In December 2025, ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) officially released the Q3E guideline — Extractables and Leachables: Risk Assessment and Control for Pharmaceutical Products.
This document, years in the making from draft to final release, means the global pharmaceutical industry finally has a unified, actionable framework for E&L (Extractables and Leachables) risk assessment. Prior to this, a core challenge facing pharmaceutical companies in their global expansion was the inconsistent requirements from different regulatory agencies. Companies often needed to meet multiple system requirements from FDA, EMA, PMDA, NMPA, and others for the same set of materials, resulting in duplicate investments and significant resource drain.
The release of ICH Q3E is fundamentally changing this landscape.
ICH Q3E’s Harmonization Logic: From Fragmentation to a Unified Framework
Prior to the official release of ICH Q3E, the global regulatory environment for E&L risk assessment exhibited clear fragmentation. FDA proposed a scientific framework for extractables and leachables assessment in USP 〈1663〉 and 〈1664〉, but relied on individual company judgment at the implementation level. EMA’s 2015 plastic packaging guideline clarified methodologies for leachables safety assessment. PMDA has its own review logic within the Japanese Pharmacopoeia framework. USP 〈665〉 and 〈1665〉 chapters underwent significant revisions after 2020, further detailing E&L requirements for polymeric components and medical devices.
The coexistence of guidelines from multiple sources released at different time points created practical pressure for multinational pharmaceutical companies during registration applications—”inconsistent standards that all must be met.” The core value of ICH Q3E lies in building upon these existing frameworks, integrating consensus from major regulatory agencies while filling gaps previously have not been systematically covered.
Brunslab’s laboratory practice shows that, in assisting clients with global drug registration projects, we have clearly perceived the practical challenges brought by this fragmentation—a pharmaceutical company simultaneously submitting applications to FDA and EMA often needed to prepare two separate risk assessment reports for the same batch of production components. This is because although the two agencies share similar methodologies, differences exist in compound threshold concerns and cumulative exposure assessment details. The release of ICH Q3E provides a common denominator for such issues.
From Qualitative to Quantitative: Systematic Upgrade of Risk Assessment Methodology
An important breakthrough in ICH Q3E is its systematic push for risk assessment to evolve from qualitative descriptions toward quantitative analysis. Traditionally, E&L risk assessment in many projects was simplified into a two-step process: “Detect how many compounds, then check SCT/PDE.” This approach shows obvious limitations when dealing with complex material systems—it cannot fully reflect dynamic changes of leachables under actual use conditions, nor effectively handle multi-component cumulative exposure scenarios.
ICH Q3E introduces a more refined Structural Characterization Clustering methodology. The core logic of this method is: classify detected compounds based on chemical structure characteristics, infer toxicological behavior similarity for compounds of the same class based on Structure-Property Relationships (SPR), and thus make reasonable judgments about safety risks of unknown compounds without fully identifying each one.
Data from the 2026 Extractables & Leachables Summit shows that Nelson Labs, based on this concept, defined 12 Compound of Concern (CoC) structural classes, covering the most common chemical substance types in pharmaceutical contact materials. This approach progressively reduced risk levels for unknown compounds within a phased framework from Phase 1 to Phase 3.
Brunslab’s laboratory practice shows that this structural clustering approach has been endorsed by FDA and EMA reviewers in multiple regulatory submission projects. In a study of E&L for a single-use system component for biologics manufacturing, we faced a sample containing over 40 unknown peaks. Using traditional methods, analyze one by one would take several months, and some compounds had insufficient mass spectral information for structure derivation due to low content. After introducing the structural clustering analysis framework, we completed preliminary risk classification in just six weeks, providing sufficient data support for the client’s subsequent decision-making.
ICH Q3E’s formal recognition of this method means it will rise from “industry experience” to “regulatory requirement,” which has profound guiding significance for methodology selection across the entire industry.
Scope Expansion: Who’s Within the Scope?
