Alert level: yellow OPQ: Q-225 Session: 451 Suggested file name: HC_impurities_LNPs_Sep_2025 Tabled on: Agencies: Estimated questions: 2 Estimated responses: 1 Original filename: Q-225_HC, impurities, LNPs, Sep 2025.pdf External links / references: (none detected) Extracted PDF text preview: INQUIRY OF MINISTRY DEMANDE DE RENSEIGNEMENT AU GOUVERNEMENT PREPARE IN ENGLISH AND FRENCH MARKING "ORIGINAL TEXT" OR "TRANSLATION" PRÉPARER EN ANGLAIS ET EN FRANÇAIS EN INDIQUANT "TEXTE ORIGINAL" OU "TRADUCTION" QUESTION NO./NO DE LA QUESTION Q-225 BY / DE Dean Allison (Niagara West) DATE June 18, 2025 Reply by the Minister of Health Réponse du ministre de la Santé Signed by Maggie Chi PRINT NAME OF SIGNATORY INSCRIRE LE NOM DU SIGNATAIRE SIGNATURE MINISTER OR PARLIAMENTARY SECRETARY MINISTRE OU SECRÉTAIRE PARLEMENTAIRE QUESTION With regard to Health Canada’s review of the manufacturing data, quality control and safety of lipid nanoparticles in the mRN A COVID-19 vaccines including all versions of Moderna’s SpikeVax, Pfizer-BioNTech’s Comirnaty and the boosters, and Onpattro (patisaran): (a) was the purity of the starting materials for the lipids, such as residual halogenated solvents and elements, including metals, assessed for mutagenic risk in accordance with established norms and guidelines, and, if so, what were the results, and, if not, why not; (b) was the total amount of observed impurities assessed for mutagenic risk, and, if so, what were the results, and, if not, why not; (c) were any individual element impurities considered mutagenic; (d) if the answ er to (c) is affirmative, was this assessed with respect to multiple doses and with respect to the nature of transfection of the lipid nanoparticles; (e) was any assessment of the lipid nanoparticle as a nanoparticle performed; (f) if the answer to (e) is affirmative, did this include an assessment of the polyethylene glycol moiety; (g) was an assessment of the risk of complement activation-related pseudoallergy due to the polyethylene glycol moiety performed, and, if so, what were the results, and, if not, why not; and (h) were any complement-related assays requested from the manufacturer, and, if not, why not? REPLY / RÉPONSE ORIGINAL TEXT TRANSLATION TEXTE ORIGINAL TRADUCTION Health Canada Health Canada exercises stringent regulatory oversight over all pharmaceutical and biologic drugs, including vaccines. Before a drug is authorized in Canada, Health Canada conducts a rigorous scientific review of its safety, efficacy and quality. For the quality of the mRNA COVID-19 vaccines (COMIRNATY and SPIKEVAX), impurities in lipid nanoparticles (LNPs) are assessed according to guidelines from the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use. These guidelines include: • ICH Q3C Impurities: Guideline for Residual Solvents • ICH Q3D Guideline for Elemental Impurities. Assessment of the risks associated with potential and known impurities in the mRNA vaccines was performed using common industry software that is accepted as part of the ICH M7 Guideline: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Impurities from the lipid excipients were below the limits set in the ICH Q3D and ICH Q3C guidelines. All solvents assessed were classified as non-mutagenic. Assessment of elemental impurities concluded that levels were below the Permitted Daily Exposure (PDE). The methodologies used by the manufacturer to assess mutagenic risk from solvents and elemental impurities and their conclusions were considered acceptable. X - 2 - LNPs in the mRNA vaccines were characterized and controlled using a variety of tests. The polyethylene glycol (PEG) moiety is conjugated to the lipid excipient and was assessed as part of the lipid. Residual unconjugated PEG is considered a process-related impurity in