EU GMP Annex 1 and Single-Use Systems: How to Manage Extractables & Leachables Without Inspection Risks

If you manufacture sterile products and use Single-Use Systems (SUS), the topic of Extractables & Leachables (E&L) is no longer a “nice to have”.

The revision of EU GMP Annex 1 has made regulatory expectations much more explicit: risks related to single-use systems must be assessed as part of the Contamination Control Strategy (CCS), including extractables, leachables and potential interactions between the product and contact materials.

The operational point is clear: for high-risk SUS components, you must consider leachables studies, including under simulated conditions, provided they are scientifically justified.

The real challenge is not to “test everything”, but to build a risk-based, documented and audit-ready process capable of demonstrating control for each critical component.

Table of Contents

• What Annex 1 says about SUS and E&L
• Why Single-Use Systems are critical from an E&L perspective
• The 7-step operational model to manage E&L in SUS
• Where USP <665> fits
• The 10 typical inspector questions
• Conclusion
• Do you want a complete practical guide on E&L and Single-Use Systems?

1. What Annex 1 says about SUS and E&L

EU GMP Annex 1 requires risks associated with Single-Use Systems to be assessed in a structured way and integrated into the overall contamination control strategy.

Having a supplier dossier is not enough. You must demonstrate that the data are applicable to your process, your product and your actual conditions of use.

1.1 Annex 1 §8.132: which risks must be included in the CCS

Specific risks associated with Single-Use Systems that must be assessed in the Contamination Control Strategy include:

• interaction between the product and contact surfaces;
• extractables and leachables;
• adsorption of the product onto materials;
• system fragility;
• increased number of manipulations and connections;
• particulate risk;
• leakage risk;
• potential loss of system integrity.

In practice, Annex 1 asks you to look at SUS not as a simple purchased component, but as a critical part of the sterile process.

1.2 Annex 1 §8.136: the key requirement on E&L

The most important operational requirement is that you must:

• assess extractables profiles and their possible impact on product quality;
• perform an assessment for each component on the applicability of available extractables data;
• for high-risk components, consider leachables studies and safety concerns;
• if simulated conditions are used, ensure that they reflect the actual process and are supported by scientific rationale.

The practical translation is simple:

It is not enough to archive the supplier’s PDF. You must demonstrate applicability, gap assessment and a decision proportionate to risk.

2. Why Single-Use Systems are critical from an E&L perspective

Single-Use Systems concentrate many of the main E&L risk drivers.

Compared with traditional systems, SUS may present:

• very large contact surfaces, such as bags, tubing and manifolds;
• prolonged contact times during hold, mixing or intermediate storage;
• stress linked to sterilisation, gamma irradiation, freeze-thaw or transport;
• polymers, additives and multilayer materials;
• variability between suppliers, batches and component versions;
• presence of gaskets, connectors, sensors, filters and accessory parts that are often underestimated.

This is why Annex 1 places SUS under a specific lens.

The risk is not only chemical. It is also documentary, because during an inspection you must demonstrate that you have a complete view of the system and its critical points.

3. The 7-step operational model to manage E&L in SUS

A robust process must be simple to apply, but complete enough to withstand inspection scrutiny.

3.1 Step 1 — Build a contact map of the process

The first step is to build a clear map of all contact points between the product and materials.

The guiding question is:

Who touches what, for how long and under which conditions?

In the contact map, you should include, for example:

• buffer preparation bags;
• single-use bioreactors;
• tubing;
• manifolds;
• pre-sterilising and sterilising filters;
• connectors;
• valves;
• sensors;
• hold containers;
• accessory components potentially in direct or indirect contact.

The minimum output should be a table with:

• component;
• material;
• contact time;
• temperature;
• process phase;
• sterilisation method;
• criticality;
• any available data.

This is also the fastest way to avoid forgetting “minor” components that an inspector may identify during the facility tour.

3.2 Step 2 — Collect supplier data with a QA mindset

Supplier data are essential, but they must not be treated as marketing material.

You should request and assess, where available:

• material composition;
• information on additives, if available;
• extractables reports;
• analytical protocol used;
• solvents used;
• LOQ and LOD;
• list of identified compounds;
• extraction conditions;
• change notification statements;
• CoC and CoA;
• sterilisation data;
• gamma dose, if applicable;
• standard protocols, such as BPOG or equivalent approaches.

The objective is not to collect paper. It is to understand whether those data are truly usable for your process.

3.3 Step 3 — Perform an applicability gap assessment

This is often the point that determines whether the E&L package is defensible or not.

The key questions are:

• Did the supplier use solvents consistent with your matrix?
• Do the time and temperature conditions cover your worst case?
• Was the material tested post-sterilisation, for example after gamma irradiation, if you use it in that condition?
• Does the report include relevant compounds above threshold?
• Are there unknowns or compounds of potential concern?
• Do the available data cover the specific component, or only a generic material family?
• Are the simulated conditions scientifically justified?
• Are there gaps compared with your real manufacturing process?

If the gap is relevant, you have two main options:

• ask the supplier for additional information;
• perform a targeted study, often faster and more defensible than a long documentation negotiation.

3.4 Step 4 — Classify the risk of SUS components

Annex 1 leads you to think component by component.

Not all SUS have the same impact and not all require the same level of evidence.

Typical criteria that increase risk include:

• long contact with bulk or drug substance;
• additive-containing or elastomeric material;
• contact after the sterile boundary;
• contact with sterile or filtered product;
• components that may adsorb the product;
• components with a large contact surface;
• elevated temperatures;
• aggressive conditions;
• use after gamma irradiation;
• absence of representative supplier data;
• new materials or recent supplier changes.

