Creation of a Regulatory Framework for the Implementation of Good Manufacturing Practices for Active Pharmaceutical Ingredients (API) - 2009 Health Canada Consultation Document

Health Products and Food Branch
Inspectorate
Graham Spry Building
250 Lanark Avenue
Address Locator # 2006C
OTTAWA, Ontario
K1A 0K9

September 17, 2009

09-124071-184

To: Stakeholders

Re: Creation of a regulatory framework for the implementation of good manufacturing practices for active pharmaceutical ingredients

This is to provide you with an opportunity to comment on Health Canada's proposed regulatory framework for the purpose of implementing the International Conference on Harmonization (ICH) guideline Q7. Q7 is an internationally recognized guideline that was developed to provide internationally harmonized guidance regarding good manufacturing practices (GMPs) for active pharmaceutical ingredients (APIs).

APIs are defined in Q7 as: "any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function o the body."

In Canada, GMP compliance is already required for facilities manufacturing, packaging, labelling, testing, importing, and/or distributing dosage form drugs and in the case of biologic (Schedule D) or radiopharmaceutical (Schedule C) drugs, GMP compliance is required for sites conducting the aforementioned activities for intermediates as well. In this proposal, GMP requirements would also be extended to facilities involved with APIs and partially processed drug products (PPDPs). The scope will include APIs and PPDPs used in the manufacture of dosage forms for human use. The inclusion of APIs and PPDPs for veterinary use is under consideration, and a final decision will be made taking into consideration the feedback of stakeholders.

The primary aim of creating a regulatory framework for GMPs for APIs and PPDPs is to ensure that activities involving APIs and PPDPs, including imported APIs and PPDPs for use in dosage form drugs, and those used in clinical trial drugs, meet good manufacturing practices expressed in Q7. A stakeholder consultation took place on May 26-27, 2004, on the elements of a regulatory framework for implementing Q7, and the feedback received at this session was essential in the creation of the following proposed regulatory framework. Since 2004, there has been on-going work on this file to tailor the requirements to the Canadian regulatory environment. We are now planning to publish draft regulations in 2010. Health Canada proposes to create a regulatory framework with five key elements as its foundation. These proposed elements are as follows:

1. Incorporating GMP requirements for APIs and PPDPs into regulation by revising Divisions 1A and 2 of the Food and Drug Regulations.
2. Creating regulatory prohibitions that appropriately manage risk related to APIs and PPDPs, as well as provide for a level playing field for domestic and foreign manufacturers.
3. The inclusion of supplemental documentation requirements to foster traceability of the API or PPDP from the original manufacturer to the dosage form manufacturer.
4. The use of establishment licensing (EL) as the site authorization mechanism.
5. A tailored scope of Q7, which takes into account the Canadian regulatory context within which Q7 will be implemented.

Description

1. Division 2 of the Food and Drug Regulations outlines the good manufacturing practices for dosage form drugs. A comparison of Q7 and Division 2, as well as a comparison of Q7 and the current Canadian GMP guidance for dosage form drugs has been completed by Health Canada. The finding was that using Division 2 as the regulatory foundation for GMPs for APIs would be appropriate as long as a number of revisions were completed. With this approach all applicable sections in Division 1A and 2 would have API-specific equivalents in regulation. Most of the revisions required in order to make Division 2 applicable to the API industry are minor.
   • High level requirements would be drafted to supplement Division 2 in particular instances where Q7 requirements are not currently supported by Division 2.
   • A GMP Guide for APIs based on Q7 will provide interpretations of requirements in the revised Division 2 of the Regulations.
2. A single regulatory prohibition would not provide an adequate foundation for appropriate management of the risk related to APIs. Thus, a multi-pronged approach is necessary in order to effectively manage risk. The proposed prohibitions are. ¹
   • No distributor or importer shall sell a dosage form drug that has not been manufactured with GMP compliant APIs (and/or PPDPs). Thus, the sale of dosage form drugs, both domestically manufactured and imported, would be prohibited unless that drug was manufactured with APIs (and/or PPDPs) from a GMP-compliant site.
   • Dosage form manufacturers must use only APIs (and/or PPDPs) that were manufactured at a GMP-compliant site in the fabrication of dosage form drugs.
   • No person shall, except with an establishment license, manufacture, package/label, distribute or import, and any other activities that fall within the scope of Q7, an API (and/or PPDP). GMP compliance would be assessed by Health Canada prior to the issuance of an EL.
   • No distributor or importer shall sell an API (and/or PPDP) intended for pharmaceutical purposes unless the API (and/or PPDP) has been manufactured in accordance with Q7. This prohibition would capture all APIs (and/or PPDPs) to be used in or as a dosage form drug while excluding APIs to be used for industrial purposes, to be used in a natural health product or any other purpose that does not fall within the scope of Q7.
3. Q7 contains API labelling requirements. However, additional documentation requirements in the regulations could better facilitate the traceability of APIs. The supplemental requirements would include additional information (such as the establishment licence number) on the product label or accompanying documentation, as well as a new requirement for a party responsible for the APIs in Canada. These new requirements would provide a link between a shipment of API product and the origin of the manufacturer. Furthermore, a party responsible for the APIs would be required in Canada, similar to the requirement for dosage form drugs under C.01.004.1 of Division 1A of the Food and Drug Regulations.
4. Compliance with drug GMP requirements for dosage form drugs is assessed by conducting inspections of those establishments pursuant to the powers provided in the Food and Drugs Act and its Regulations. These inspections and the determination of compliance with drug GMP requirements are the basis for the issuance of establishment licenses to domestic sites. Foreign sites are assessed for compliance with drug GMP requirements and may be listed on the importer's Canadian establishment license.
   
