Extractables and Leachables Testing for Supplement Packaging: What Your COA Isn't Telling You

A supplement brand came to us last year with what seemed like a routine request. They’d passed every test — heavy metals, microbials, potency, identity verification — and needed documentation for a new retail partnership. We ran a broad-spectrum chemical screen on their finished product as part of the package. It turned up traces of di-(2-ethylhexyl) phthalate at 1.8 µg/serving. Not in the formulation. Not in the raw materials. In the packaging.

The culprit was a flexible foil-lined stick pack from a supplier they’d used for two years. Nobody had ever tested the packaging for chemical migration. Nobody had thought to ask.

That’s the extractables and leachables problem in a sentence. Brands spend real money on formula testing and almost nothing on the containers holding those formulas. And those containers are doing something — slowly, quietly — across every month your product spends in a warehouse or on a shelf.

What “Extractables” and “Leachables” Actually Mean

The terms sound interchangeable. They’re not, and conflating them leads to poorly scoped — and therefore misleading — testing programs.

Extractables are the compounds that can be released from a packaging material under aggressive conditions: high temperatures, organic solvents, extended contact times. Think of it as a chemical inventory. An extractables study is deliberately worst-case. You’re stress-testing the material to map its complete chemical profile, not mimicking what happens on a store shelf.

Leachables are the subset that actually migrate into your product under real-world conditions — the temperatures, contact times, and product matrices your customers encounter. A leachables study analyzes the finished product itself, typically after accelerated stability storage, to confirm which compounds have actually crossed from packaging into formulation.

The extractables profile informs the leachables study. You can’t run a meaningful targeted leachables analysis if you don’t know what to look for. That two-phase sequence — broad extraction first, targeted product analysis second — is exactly how ICH Q3E, finalized by the International Council for Harmonisation in 2023, structures the work for pharmaceutical packaging and delivery systems. Supplement manufacturers would do well to borrow that logic.

The Regulatory Framework: Gaps and Growing Expectations

Here’s where supplement brands routinely get caught off guard. The regulatory requirements for E&L testing in dietary supplements are principle-based, not prescriptive.

FDA’s 21 CFR Part 111 — the cGMP rule governing dietary supplement manufacturing — requires that manufacturers establish written specifications for packaging materials and verify that containers don’t “react with, add to, or absorb the dietary ingredient or dietary supplement in a manner that adulterates the dietary supplement.” That’s the regulatory mandate. How you demonstrate compliance is entirely left to you.

There’s no FDA guidance document telling supplement brands to run GC-MS/MS with a specific analytical threshold. Those details come from the pharmaceutical framework: ICH Q3E sets a 1.5 µg/day Analytical Evaluation Threshold (AET) for oral dosage forms, meaning any leachable detected above that level requires formal toxicological qualification. Below the threshold, you document and move on. For most supplement packaging combinations, the vast majority of detected compounds fall comfortably below that line.

But the regulatory baseline isn’t the only pressure. Amazon’s compliance requirements have expanded steadily and now include third-party chemical testing for certain product categories. Sophisticated retailers are increasingly requesting packaging safety data alongside formulation test results. And brands pursuing EU market access under Regulation (EC) No 178/2002 on general food safety face a regulatory environment that treats packaging migration as a first-order safety question, not an afterthought.

The brands building E&L documentation now are ahead of where compliance expectations are almost certainly heading. The ones who aren’t may find out the hard way — through a retailer quality sweep or a third-party screen they didn’t run themselves first.

Which Packaging Types Carry the Most Risk

Not all packaging formats are equal. The migration risk profile varies in ways that aren’t always intuitive.

Flexible foil-lined pouches and stick packs are among the higher-risk formats, primarily because of the printing inks on the outer laminate layers. Photoinitiators — compounds used to cure UV-printed inks — are semi-volatile and can migrate through laminate structures into the package interior. Benzophenone and 4-methylbenzophenone are the most commonly detected. EFSA has established a combined Tolerable Daily Intake of 0.03 mg/kg body weight/day, which works out to roughly 1.8 mg/day for a 60 kg adult. Depending on serving size and pouch surface-area-to-volume ratio, some products in printed flexible packaging approach that figure. EU Regulation 10/2011 on plastic materials in food contact — which many US-focused brands are unaware of — sets specific migration limits that are frequently more restrictive than anything FDA has articulated for supplement packaging. If you sell into European markets, both frameworks apply.

Softgel capsules present a specific challenge because the gelatin or HPMC shell stays in intimate contact with the fill oil for the entire shelf life. Lipophilic compounds partition preferentially into oil-based matrices. A plasticizer migrating at 0.3 µg/g into a solid tablet behaves very differently from the same compound at 0.3 µg/g into a fish oil fill — the oil matrix effectively concentrates the migrant’s delivered dose per serving. For oil-based softgels (fish oil, vitamin D in oil, CoQ10), packaging contact chemistry deserves considerably more scrutiny than it typically gets.