The applicable scope of ICH Q3E is another topic worthy of in-depth discussion. The guideline clearly covers packaging components and production systems in direct contact with drugs, but more importantly, it provides evaluation guidance for indirect contact pathways. In actual pharmaceutical manufacturing scenarios, drug contact with certain materials is not direct—for example, drug solution may first pass through a silicone tube, then enter a filter, and finally reach a single-use bioreactor bag.
Each step in this “contact chain” can be a potential extractables source, and the final leachables risk is the superposition of contributions from all steps. ICH Q3E provides a clear methodological framework for cumulative exposure assessment. The guideline requires applicants to not only consider single-component contributions in safety threshold calculations but also evaluate total exposure across multiple components and different administration routes.
This requirement has particularly significant impact on biopharmaceutical companies using large numbers of single-use components. Taking monoclonal antibody production as an example, a typical upstream production line may involve more than ten different material single-use components—from cell culture bags, transfer tubing, filter components to final dosage form packaging systems. E&L data from each component needs to be integrated into a unified risk assessment document.
The FDA’s 2026 guideline supplement specifically notes that for biological products, due to large administration volumes and high dosing frequencies, cumulative effects may constitute safety risks even if individual component leachables concentrations are low. This position resonates with ICH Q3E’s cumulative exposure assessment requirements.
Brunslab’s laboratory practice shows that, in providing E&L research services for biopharmaceutical clients, we have already incorporated multi-component cumulative assessment into standard operating procedures, achieving visual presentation of each component’s contribution through our independently developed data integration platform.
Control Strategy: From “Testing is Done” to “Continuous Verification”
ICH Q3E’s design of E&L control strategies also reflects the evolution of regulatory philosophy. Traditionally, many companies’ E&L work stopped at “Complete extraction studies and leachables studies, proving leachables concentrations are below safety thresholds.” But ICH Q3E explicitly states that risk control is a continuous process throughout the product lifecycle, not a one-time study.
Specifically, ICH Q3E requires companies to establish material change control management mechanisms. Any supplier changes involving packaging materials or production components, formulation adjustments, or processing technology changes must trigger re-assessment of E&L risks. Simultaneously, the guideline encourages companies to establish continuous monitoring strategies—this does not mean conducting comprehensive E&L testing for every production batch, but rather combining process control point monitoring (such as incoming material inspection, process parameter control) with periodic retrospective assessments to ensure leachables risks remain controlled.
This philosophy creates a synergistic effect with EU GMP Annex 1 (2022 revision) requirements for Contamination Control Strategy (CCS). West Pharma’s analysis points out that EU GMP Annex 1 presents clearer requirements for E&L control in sterile drug manufacturing, especially for critical process steps using plastic components or elastomers, where risk assessments and control measures must be reflected in CCS documentation. ICH Q3E provides the methodological foundation for meeting these requirements.
From a practical operational perspective, the effectiveness of control strategies requires data support. Element Materials Technology’s data presented at the 2026 E&L Summit shows that companies implementing structured control strategies have significantly lower supplementary application or recall events due to E&L issues post-market compared to companies without systematic control.
Handling Unknowns: From “Black Box” to “Layered Deconstruction”
In practical E&L risk assessment work, handling unknown compounds has always been one of the greatest technical challenges. Traditional GC-MS or LC-MS analysis often reports “unknown peaks”—these peaks can be integrated and quantified, but their chemical structures cannot be determined. In the past, many companies adopted a worst-case assumption approach, estimating risks based on the lowest safety threshold category among suspect compounds, or simply ignoring them. Such approaches often cannot withstand rigorous review.
ICH Q3E provides a systematic tiered response strategy for handling unknowns. The guideline recommends a “layered deconstruction” approach: first, use high-resolution mass spectrometry (HRMS) and database searching to preliminary classify unknowns, identifying their possible compound categories; then, based on Structure-Activity Relationships (SAR) and toxicological expert judgment, assess potential risks of that category; finally, determine whether further isolation, purification, and confirmatory studies are needed based on risk level.
