Extractables and Leachables Testing for Canadian Drug Submissions: What Health Canada Reviewers Actually Expect

Container closure system failures don’t announce themselves at batch release. They show up six, twelve, sometimes twenty-four months into shelf-life stability studies — as unknown peaks on an HPLC chromatogram, or as a Level 2 deficiency notice from Health Canada asking why the leachables qualification package is incomplete. By that point, you’ve already committed your formulation, your packaging, and your timeline.

E&L testing — extractables and leachables — is one of those areas where the gap between what sponsors think they need and what Health Canada reviewers actually expect has widened considerably since ICH Q3E was finalized at Step 4 in December 2023. If your submission strategy was built on pre-Q3E assumptions, some of those assumptions may not hold up.

Why E&L Data Is a Bigger Submission Risk Than Most Sponsors Realize

The core issue is conceptual confusion. Extractables are chemical compounds released from packaging materials under exaggerated laboratory conditions — high-temperature organic solvents, extended contact times — designed to force migration. Leachables are the subset of those compounds that actually migrate into your drug product under real storage conditions. They’re related, but they’re not the same, and Health Canada reviewers assess them very differently.

A sponsor who submits extractables data from their polymer supplier’s drug master file (DMF) and calls the E&L package complete has made an error that’s surprisingly common. The DMF tells Health Canada what could potentially migrate out of the material under extreme conditions. What reviewers need to see is how your specific formulation — with its pH, excipient profile, and solvent characteristics — interacts with that material over your proposed shelf life. Those are two different questions, and only one of them gets answered by a supplier DMF.

Under Canada’s Food and Drug Regulations and Health Canada’s quality guidance for new drug submissions (NDS) and abbreviated new drug submissions (ANDS), the sponsor bears the responsibility for demonstrating that the container closure system doesn’t adversely affect product safety, quality, or efficacy. Referencing a DMF is part of the story. It’s not the whole story.

Health Canada’s E&L Framework After ICH Q3E

Canada became a regulatory member of the International Council for Harmonisation (ICH) in 2018, and Health Canada has been implementing ICH guidelines progressively since. ICH Q3E — “Guideline for Extractables and Leachables for Oral and Inhalation Drug Products” — was finalized in December 2023 and represents the most significant restructuring of E&L expectations in nearly two decades.

The guideline formalizes the concept of an Analytical Evaluation Threshold (AET): the concentration below which a leachable compound doesn’t need to be identified and formally reported in stability samples. The AET is calculated working backward from the Safety Concern Threshold (SCT) for that route of administration — adjusted for the analytical recovery of your method and the daily dose. For inhalation products, the genotoxin SCT sits at 1.5 μg/day, reflecting the direct pulmonary exposure pathway. Oral solid dose products are treated less stringently, but the calculation logic is the same.

What this means practically: you need to establish your AET calculation before your leachables monitoring program is designed. The method sensitivity required depends on your dose, your dosing frequency, and your route. A sponsor filing an NDS for an inhalation product may need analytical methods capable of detecting and identifying compounds at sub-ppm concentrations in the dosage unit — which has real implications for the labs you engage and the analytical platforms they run.

The other significant shift ICH Q3E introduces is an explicit risk-based tiering framework. Not all container closure components carry the same risk. An HDPE bottle cap behaves very differently from a rubber closure on a parenteral vial or a valve stem on a pressurized metered-dose inhaler. ICH Q3E asks sponsors to document that risk-ranking rationale and design testing intensity accordingly. Health Canada reviewers — trained on the same ICH guidance — will look for that logic in your CTD Module 3 quality sections.

Designing Your Extraction Studies the Way Health Canada Will Review Them

Extraction study design is where technical execution either earns or loses reviewer confidence.

Worst-case solvent selection matters enormously. A common mistake is running extraction studies only in solvents that resemble the drug product formulation. The point of extraction studies is to force migration — to create an inventory of what’s in the material so you know what you might eventually see in your product. That means using solvents across a polarity range: water, dilute acid, dilute base, and a polar organic solvent (typically ethanol or isopropanol at concentrations up to 50%). Elevated temperatures — often 40°C or higher, for 24 to 72 hours — simulate accelerated worst-case conditions. If the approach sounds aggressive, it’s supposed to be.

