customer without the product physically being received in Canada even if the purchaser is responsible for the commercial transaction and any quality problems?

   If the purchaser is not conducting a licensable activity, does not take title of the API, and only provides a service, then GUI-0104 does not apply.  If the purchaser sells or offers for sale the API and acts on behalf of another company located in Canada or abroad, then the purchaser would be considered a wholesaler and GUI-0104 does apply. Section 2 (Interpretation) of the Food and Drug Act defines "sell" as "includes offer for sale, expose for sale, have in possession for sale and distribute, whether or not the distribution is made for consideration;"

6. How will Health Canada verify the compliance of Canadian fabricators, packagers/labellers, testing laboratories, importers, wholesalers and distributors of active ingredients with the amended Food and Drug Regulations?

   As of November 8, 2013, a first Good Manufacturing Practices (GMP) inspection of all Canadian API fabricators, packagers/labelers, testing laboratories and importers will be performed according to a risk-based approach. A new inspection strategy for APIs will be available early in 2014 on the Health Canada website.

   Canadian finished dosage form fabricators importing APIs for use in their own manufacturing will be required to demonstrate their compliance with the new GMP requirements during their regular inspection of finished dosage form related activities. Canadian finished dosage form importers will be subject to GMP requirements for the API used in the finished dosage form drugs they import and will be required to demonstrate their compliance with the new GMP requirements during their regular inspection of finished dosage form related activities. Finished Dosage form fabricators and/or importers will continue to be subject to the GMP Inspection Policy for Canadian Drug Establishments (POL-0011).

   Canadian API distributors and wholesalers, who only store and transport already packaged and labelled APIs, will be subject to the applicable GMP requirements but will not be subject to the API GMP inspection program. However, an inspection may be conducted if a GMP non-compliance issue arises.

7. Will there be different requirements for active ingredients used in Category IV Monograph drugs, similar to the Annex 1 to the Current Edition of the Good Manufacturing Practices Guidelines - Selected Category IV Monograph Drugs (GUI-0066)?

   Pharmaceutical drugs include both prescription and over-the-counter drugs, such as Category IV Monograph drugs. The amended Food and Drug Regulations apply to active ingredients in pharmaceutical drugs for human use. Health Canada has launched a pilot project concerning the implementation of GMP requirements for APIs for selected consumer health products.  This pilot project arises in part from Health Canada's commitment, set out in the Regulatory Impact Analysis Statement accompanying the publication of the amended regulations in Part II of the Canada Gazette, to implement the new regulatory requirements in a manner which ensures that the administrative and compliance burden of the requirements is proportional to the quality risks presented by such products. Further initiatives are underway in consultation with affected stakeholders to determine with greater specificity the quality risks associated with API used in the products selected for this pilot, to evaluate current industry practice concerning the qualification of such API, and to develop, where appropriate, specialized GMP guidance pertaining to such API.

   For more details regarding the pilot project, please refer to the Notice to Stakeholders - Good Manufacturing Practices for Active Pharmaceutical Ingredients - Implementation Pilot Project for Selected Consumer Health Products.

Importation / Foreign Buildings / Foreign Building Table (referenced in Part B Section 5.1 of FRM-0033

1. Will the amended Food and Drug Regulations help improve the quality of drugs coming from other countries?

   Yes. The amended Food and Drug Regulations will strengthen the rules that govern drug manufacturing, thereby enhancing the quality and safety of drugs, regardless of whether they come from other countries or are made here in Canada.

2. How can Canadian importers demonstrate that foreign buildings where active ingredients are fabricated, packaged/labelled and tested are in compliance with regulatory requirements?

   Canadian importers are required to sign an attestation to demonstrate the Good Manufacturing Practices (GMP) compliance status of the foreign buildings where fabrication, packaging/labelling and/or testing of APIs occur. For the initial phase of the coming into force of the amended Food and Drug Regulations, Health Canada will use these attestations as proof of GMP compliance for non-sterile APIs and it will not be necessary for importers to submit at this time additional GMP evidence such as an inspection report from a trusted international regulator. However, information must be readily available within 48 hours upon request by Health Canada. As and when necessary, Health Canada may also assess foreign buildings for compliance with the applicable GMP requirements in Division 2 of the Food and Drug Regulations.

3. Who is required to sign the attestation for the GMP compliance of the foreign buildings where fabrication, packaging/labelling and/or testing of APIs occur?

