Introduction
Drug product in-use studies represent critical yet underestimated components of drug product quality, particularly when compared to primary drug product stability studies. Food and Drug Administration (FDA) and similar agencies expect sponsors to demonstrate that drug products maintain stability, potency, and safety throughout real-world administration scenarios. The definitive in-use device study, conducted prior to marketing approval (BLA/NDA) submission, must account for diverse containers and administration sets, diluents, hold times, and handling conditions that extend beyond the primary stability programs. Early planning ensures high-quality Common Technical Document (CTD) Module 3 documentation that satisfies regulatory review the first time, avoiding information requests and unintended post-commercial clinical constraints.
The following guide provides a strategic roadmap for building a filing-ready in-use device program that satisfies regulatory expectations while optimizing development resources. We begin by dissecting the regulatory framework governing Section 3.2.P.2.6 Compatibility, clarifying what agencies demand in terms of data comprehensiveness, worst-case justification, and documentation rigor. Next, we examine Section 3.2.P.8 Stability, detailing how in-use studies integrate into the broader stability program and where compatibility evidence must appear across Sections 3.2.P.8.1 and 3.2.P.8.3. The discussion then turns practical, addressing how to design and execute in-use studies throughout the commercialization lifecycle, from early clinical development through commercial scale manufacturing, with stage-appropriate actions that maintain rapid development timelines.
The second half explores operational excellence through best practices for robust device compatibility programs, including study design principles that satisfy regulators, documentation templates that ensure consistency, and vendor management strategies for Contract Manufacturing and Development Organizations (CDMOs). We then identify the most common pitfalls that derail compatibility programs, inadequate statistical power, insufficient administration device diversity, and poor documentation that trigger costly information requests. Finally, we examine future-proofing strategies that address emerging regulatory trends, real-world evidence expectations, and technology considerations for next-generation biologics, each demanding innovative compatibility assessment approaches tailored to their unique administration profiles.
Understanding 3.2.P.2.6 Compatibility Requirements
Regulatory Framework and In-Use Device Compatibility Requirements
Section 3.2.P.2.6 formally titled “Compatibility” per International Council for Harmonisation (ICH) M4Q guidance, requires comprehensive data demonstrating that drug products maintain stability, potency, and safety when used with diluents and administration devices. The requirements encompass evaluation of drug substance precipitation in solution, sorption onto injection vessels, and stability throughout the administration window. For biologics, ICH Q5C and the draft ICH Q1 EWG guideline emphasize that in-use device testing must simulate the intended use of the drug product in common practice, including reconstitution procedures, dilution protocols, administration methods, interactions with containers and administration sets, and maximum hold times.
Biologics face heightened regulatory scrutiny in compatibility assessments due to the inherent sensitivity of protein-based therapeutics to surface interactions, pH shifts from diluents, leachables and extractables from containers, and mechanical stress during administration. Advanced therapies present additional complexity when limited manufacturing batch sizes constrain the material available for comprehensive in-use testing. Despite material constraints, the FDA expects comprehensive data sets demonstrating that product in-use procedures do not compromise product quality, safety, efficacy, or market access.
Study Design and Worst-Case Conditions
The definitive in-use device study, executed prior to marketing approval submission, must be designed to simulate actual drug administration scenarios, informed by provider feedback and pharmacy manuals or proposed package inserts. Worst-case scenario testing provides particularly critical value in characterizing parameter limits and establishing the control strategies that support robust labeling claims. Comprehensive study designs should evaluate worst-case boundaries for hold time, temperature, light exposure, concentration range, and material contact duration to ensure the data package addresses regulatory expectations across all administration conditions.
Robust data packages require systematic protocol design that addresses all critical parameters while minimizing experimental burden and material consumption. Study protocols must evaluate reconstitution and dilution procedures, cumulative hold time across sequential processing steps from pharmacy preparation through ward transfer and administration, temperature conditions throughout the handling chain, light exposure risks during storage and delivery, material compatibility with containers and administration sets, mechanical stress during infusion, and microbiological risks differentiated by single-use versus multi-use configurations. Each parameter requires careful alignment with regulatory guidance to ensure sufficient evidence for labeling support and regulatory defense.