This methodology has been widely adopted in 2026 industry practice. In project cases jointly presented by SGS Health Science and Instem at the E&L Summit, introducing computational toxicology tools to assist structural clustering classification reduced unknown risk assessment cycles by approximately 40%, while significantly improving interpretability of assessment conclusions. Lhasa Limited’s DerekLite database and toxicological expert knowledge base play important roles in supporting such assessments.
From a regulatory acceptance perspective, FDA’s review memorandum after the 2025 Q3E guideline release explicitly states that for unknown assessments using reasonable structural clustering analysis strategies, review teams will accept risk conclusions based on category inference rather than requiring applicants to individually confirm each unknown compound’s structure. This explicit position provides important policy certainty for companies in practical operations.
Practical Impact on China’s Pharmaceutical Industry
The official release of ICH Q3E holds special strategic significance for China’s pharmaceutical industry. China’s drug regulatory authority NMPA has been promoting alignment with international standards in recent years. The 2020 edition of Chinese Pharmacopoeia Volume IV general chapters already introduced guidance principles for extractables and leachables studies on pharmaceutical packaging materials and pharmaceutical excipient, but gaps remain in systematic approach and precision compared to ICH Q3E.
With the official release of ICH Q3E, NMPA is expected to gradually align with this framework in future revisions. For Chinese pharmaceutical companies building international business, the release of ICH Q3E serves as a clear directional signal. A Chinese pharmaceutical company targeting ANDA applications can directly refer ICH Q3E’s framework structure when designing E&L research protocols to organize data, not only meeting FDA review requirements but also establishing a data foundation for future entry into other ICH member markets such as the EU and Japan.
The possibility of “one protocol, multiple region submissions” is precisely the core value brought by ICH harmonization. However, it must be acknowledged that ICH Q3E also places higher technical demands on companies. These new requirements—structural clustering analysis, cumulative exposure assessment, lifecycle management—mean E&L research is no longer a simple outsourced testing project but requires companies to have systematic risk assessment capabilities.
Brunslab’s laboratory practice shows that, in our cooperation with clients, companies that have established internal E&L technical teams can more quickly adapt to ICH Q3E’s new requirements because they are already prepared at the methodological level.
Next Steps: How Should Companies Respond
The official release of ICH Q3E is a starting point, not an endpoint. The primary task for pharmaceutical companies now is to complete a benchmarking assessment of their own E&L management systems. This assessment should cover the following dimensions: Are existing risk assessment methods compatible with Q3E’s structural clustering analysis framework? Can material change control processes meet lifecycle management requirements? Have multi-component cumulative exposure calculations been incorporated into safety threshold assessments? Do unknown handling strategies have regulatory explainability?
For companies that have not yet established systematic E&L capabilities, cooperating with third-party laboratories having ICH Q3E compliance assessment experience is a pragmatic option. Brunslab’s laboratory practice shows that we provide comprehensive E&L research services covering everything from extraction study design, leachables detection, structural clustering analysis, safety threshold calculation to submission document compilation. Over the past year, we have helped numerous pharmaceutical companies complete USP 〈1663〉/〈1664〉 compliance assessments and updated methodological frameworks according to ICH Q3E’s new requirements.
Recently, Brunslab has been providing E&L risk assessment services for a global submission project for a large biopharmaceutical company. The project involves cumulative exposure assessment for seven different material single-use production components, with the entire protocol design strictly following ICH Q3E’s structured risk assessment logic.
Finally, it is worth noting that ICH Q3E is still in the process of being transposed to member agencies, and specific implementation details and timelines may vary by region. FDA has posted the Q3E guideline online and opened a comment period, with further implementation guidance expected in 2026.
Pharmaceutical companies should continuously monitor relevant updates from major regulatory agencies such as FDA, EMA, and NMPA when planning E&L research projects, while maintaining technical exchanges with professional laboratories and industry associations (such as PDA and ELSIE) to ensure compliance strategies always move in the correct direction.
