Extractables and Leachables Testing for Pharmaceutical Packaging: What Canada GMP Requirements Actually Demand

Most drug manufacturers entering Canada spend months building out their formulation packages, stability data, and bioequivalence dossiers. Container closure system documentation tends to get assembled in the final weeks — sometimes using nothing more than a material declaration or compatibility certificate from the packaging vendor. That approach is routinely insufficient. Health Canada reviewers flag incomplete extractables and leachables (E&L) assessments as a consistent source of quality-related questions on new drug submissions, and a single round of clarification on packaging chemistry can add four to six months to your review timeline.

The E&L framework isn’t new. What has changed is that the global analytical guidance — ICH Q3D, the revised USP <1663> and <1664> chapters, and PQRI’s leachables threshold recommendations — has matured enough that Health Canada reviewers now arrive at submissions with defined expectations. Arriving with a supplier’s safety data sheet and a statement that the packaging is “food-contact approved” will generate a question letter.

Container Closure Systems Under C.02.018 and Canada GMP

Section C.02.018 of Canada’s Food and Drug Regulations requires that drug products be packaged in containers that do not adversely affect the quality, purity, or potency of the drug. The language is deliberately broad. In practice, it means sponsors must demonstrate through analytical evidence that no harmful substance migrates from the packaging into the drug product at any point during the approved shelf life.

Health Canada’s Good Manufacturing Practices Guidelines (GUI-0001, 2022 edition) reinforce this at the operational level. GUI-0001 requires that packaging materials meet defined specifications and that suppliers be qualified — not simply trusted. For primary packaging materials in direct contact with the drug product, that qualification should include E&L characterization data. A certificate of compliance from the component manufacturer is a starting point, not a conclusion.

GUI-0001 is relatively high-level on analytical expectations. The detail comes from the ICH guidelines and USP chapters Health Canada references in its NDS and ANDS submission guidance. If you’re preparing a filing for a parenteral, ophthalmic, or inhalation product, Health Canada expects the container closure section of Module 3 to reflect the same rigour you’d apply to a U.S. FDA NDA — because the underlying framework is functionally identical. We see sponsors routinely underestimate this alignment, assuming Canada will accept a lighter package simply because the market is smaller.

The ICH and USP Framework Driving Health Canada’s E&L Expectations

Two ICH guidelines govern the impurity thresholds most directly relevant to E&L from packaging systems:

ICH Q3C classifies residual solvents by toxicological risk. Class 1 solvents — benzene, carbon tetrachloride, and a handful of others — should be absent from packaging materials; they’re confirmed or suspected human carcinogens. Class 2 solvents carry established permitted daily exposures (PDEs). Methylene chloride, for instance, has an oral PDE of 6 mg/day. When organic extractables from plastic or rubber components include residual processing solvents, Q3C thresholds apply directly to the leachables safety evaluation.

ICH Q3D is the more operationally significant guideline for most packaging E&L programs. It establishes PDEs for 24 elemental impurities across four routes of administration. Mercury is the clearest example of why route matters: its PDE for oral drug products is 30 µg/day, but for parenteral products that tightens to 3 µg/day — a 10-fold reduction reflecting the complete absence of a GI absorption barrier. Inhalation tightens it further, to 1 µg/day. Cadmium follows a similar pattern: 2 µg/day for oral, dropping to 0.2 µg/day for inhaled products.

Metal-based pigments, rubber vulcanization accelerators, and processing stabilizers are all potential sources of elemental leachables in pharmaceutical packaging. Q3D’s route-specific PDEs are what your acceptance criteria must be anchored to — not a generic “heavy metals” pass/fail test.

On the analytical methods side, USP <1663> (Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems) and USP <1664> (Assessment of Drug Product Leachables) provide the methodological framework Health Canada expects sponsors to follow. USP <1663> outlines a tiered screening approach using volatile analysis (headspace GC-MS), semi-volatile analysis (GC-MS), and non-volatile analysis (LC-UV/MS) to build a comprehensive extractables profile under exaggerated laboratory conditions. USP <1664> bridges from that extractables profile to the drug product matrix, covering how to set the analytical evaluation threshold (AET) — the minimum detectable concentration required to ensure no safety-relevant leachable is missed.

For orally inhaled and nasal drug products, the PQRI working group has established a safety concern threshold (SCT) of 0.15 µg/day. That number demands LC-MS/MS detection capability. Standard HPLC-UV won’t get you there.

Risk Stratification: Matching Testing Intensity to Product Risk

Not every packaging system requires the same E&L testing battery, and Health Canada doesn’t expect otherwise. A risk-based approach is expected — but “risk-based” means documented, justified, and proportionate. It doesn’t mean abbreviated.

