On December 22, 2022, Health Canada opened consultation on a proposal to amend the Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs). The amendments that have been proposed were to section C.01.011 of the Food and Drug Regulations as well as to introduce new guidance around nitrosamines.

What are the Proposed Amendments?

For your convenience, we have outlined the proposed amendments to the regulations.

S.3.1 Elucidation of Structure and other Characteristics

• From: Confirmation of structure based on the synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.
• To: Confirmation of the molecular structure of the drug substance, based on spectroscopic and other relevant techniques, should be provided. Data should be provided that addresses potential isomerism, including absolute and relative stereochemistry, where applicable. When elucidating the internal structure of the drug substance (such as amorphous or alternative crystalline forms), characterization should use appropriate techniques (such as single crystal and powder x-ray diffraction). Samples that are representative of the proposed manufacturing process should be used.

S.3.2 Impurities – Identification of Potential and Actual Impurities

• From: Potential impurities should be examined for structural alert(s). Assessment and control of any potentially mutagenic impurities should be performed as per ICH M7 when appropriate.”
• To: Potential impurities should be examined for structural alert(s). Assessment and control of any potentially mutagenic impurities, including the potential formation or introduction of high-potency mutagenic carcinogens identified in the ICH M7 guideline as the cohort of concern (comprising aflatoxin-like, N-nitroso and alkyl-azoxy compounds) should be performed as per ICH M7 when appropriate.
• Added Reference: Nitrosamine impurities in medications: Guidance

S.4.1 Specification – Specifications

• From: If a Schedule B compendial monograph is applicable to the drug substance, a sponsor can choose to declare a Manufacturer’s Standard on the labelling (which indicates that the material may differ in some respect from the compendial standard). However, according to section C.01.011 (4) of the Food and Drug Regulations, no person shall use a manufacturer’s standard for a drug that provides (a) a lesser degree of purity than the highest degree of purity and (b) a greater variance in potency than the least variation in potency, provided for that drug in any publication mentioned in Schedule B to the Act. Therefore, if a manufacturer’s standard is used where there is a compendial standard, the controls on purity (e.g. limits on specified identified impurities and total impurities) and potency (i.e. assay) should be at least as stringent as the most stringent of those limits listed in any of the applicable Schedule B compendial monographs. If a solvated form of the drug substance is used other than that declared in a compendial monograph, the compendial monograph should be considered when setting specifications, but not all requirements would necessarily apply to the drug substance.
• To: If a Schedule B compendial monograph is applicable to the drug substance, a sponsor can choose to declare a Manufacturer’s Standard on the labelling (which indicates that the material may differ in some respect from the compendial standard).
• Added: The drug substance specification should include routine testing for nitrosamine impurities when the risk for presence is high or the concentration of any nitrosamine is at significant levels (for example, greater than 30% of the acceptable intake limit).
• Added Reference: Nitrosamine impurities in medications: Guidance

P.2 Pharmaceutical Development – Dosage and Administration – Directions for Use

• Added: A summary and discussion should be provided of the following:
  • the measures taken during development to mitigate the presence of high-potency mutagenic carcinogens identified in the ICH M7 guideline as the cohort of concern (comprising aflatoxin-like, N-nitroso and alkyl-azoxy compounds) in the drug product and its components
  • a risk assessment for the potential presence of nitrosamine impurities in the drug product
    • provided in sections 2.3 and 3.2.P.2 of the drug application
  • Relevant analytical data, procedures and proposed controls should be provided in relevant sections of the drug application (e.g. 3.2.S.2, 3.2.S.4, 3.2.S.7, 3.2.P.3, 3.2.P.4, 3.2.P.5, 3.2.P.7, 3.2.P.8)
• Added Reference: Nitrosamine impurities in medications: Guidance

P.5.1 Control of Drug Product: Specification(s)

• From: If a Schedule B compendial monograph is applicable to the drug product, a sponsor can choose to declare a Manufacturer’s Standard on the labelling which indicates that the material may differ in some respect from the compendial standard. However, according to section C.01.011 of the Food and Drug Regulations, no person shall use a manufacturer’s standard for a drug that provides (a) a lesser degree of purity than the highest degree of purity and (b) a greater variance in potency than the least variation in potency, provided for that drug in any publication mentioned in Schedule B to the Act. Therefore, if a manufacturer’s standard is used, the controls on purity (e.g. limits on specified degradation products and total degradation products) and potency should be as tight as the most stringent of those listed in the applicable Schedule B compendial monographs.
• To: If a Schedule B compendial monograph is applicable to the drug product, a sponsor can choose to declare a Manufacturer’s Standard on the labelling which indicates that the material may differ in some respect from the compendial standard. However, the specifications must be acceptable to the Minister.
• Added: Routine testing for nitrosamine impurities should be included in the drug product specification when:
  • the potential for nitrosamine introduction during drug product manufacturing, packaging and storage is identified or
  • a nitrosamine impurity is detected in the drug product during confirmatory testing and the root cause of its presence is unknown
  • Where such a risk is identified, a test and acceptance criteria for both release and shelf-life specifications should be included in the drug application.

• Added Reference: Nitrosamine impurities in medications: Guidance

Who Can Participate?

Anyone. This consultation is open to academics, consumer and patient safety organizations, drug and medical device industry, health system partners, and the general public.

How to Participate?

Submission of comments can be done by downloading this fillable PDF form and sending it to hpfb.engagement-mobilisation.dgpsa@hc-sc.gc.ca

For your convenience, you can access the original version of the guidance document here.

Consultation is closing on March 27, 2023

If you have any questions or concerns about this consultation and how it can impact you or your business, please contact us.