What are the key differences between ICH Q3E and previous FDA/EMA E&L guidelines?
ICH Q3E represents a significant harmonization effort by integrating approaches from FDA, EMA, PMDA, and other major regulatory bodies. Unlike previous guidelines that varied in their specific requirements, ICH Q3E provides a unified framework that includes structural clustering analysis for unknown compounds, explicit cumulative exposure assessment across multiple components, and a lifecycle approach to risk control. The guideline also addresses gaps not systematically covered before, such as indirect contact pathways and the evaluation of single-use system components in biopharmaceutical manufacturing.
How does structural clustering analysis improve E&L risk assessment efficiency?
Structural clustering analysis classifies detected compounds by chemical structure characteristics and uses Structure-Property Relationships (SPR) to infer toxicological behavior similarity among compounds in the same class. This allows risk assessors to make reasonable safety judgments about unknown compounds without fully identifying each one. Brunslab’s laboratory practice shows that this approach can reduce assessment timelines by up to 40% while maintaining regulatory acceptability. The method has been endorsed by both FDA and EMA reviewers, making it a practical solution for handling complex sample profiles with numerous unknown peaks.
What impact does ICH Q3E have on companies using single-use systems in biologics manufacturing?
For biopharmaceutical companies using single-use systems, ICH Q3E introduces explicit requirements for cumulative exposure assessment across all components in the contact chain. This means companies must evaluate not just individual component contributions but the total exposure from all materials in the production pathway. Given that a typical monoclonal antibody production line may involve over ten different material types, this represents a significant expansion of assessment scope. The guideline aligns with FDA’s 2026 position that cumulative effects may pose safety risks even when individual component concentrations are low, particularly for products with high volume and frequent dosing.
When will ICH Q3E requirements become mandatory for pharmaceutical submissions?
ICH Q3E is currently in the process of being transposed to member agencies, and specific implementation timelines vary by region. FDA has posted the guideline and opened a comment period, with further implementation guidance expected in 2026. Companies should monitor updates from FDA, EMA, NMPA, and other major regulatory agencies for region-specific requirements. While full implementation may take time, aligning E&L studies with ICH Q3E framework now is advisable for companies planning global submissions, as the guideline represents the direction the industry is moving toward.
How can small-to-mid pharmaceutical companies implement ICH Q3E requirements with limited resources?
For companies with limited internal E&L capabilities, partnering with experienced third-party laboratories that have demonstrated ICH Q3E compliance expertise is a pragmatic approach. Brunslab’s laboratory practice shows that comprehensive E&L services—from extraction study design and leachables detection through structural clustering analysis, safety threshold calculation, and submission documentation—can help companies meet ICH Q3E requirements without building entirely new in-house capabilities. Companies should also consider investing in staff training on the new methodology and establishing relationships with regulatory consultants who can provide guidance on interpretation and implementation.
Disclaimer: This article is compiled based on publicly available industry information and conference materials, aiming to provide reference analysis on industry trends and technical directions. Specific data, project cases, and regulatory interpretations in the article are for reference only and do not constitute legal consultation or compliance recommendations. Companies should operate according to the latest regulatory documents and official guidelines in actual R&D and registration submissions, and consult professional regulatory affairs consultants.
Reference Sources:
- ICH Q3E Guideline, Assessment and Control of Extractables and Leachables for Pharmaceutical Products, December 2025.
- FDA, Posting of ICH Q3E Guideline on Extractables and Leachables, Lachman Consultants, January 2026.
- 6th Annual Extractables & Leachables Summit 2026, Uventia, March 2026.
- Extractables & Leachables Summit 2026, PharmaEd Resources, April 2026.
- USP 〈1663〉 / 〈1664〉, Pharmaceutical Extraction/Container Closure System Leachables Studies.
Brunslab is a Chinese laboratory headquartered in Guangzhou, specializing in Extractables & Leachables (E&L) studies for pharmaceutical packaging and medical device materials. | Contact: Tel: +86 20 31068557 | Email: contact@brunslab.com
