Consultation Summary: Notice to Stakeholders - Implementation of Establishment Licensing Requirements for Atypical Active Pharmaceutical Ingredients

November 23, 2017

Health Canada is pleased to announce that the interim approach for atypical Active Pharmaceutical Ingredients (APIs) has been finalized. This document outlines the updates made to the Notice to Stakeholders - Implementation of Establishment Licensing Requirements for Atypical Active Pharmaceutical Ingredients (Notice) as a result of the December 2, 2016, public consultation.

Background

An online public consultation on the interim approach comprising the List of Atypical APIs was held between December 2, 2016 and January 15, 2017.

The objective of the consultation was to provide stakeholders the opportunity to propose specific ingredients for inclusion on, or exclusion from the List of Atypical APIs, with adequate rationale.

Further to Health Canada’s review of the feedback received, the following changes were made to Notice and the List of Atypical APIs:

1. Clarification in the scope of Notice
2. Changes to the List of Atypical APIs
3. Standardization of ingredient names

---

1. Clarification in the scope of the Notice
   • This Notice only applies to active ingredients used in human pharmaceutical drugs. Ingredients that are only used as excipients of drug products, natural health products (NHPs) or cosmetics are not covered under the API Regulatory Framework and, as such, are not covered by this interim approach.
   • The “manufacturing” activity indicated in the Notice was expanded to explicitly include “fabrication, packaging, labelling and testing”, as all these activities could be performed by the same specialized manufacturing facility.
   • It was clarified that regardless of the manufacturing standard (e.g. GMP, ISO, HACCP, etc.) of the fabricator’s facility, in cases where there is a pharmacopoeial standard (Schedule B to the Food and Drugs Act) for the atypical API, that API should be manufactured and tested against that standard.
   • Clarification to stakeholders: The expectation to meet “Raw Material Testing sections C.02.009 and C.02.010” means that fabricators of the drug in dosage form cannot rely on fabricators who do not meet drug Good Manufacturing Practices (GMP) to fulfill their testing obligations. Complete testing in a GMP-compliant facility is required prior to the use of the Atypical API in the authorized drug product.
2. Changes to the List of Atypical APIs
   • Inclusions or exclusions of ingredients were based on factors such as primary and alternate uses of the ingredient, authorised drugs using the ingredient as an active, risk associated with the final drug product and pharmacological activity.
   • Thirteen (13) ingredients out of the twenty-three (23) proposed by stakeholders were included:
     1,3-Butanediol, Caffeine, Chlorhexidine Gluconate, Choline Chloride, Lipoic Acid (Alpha Lipoic Acid), Mannitol, Propyl Alcohol (1-Propanol), Propylene Glycol, Sodium Carbonate, Sodium Citrate, Sodium Gluconate, Sorbitol and Taurine
   • The categories / ingredients below were excluded from the December 2, 2016 List.
     1. Colouring agents such as D&C Red No. 28, Fluorescein Sodium, Methylene Blue, Patent Blue Sodium and Trypan Blue were excluded for their use in sterile ophthalmic products.
     2. Alkyl Benzoate, L-Alanyl-L-Glutamine and Piroctone were excluded based on Standardization of ingredient names (Section 3.b).
     3. Salicyl Alcohol was excluded, as it is an intermediate of acetylsalicylic acid, which is not an atypical API.
     4. Iron III Hydroxide and Lactose were excluded due to their sole use as excipients.
     5. Sodium Sulfadimethoxine was excluded as currently, it is only authorised in veterinary drugs.
     6. Chlorpheniramine was excluded due to its potential to be used in combination with other high-risk drugs.
   • The majority of APIs listed in the Category IV Monographs of the Pilot Project for APIs were included based on the similarity in approach to that of Atypical APIs.
3. Standardization of ingredient names
   • CAS Registry Numbers were not added to the Atypical APIs to prevent limitations for those groups or categories that encompass more than one (1) chemical entity.
   • The most common name of each ingredient was used, followed by potential alternative names for ease of reference. Some atypical APIs were consolidated under the same common name. Some ingredients that were too specific were also removed, as they would be a salt or derivative of an existing atypical API.

Buildings fabricating, packaging, labelling and testing Atypical APIs continue to be required to appear on the Drug Establishment Licence (DEL). Further consideration will be given to APIs for use in veterinary drugs, as the GMP and DEL provisions of the amended Food and Drug Regulations (Veterinary Drugs — Antimicrobial Resistance) (published in Canada Gazette II on May 17, 2017 - SOR/2017-76) come into force. Stakeholders are encouraged to verify the List regularly as it may change and to search for alternate names of the ingredients.

Contact us:
E-mail: API_questions_IPA@hc-sc.gc.ca