the manufacturing process of the lipid excipient and must be present below established limits. The PEG moiety itself is also classified as non-mutagenic according to ICH M7 guidelines. Each lot of drug product is tested to ensure that it conforms with approved specifications. The control strategy for the LNPs was considered acceptable. Non-clinical safety studies were performed for the novel lipid excipients. Complement-related assays were not requested from the manufacturer as there is no established assay that can be performed to assess hypersensitivity to PEG. For ONPATTRO, impurities are assessed according to guidelines from the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use. These guidelines include: • ICH Q3C Impurities: Guideline for Residual Solvents • ICH Q3D Guideline for Elemental Impurities • ICH M7 Guideline: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Impurities from the lipid excipients were below the limits set in the ICH Q3D and ICH Q3C guidelines. All solvents assessed were classified as non-mutagenic or unlikely to be present. LNPs in the drug product ONPATTRO were assessed using a pharmacologically inactive short-interfering RNA (siRNA) encapsulated in the same lipid particle as the one with the active siRNA, patisiran. The LNP comprised two novel excipients which were fully characterized with a complete toxicology evaluation. INQUIRY OF MINISTRY DEMANDE DE RENSEIGNEMENT AU GOUVERNEMENT PREPARE IN ENGLISH AND FRENCH MARKING "ORIGINAL TEXT" OR "TRANSLATION" PRÉPARER EN ANGLAIS ET EN FRANÇAIS EN INDIQUANT "TEXTE ORIGINAL" OU "TRADUCTION" QUESTION NO./NO DE LA QUESTION Q-225 BY / DE Dean Allison (Niagara-Ouest) DATE Le 18 juin 2025 Reply by the Minister of Health Réponse du ministre de la Santé Signé par Maggie Chi PRINT NAME OF SIGNATORY INSCRIRE LE NOM DU SIGNATAIRE SIGNATURE MINISTER OR PARLIAMENTARY SECRETARY MINISTRE OU SECRÉTAIRE PARLEMENTAIRE QUESTION En ce qui concerne l’examen par Santé Canada des données relatives à la fabrication, au contrôle de la qualité et à l’innocui té des nanoparticules lipidiques contenues dans les vaccins à ARNm contre la COVID -19, y compris toutes les versions du SpikeVax de Moderna, du Comirnaty de Pfizer-BioNTech et des doses de rappel, ainsi que dans l’Onpattro (patisaran) : a) a -t- on évalué la pureté des produits de départ utilisés pour les lipides, tels que les solvants et éléments halogénés résiduels, y compris les métaux, conformément aux normes et aux lignes directrices établies en vue d’en déterminer le risque mutagène et, le cas échéant, quels ont été les résultats et, si ce n’est pas le cas, pourquoi pas; b) a -t-on évalué la quantité totale d’impuretés observées en vue d’en déterminer le risque mutagène et, le cas échéant, quels ont été les résultats et, si ce n’est pas le cas, pourquoi pas; c) des impuretés élémentaires ont-elles été considérées comme étant mutagènes; d) si la réponse en c) est affirmative, l’évaluation a-t-elle tenu compte de multiples doses et de la nature de la transfection des nanoparticules lipidiques; e) une évaluation des nanoparticules lipidiques en tant que nanoparticules a -t-elle été effectuée; f) si la réponse en e) est affirmative, cette évaluation comprenait-elle une évaluation du fragment polyéthylène glycol; g) une évaluation du risque de pseudo-allergie liée à l’activation du système du complément attribuable au fragment polyéthylène glycol a -t-elle été réalisée et, le cas échéant, quels en ont été les résultats et, si ce n’est pas le cas, pourquoi pas; h) des essais liés au complément ont-ils été demandés au fabricant et, si ce n’est pas le cas, pourquoi pas? REPLY / RÉPONSE ORIGINAL TEXT TRANSLATION TEXTE ORIGINAL TRADUCTION Santé Canada Santé Canada exerce une surveillance réglementaire rigoureuse sur tous les pro