   A Senior Official and the Quality Assurance Official of the Canadian importer are required to sign the attestation.

4. After February 8, 2014, if a company changes API foreign suppliers or if a company starts using a new API foreign supplier, must the Foreign Building Information Table be completed and submitted to Health Canada? If yes, is the company required to wait for the approval from Health Canada prior to using the new API foreign supplier?

   For the initial phase of coming into force of the amended Regulations, Health Canada is using attestations (Part B, section 5.1 of FRM-0033) as proof of GMP compliance for foreign buildings where the fabrication, packaging/labelling and testing of APIs occurs.

   Canadian importers that hold a Drug Establishment Licence (DEL) are required to maintain and provide current, accurate and complete information related to their foreign buildings by submitting an updated API Foreign Building Information Table (referenced in Part B section 5.1 of FRM-0033) to Health Canada before implementing the change. As long as the appropriate paperwork is submitted to Health Canada, companies can import APIs from the new API foreign building, with the exception of API testers and all activities related to sterile APIs.  Applicants should keep records of submitting the application and the auto-reply email for that application.

   Applicants are required to inform Health Canada of changes prior to the change taking place. After the initial application is submitted (between November 8 2013 and February 8 2014), follow the same process as above but also complete and submit the first pages of the form (table 1 to 5 of FRM-0033) with your amendment application. If you are amending information in Table A, submit a new Table A and include only the new or modified information relating to the amendment. Companies can import from the new/amended API foreign building as soon as they have filed the amendment (same exceptions above apply).

   If the amendment is to add a new licensable activity, category or dosage form (for example, starts importing APIs) the company is required to submit the application and have the EL issued by Health Canada prior to starting this new licensable activity.

5. With respect to the API Foreign Building Information Table, is a company expected to keep adding information to the table (cumulative) and submit it to Health Canada? Or is a company expected to only include changes (updated information, additions, deletions) to the table (non-cumulative) and submit to Health Canada?

   After February 8, 2014, companies that change API foreign suppliers or start using a new API foreign supplier are required to provide only changes (updated information, additions, deletions) to the API Foreign Building Information Table (referenced in Part B section 5.1 of FRM-0033) and submit to Health Canada.

6. Will Canada have a Mutual Recognition Agreement for active ingredients like the one it has with other countries for pharmaceutical drugs?

   In the context of drugs, a Mutual Recognition Agreement (MRA) enables countries to share information on the inspections they perform and to accept one another's results as being equivalent. The development and implementation of an MRA requires a thorough analysis and comparison of the inspection programs of the interested parties. It is a long process. Health Canada has been working with international partners towards the inclusion of active pharmaceutical ingredients in our MRAs.

7. What period of GMP compliance validity will Health Canada assign to foreign buildings where the fabrication, packaging/labelling and testing of active ingredients occurs based on the Attestation form?

   At this time, no validity periods or expiry dates will be assigned to API foreign buildings listed on ELs. The interim measure of an attestation process will be in place until mid-2015. During this period, Health Canada will gather and analyse data contained in the Establishment Licence Applications. Based on this analysis, Health Canada will determine the risk-based strategy moving forward.

8. Are foreign buildings that perform the required raw material testing on APIs as per Division 2 of the Food and Drug Regulations prior to their use in the fabrication of finished dosage form captured by this regulatory proposal as API testing laboratories?

   For foreign buildings that test non-sterile APIs prior to its use in the fabrication of finished products that were already being regulated prior to November 8, 2013, Canadian importers are required to continue submitting GMP evidence as per the Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080)in addition to submitting the attestation and the Foreign Building Information Table. If a Canadian importer starts using a new foreign building that tests non-sterile APIs prior to its use in the fabrication of finished products on or after November 8, 2013, the Canadian importer is required to submit GMP evidence as per GUI-0080 in addition to submitting the attestation and the Foreign Building Information Table.

9. What level of evidence is required to be on site in Canada for foreign buildings where fabrication, packaging/labelling and testing of APIs occurs?

   Health Canada has decided to issue a separate guidance document on evidence to demonstrate GMP compliance of API foreign buildings. The guidance document will be available early in 2014 on the Health Canada website. The initial implementation phase of the API regulatory framework is a phase of information-gathering to determine what evidence is currently available on the premises of Canadian importers. Inspectors will be taking a look at this evidence during inspections and assess compliance with Division 2 of the Food and Drug Regulations.