   It is proposed that this system be extended to API manufacturing sites as a key component of a regulatory framework for the implementation of Q7. Parties in Canada who are engaged in API activities who will now be required to hold an establishment licence (EL) are: fabricators, packagers/labellers, testers, importers and distributors. API fabricators, packagers/labellers and testers located outside of Canada must be listed on the EL of the Canadian importer. The specific requirements for importers of APIs to have evidence of the GMP compliance of these foreign sites will be outlined in guidelines and policies. Similar to the dosage form drug inspection program, a risk-based approach will be used for prioritizing API sites for inspection. Until such time as the inspection API program is fully implemented, domestic API sites may be inspected on a voluntary basis.
5. The regulatory framework must clearly define the scope of Q7 as it applies to the Canadian specific context. Elaboration on the scope of Q7 would be supplemented with further clarification in policy and guidance documents. Examples of product-specific policies and/or documents could include:
   • Veterinary drugs: In December 2003, the Veterinary Drugs Directorate of the Health Products and Food Branch wrote to stakeholders advising them of its intention to adopt GMPs for APIs for veterinary use.
   • Category IV monograph products: Category IV monograph products are over-the-counter products that present a different risk than other dosage form drugs. Health Canada will provide the needed flexibility that takes into account the risk presented by this category of products.
   • Natural health products: A regulatory framework for natural health products (NHPs) came into effect January 1st, 2004. This regulatory framework outlines good manufacturing practices for natural health products, which will continue to apply to NHPs. Q7 will apply to a very small number of substances that may be used in a pharmaceutical drug, while also meeting the definition of an NHP. Health Canada will create a regulatory framework that mitigates overlap between the two sets of GMPs.
   • Bulk process intermediates for biologic (Schedule D) or radiopharmaceutical (Schedule C) drugs: Bulk process intermediates (BPIs) are regulated under Division 2 of the Food and Drug Regulations, and as such have a history with respect to the application of GMPs. The status quo will continue for BPIs, which means that Division 2 will continue to apply as the GMPs for BPIs.
   • Clinical trial drug products: APIs and PPDPs for clinical trial drug products will be required to follow GMPs. However, as outlined in chapter 19 of Q7, not all the requirements of Q7 are appropriate for the manufacture of a new API for investigational use. The controls should be consistent with the stage of development of the drug product incorporating the API. Therefore, for clinical trial products which are already marketed, it would be expected that the API would be GMP compliant. However, there will be more flexibility for products in earlier stages of development. There is no plan to inspect sites conducting activities with respect to clinical trial APIs or PPDPs.

Any comments regarding these proposed amendments should be addressed to: Policy and Strategic Planning Division, HPFB Inspectorate, 250 Lanark Avenue, Address Locator 2006C, Ottawa, Ontario, K1A 0K9, or by email to Strategic Planning Division  within 45 days.

Original signed by

Diana Dowthwaite
Director General