HDPE bottles, by far the most common supplement container, generally have a favorable safety profile. The main extractables of note are antioxidant stabilizers added during polymer manufacturing: Irganox 1010, Irgafos 168, and related phenolic compounds. These appear in nearly every HDPE extractables study we run. At typical migration levels they don’t approach any threshold of concern — but they need to be characterized so your risk assessment isn’t built on an unexamined data gap.

Rubber stoppers and silicone gaskets in dropper-cap bottles are frequently overlooked. Vulcanization residues, processing oils, and sulfur compounds are known leachables from elastomeric materials. For liquid dietary supplements — tinctures, oil-based drops, liquid vitamins — the gasket represents a high-surface-area contact point that belongs in any E&L assessment. We’ve seen it be the primary source in a handful of cases where the bottle itself was clean.

How a Scoped E&L Study Actually Runs

A practical E&L program for a dietary supplement product follows a consistent sequence.

The extractables phase involves aggressive extraction of the packaging components themselves — not the finished product. We typically run three extraction solvent conditions: reflux in n-hexane (targets non-polar, lipophilic compounds like plasticizers and process oils), reflux in ethanol (mid-polarity, catches a broad organic spectrum), and a simulated oral medium such as dilute acetic acid or pH 7.4 phosphate buffer for aqueous or semi-aqueous products. Extraction runs 24 to 72 hours at elevated temperature. The resulting extracts go through:

• GC-MS/MS for volatile and semi-volatile organics (photoinitiators, antioxidants, residual solvents)
• LC-QTOF (liquid chromatography with quadrupole time-of-flight) for non-volatile compounds — polymer stabilizers, UV absorbers, slip agents
• ICP-MS for trace elemental leachables, including antimony from PET catalyst residues, tin from coated metal packaging, and barium from rubber additives

The output is a compounds list with semi-quantitative concentration estimates above the AET — the chemical universe your packaging is capable of releasing.

The leachables phase then shifts to the finished product. Samples are stored under accelerated stability conditions — typically 40°C and 75% relative humidity for 3 to 6 months, per ICH Q1A(R2) stability protocols — and analyzed using a targeted method built from the extractables inventory. Any compound identified above the 1.5 µg/day AET gets toxicological characterization: comparison to established ADI or TDI values, or if those don’t exist, a structure-activity relationship review under the Threshold of Toxicological Concern framework.

In practice, the extractables work takes 3 to 4 weeks of laboratory time. The leachables confirmation follows the accelerated storage period. For most dietary supplement brands in standard HDPE packaging, the program confirms what they hoped was true — and now they have data proving it.

When a Compound Flags: What Comes Next

Finding something above the AET doesn’t mean your product is unsafe. It means characterization is required, and that’s a different thing.

For the majority of flagged leachables, you’re looking at a polymer stabilizer or processing aid with a decades-long safety history and a no-effect level that sits well above the detected concentration. A straightforward comparison to available ADI or TDI values closes the finding: document the margin of safety, note the toxicological basis, move on.

Where things get more involved is when a compound has limited toxicological precedent, or when migration concentrations are unexpectedly elevated — which occasionally happens with packaging from new or unqualified suppliers. In those cases, the practical options are working with the supplier to reformulate the affected material (switching antioxidant packages is a common fix), requalifying an alternative container, or adjusting fill quantities to alter the product-to-headspace ratio and reduce migration.

What you don’t want is to encounter packaging-migration data for the first time in a consumer complaint, a retailer compliance sweep, or a product liability context where the absence of prior testing is itself a problem. Regulatory defensibility is built from documentation, and documentation has to exist before the question gets asked.

A reasonable starting point: identify your three highest-risk packaging-product combinations — typically a liquid product, your highest-volume oil-based softgel, and anything in printed flexible packaging. Run extractables on those materials first. Build the watch-list. Then design a targeted leachables program around what you find. That sequence gives you a proportionate, defensible program without overspending on testing that doesn’t match your actual risk profile.

Your COA tells you a lot about what’s in your formula. It tells you almost nothing about what your formula is sitting inside. Those are two different questions — and right now, most brands are only asking one of them.

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Written by Nour Abochama, Vice President of Operations, Qalitex Laboratories. Learn more about our team

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Related from our network

• FDA Regulatory Strategy for Supplement and Nutraceutical Packaging Compliance — Aurora TIC provides FDA consulting services including container-closure system guidance and labeling compliance for dietary supplement manufacturers
• Raw Material and Packaging Component Testing for Supplier Qualification — Ayah Labs offers contract testing for raw materials and packaging components, including extractables screening to verify supplier COAs before production begins