The result should be a clear ranking: low, medium or high risk, with documented rationale.

3.5 Step 5 — Define a proportionate testing strategy

The testing strategy must derive from risk, not from habit.

Low risk

For low-risk components, the following may be sufficient:

• supplier dossier;
• gap assessment;
• documented rationale;
• change control;
• periodic supplier verification;
• confirmation that there are no critical conditions of use.

Medium risk

For medium-risk components, it may be appropriate to include:

• targeted extractables;
• analytical confirmation on compounds of concern;
• assessment of the representativeness of supplier data;
• possible comparison with real process conditions;
• involvement of QA, Validation and, if necessary, Toxicology.

High risk

For high-risk components, the expectation is more robust:

• real or simulated leachables assessment;
• scientific rationale for simulated conditions;
• safety assessment;
• toxicological evaluation;
• definition of acceptable limits or thresholds;
• lifecycle control strategy;
• enhanced monitoring and change control.

The guiding principle is simple:

The higher the risk, the stronger the evidence must be.

3.6 Step 6 — Involve Toxicology in critical cases

Without Toxicology, analytical data remain a list of peaks.

In more critical cases, you must demonstrate that someone has assessed the potential impact on the patient.

The toxicological assessment helps interpret:

• identified compounds;
• unknown peaks;
• estimated concentrations;
• patient exposure;
• duration of therapy;
• route of administration;
• acceptable limits;
• any safety concerns.

During an inspection, the question will not only be: “Did you perform the study?”, but also:

Who assessed whether these results are acceptable for the patient?

3.7 Step 7 — Integrate everything into the CCS and validation package

E&L management for SUS must not remain an isolated document.

It must be integrated into:

• Contamination Control Strategy;
• validation package;
• risk assessment;
• qualification package;
• supplier qualification;
• quality agreement;
• change control;
• lifecycle management.

The documentation package should include:

• risk-based rationale;
• contact map;
• component table;
• risk ranking;
• applicability of supplier data;
• gap assessment;
• any analytical studies;
• toxicological assessment;
• conclusions;
• control strategy;
• change management mechanism.

This is the level of integration that makes the process truly audit-ready.

4. Where USP <665> fits

USP <665> fits into the broader framework of expectations for polymeric materials used in manufacturing systems and components.

Without going into excessive technical detail, the operational message for QA and Validation is clear:

• expectations for polymers used in manufacturing are becoming more structured;
• component inventory, gap assessment and risk ranking will become increasingly important;
• supplier data must be critically assessed, not merely archived;
• E&L management must be integrated into the process lifecycle;
• a system already aligned with Annex 1 puts you in a stronger position.

If you have already properly implemented the logic of Annex 1 §8.136, you are already halfway there.

4.1 What is worth preparing now

To prepare effectively, it is useful to have:

• SUS component inventory;
• updated contact map;
• organised supplier data;
• documented gap assessments;
• component risk ranking;
• decision criteria for testing or no-testing;
• formalised change notification;
• link with CCS and validation package.

This way, the system does not depend on improvised answers during an inspection.

5. The 10 typical inspector questions

A good way to verify the robustness of your process is to simulate inspector questions.

5.1 “Show me how you assessed SUS E&L in the CCS.”

You must have a clear section in the Contamination Control Strategy or a linked document, with rationale, assessed components, ranking and conclusions.

5.2 “Why do you consider the supplier’s extractables data applicable to this process?”

Here you need the gap assessment.

You must demonstrate that solvents, times, temperatures, sterilisation, materials and conditions of use are consistent with your worst case.

5.3 “Which components did you classify as high risk and why?”

You must be able to show a component-by-component table, with objective criteria and documented rationale.

5.4 “Did you consider simulated conditions? Are they representative?”

If you use simulated conditions, you must explain why they represent the real process or a scientifically justified worst case.

5.5 “Who performed the toxicological assessment?”

For critical cases, you must be able to demonstrate the involvement of adequate toxicological expertise.

5.6 “How do you manage changes in formulation or SUS material?”

A clear link with change control, supplier notification and quality agreement is required.

5.7 “Do the data include post-gamma components?”

If you use gamma-sterilised components, you must verify that the data are representative of that condition as well.

5.8 “What incoming controls do you perform?”

Expect questions on:

• CoC;
• CoA;
• packaging integrity;
• sterility;
• transport conditions;
• batch identification;
• match with the qualified component.

5.9 “Have you had historical events potentially linked to leachables?”

You must be able to assess possible links with:

• OOS;
• complaints;
• deviations;
• particulates;
• abnormal trends;
• product quality signals.

5.10 “How do you ensure lifecycle management?”

You must show how you keep control alive over time through:

• periodic reviews;
• change control;
• supplier qualification;
• risk assessment update;
• trends;
• CCS revision.

6. Conclusion

Annex 1 is not simply asking for “more testing”.

It is asking for more control — demonstrable and component-based.

If you set up a 7-step process, you avoid two opposite mistakes:

• panic-driven blanket testing;
• documentation gaps that lead to findings during inspection.

E&L management of Single-Use Systems must be risk-based, scientifically justified and integrated into the Contamination Control Strategy.

This is what makes the system defensible.

7. Do you want a complete practical guide on E&L and Single-Use Systems?

Do you want ready-to-use examples, matrices, CCS checklists, supplier gap assessment templates and an audit-ready narrative on Annex 1 §8.136?

Download the GuideGxP premium guide:

Extractables & Leachables (E&L) – Practical Guide to Risk-Based Compliance