The extraction study generates your compound inventory. Every compound identified at or above the AET becomes a candidate for monitoring in your leachables program. The link between these two datasets is precisely what Health Canada reviewers want to see clearly documented. If a compound appears in your extraction study but not in your leachables data after 12 months of accelerated stability, that’s acceptable — but you need a scientific rationale. Maybe it’s a high-molecular-weight polymer fragment that doesn’t migrate under actual conditions, or a compound incompatible with your formulation’s pH. Either way, the explanation belongs in the submission, not in an internal file.

For Canada GMP purposes — guided by Health Canada’s GUI-0001 — the lab performing these studies needs to operate under appropriate quality standards. ISO 17025 accreditation for the relevant test methods gives Health Canada confidence in data integrity. If you’re engaging a contract lab, their accreditation scope should cover the specific methods being applied: GC-MS for volatile organic compounds, LC-MS/MS for non-volatiles, ICP-MS for elemental impurities. Accreditation to a platform in general is not the same as accreditation for the specific method being run.

Building the Leachables Section of Your CTD Module 3

By the time you’re ready to file, your leachables data package for a Canadian NDS or ANDS should demonstrate three things to a reviewer scanning Module 3.2.P.7.

First: that you’ve identified the relevant components of the container closure system and applied a documented risk-ranking to determine which require extraction studies and to what depth.

Second: that your leachables monitoring plan — built into your stability protocol — uses analytical methods sensitive enough to detect compounds at the AET specific to your product’s route and dose.

Third: that any compounds detected at or above the AET in stability samples have been toxicologically evaluated, either through published data, structure-activity relationship (SAR) analysis, or formal qualification studies. For genotoxic leachables, the bar is stricter: carcinogenic risk must be assessed against the 1.5 μg/day Threshold of Toxicological Concern.

One area where Health Canada submissions face increasing scrutiny is nitrosamine leachables. Following the global regulatory focus on nitrosamine impurities in finished drug products — which began in earnest with sartan and ranitidine recalls starting in 2018 — Health Canada issued updated guidance requiring sponsors to conduct root-cause analyses for nitrosamine risk, including secondary formation pathways from packaging components containing amine-based antioxidants. If your extractables inventory includes compounds such as hindered phenol antioxidants commonly used in polymer stabilization, a nitrosamine risk assessment is not optional. This is one of those areas where Health Canada GMP expectations and submission chemistry requirements converge — and where being caught underprepared is expensive.

Getting This Right Before You File

The single most expensive mistake in E&L management is treating it as a late-stage quality deliverable. Sponsors who select packaging at Phase I without extractables screening frequently discover incompatibilities during Phase III stability — at which point changing the container closure system means repeating stability studies, potentially triggering manufacturing site changes, and in some cases restarting portions of the development program entirely.

The practical recommendation: initiate a preliminary extractables screen on candidate packaging systems no later than the lead-in to Phase II clinical manufacturing. It doesn’t need to be the full ICH Q3E package at that stage. But knowing your compound inventory early means your formulation team can flag incompatibilities, your clinical team can design leachables monitoring into the study protocol, and your regulatory affairs team isn’t rebuilding a data package under submission timeline pressure.

Health Canada’s standard NDS review timeline is 12 months. Deficiency notices — which stop the clock while you prepare a response — typically require 3 to 6 months to address when E&L remediation is involved. A complete, well-structured container closure package at the time of filing isn’t just a compliance requirement. It’s a meaningful timeline and cost lever.

Our team regularly supports Canadian drug development programs with E&L study design, contract lab coordination, and CTD Module 3 documentation. Sponsors entering the Health Canada NDS process for the first time often don’t realize how much specificity reviewers expect in this section — or how much runway a thorough E&L package actually requires. Start early, design to ICH Q3E, and make sure the analytical lab you’re working with has the accreditation scope to support a Health Canada dossier.

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Written by Nour Abochama, Quality & Regulatory Advisor, Androxa. Learn more about our team

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Related from our network

• ISO 17025 Accreditation for Pharmaceutical Testing in the US — How US-based ISO 17025-accredited contract labs support extractables and leachables analytical programs for drug development sponsors
• EU Cosmetic and Chemical Safety Documentation Under REACH — European regulatory expectations for container material safety and chemical migration assessments under EU 1223/2009 and REACH