Parenteral products sit at the top of the risk hierarchy. A compound dissolved in an injectable solution bypasses every absorption barrier and enters systemic circulation directly. For a lyophilised parenteral in a Type I borosilicate glass vial with a bromobutyl rubber stopper, the extractables program needs to characterise both the glass (silica oligomers, boron species, trace metals from the melting process) and the rubber closure (zinc from vulcanisation accelerators, antioxidants, sulfur-containing species, plasticisers). ICP-MS is the standard tool for elemental work at parenteral thresholds; GC-MS and LC-MS/MS cover the organic fraction.

Inhalation and ophthalmic products carry comparable risk priorities. The lung’s surface area makes deposition of leachable compounds highly efficient, and there is essentially no first-pass metabolism to reduce systemic exposure. The 0.15 µg/day SCT for inhalation products means your screening methods must detect and identify compounds at concentrations that sit well below what HPLC-UV can reliably quantify. We’ve seen sponsors request Health Canada review exemptions for inhalation product E&L data on the basis that the packaging is “well-established” — the exemption is rarely granted without robust literature support.

Oral solid dosage forms are lower risk but not exempt. An HDPE bottle with an induction-sealed liner is relatively straightforward to characterise. What catches manufacturers off guard is blister packaging: PVC films, aluminium foil laminates, and the adhesives between layers each contribute independently to the leachables burden. Plasticisers like di(2-ethylhexyl) phthalate (DEHP) and related phthalate esters can migrate through PVC at elevated storage temperatures, and elevated temperature stability studies will accelerate that migration.

Topical and semi-solid formulations are stratified by the application site. Products applied to intact skin carry lower risk than those applied to compromised skin, mucous membranes, or wound beds — for the latter, the exposure scenario more closely resembles a mucosal route and the acceptance criteria should reflect that.

What a Credible E&L Package Looks Like in a Canadian NDS or ANDS

A well-prepared container closure E&L section in Module 3 of a Canadian NDS or ANDS has four components. Skipping or abbreviating any of them tends to be visible to reviewers immediately.

1. Material qualification and system description. Identify every primary packaging component by material of construction, supplier, resin grade, and processing additives. For rubber closures and plastic containers, document USP <661> compliance status and provide the full formulation summary where available from the component manufacturer. This section defines the scope of the extractables study — if the materials description is incomplete, the study design looks arbitrary.

2. Extractables characterisation study. The study should use multiple extraction solvents — at minimum a non-polar simulant (hexane or heptane), a polar organic simulant (isopropanol or 50% ethanol), and an aqueous simulant (water, or dilute acid and base to simulate pH extremes) — under exaggerated conditions of temperature, contact time, and solvent-to-surface-area ratio. GC-MS and LC-MS/MS should be run in parallel, not sequentially. Every compound identified at or above the reporting threshold needs a confirmed structure and a CAS number, not just a tentative spectral library match.

3. Leachables study in the drug product matrix. Design the study using your proposed commercial storage conditions, container orientation, and approved shelf life. Where real-time stability data aren’t yet complete at the time of submission, accelerated-condition leachables data can support the initial safety qualification, with a commitment to provide real-time confirmatory data as a post-approval stability update. Health Canada accepts this approach, but the commitment needs to be explicitly stated in the submission.

4. Compound-specific safety qualification. Each leachable identified above the AET needs an individualised safety evaluation. For elemental leachables, compare observed daily exposures against ICH Q3D PDEs adjusted for the product’s maximum daily dose. For organic leachables, apply Cramer class-based threshold of toxicological concern (TTC) analysis, or provide a literature-supported toxicological assessment where TTC isn’t applicable (genotoxic alerts, reactive functional groups). Health Canada reviewers have processed enough submissions to recognise when safety qualifications are copy-pasted across compounds without differentiation — it’s a common indicator that the rest of the package deserves closer scrutiny.

The practical reality is that a thorough E&L program for a parenteral or inhalation product — from packaging component selection through confirmed final analytical reports — takes 12 to 18 months in most cases. Extractables studies alone typically require 90 to 120 days for a full solvent battery at exaggerated conditions, followed by structure confirmation work that can take another six to eight weeks for complex samples. Starting this work at the point of formulation finalisation, not as a pre-submission activity, is the only realistic path to having complete data when you file.

If your Health Canada NDS or ANDS target date sits within the next 18 months, your container closure E&L program should already be running. Not scoped. Not planned. Running.

---

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

Talk to our team about Health Canada compliance Contact us

Related from our network

• USP compendial and container closure integrity testing for pharmaceutical packaging — ISO 17025-accredited analytical services supporting E&L characterisation, USP <661> compliance, and container closure integrity testing for FDA submissions.
• Packaging compliance and restricted substance testing for the EU market — REACH compliance and restricted substance analysis for cosmetic and pharmaceutical packaging materials entering the European market.