Reconstitution and dilution testing must bracket the minimum and maximum concentrations anticipated in product labeling to establish the validated concentration range. Cumulative hold time testing must evaluate the longest anticipated duration at worst-case temperature for each sequential step, while light exposure evaluation on diluted drug product captures worst-case photodegradation potential. Material compatibility testing at maximum concentration assesses adsorptive losses under worst-case contact conditions. Mechanical stress assessment at maximum flow rate and longest tubing length characterizes the most demanding delivery scenarios. Microbiological risk testing protocols differ fundamentally between multi-use and single-use configurations, as preserved multi-dose products face contamination risks during repeated access while unpreserved single-dose products require sterility maintenance throughout the administration window.
Analytical Package and Acceptance Criteria
In-use studies require comprehensive assessment of critical quality attributes (CQAs) that directly impact product stability, potency, and safety throughout the administration window. Stability-indicating analytical procedures encompass biological activity, physicochemical, biochemical, and immunochemical methods, as outlined in ICH stability guidance. These procedures must demonstrate sufficient sensitivity to detect degradation, aggregation, or contamination that could compromise patient safety or therapeutic efficacy.
Robust analytical testing is imperative for generating filing-ready data packages that withstand regulatory scrutiny. Sponsors must monitor potency or bioactivity to confirm therapeutic function retention, assess aggregation profiles through size-exclusion chromatography (SEC) to detect high molecular weight species formation, and evaluate charge variant distribution via ion-exchange chromatography (IEX) to track acidic and basic species shifts. Particulate matter assessment requires both subvisible particle quantification following United States Pharmacopeia (USP) <788> light obscuration or microscopic particle count methods, and visible particle inspection under controlled lighting conditions per USP <790>. Additional stability-indicating attributes include pH, osmolality, and solution appearance. For in-use periods extending beyond 24 hours or for multi-dose configurations, sterility and endotoxin testing become critical controls.
Each CQA functions as a stability-indicating attribute by revealing specific degradation pathways, container-closure interactions, or environmental stressors that manifest during in-use conditions. These attributes collectively establish the boundaries within which product quality remains acceptable for patient administration and support defensible labeling claims.
Understanding 3.2.P.8 Stability Requirements
Regulatory Framework and In-Use Stability Requirements
Section 3.2.P.8 formally titled “Stability” is the primary location for presenting stability data that substantiates a drug product’s shelf-life and its in-use handling instructions. This section is subdivided into three components: Stability Summary and Conclusions, Post-Approval Stability Protocol and Stability Commitment, and Stability Data. The stability summary and conclusions section (3.2.P.8.1) summarizes the types of studies conducted, protocols used, and results. Conclusions regarding storage conditions and in-use conditions are provided here. The stability data section (3.2.P.8.3) provides the results of stability studies in tabular, graphical, or narrative format, with information on analytical procedures and their validation. The results and findings from the in-use device study are provided here.
The draft ICH Q1 EWG guidance introduces expanded guidance on in-use studies as a category of “supportive stability studies” that support the practical use of the product, including label claims for reconstitution, dilution, and administration. These studies are distinct from formal long-term and accelerated stability studies that establish primary retest period or shelf-life for the unopened drug product.
Summarizing the Evidence: 3.2.P.8.1 Stability Summary & Conclusions
Section 3.2.P.8.1, Stability Summary and Conclusions, functions as the executive summary of the stability program, presenting conclusions on storage conditions and shelf life for the unopened drug product and in-use storage conditions and hold durations following preparation or opening. The primary function of the section is to synthesize the types of stability studies conducted, protocols employed, and results obtained, providing regulators with a clear and traceable link between stability data and proposed labeling statements.
In-use studies represent supportive investigations that complement formal long-term and accelerated stability programs. For biologics and small-molecule drugs administered parenterally or stored in multi-dose containers, these studies establish the period during which the product remains within specification after the primary container is opened or is prepared for administration.
Regulatory guidance specifies minimum study requirements: ICH Q1A(R2) for small molecules and ICH Q5C for biologics mandate testing on a minimum of two batches, with at least one batch evaluated near the end of its primary shelf-life to represent worst-case stability conditions. The European Medicines Agency (EMA) guideline CPMP/QWP/2934/99 provides additional requirements for maximum in-use period determination in the European Union. All analytical procedures used must be fully validated per ICH Q2(R2) and must be stability-indicating to detect potential degradation during the in-use period.
The central deliverable of Section 3.2.P.8.1 is the definitive in-use period conclusion, articulating the specific duration for which the product remains stable under defined temperature conditions following preparation. The conclusion must be supported by clear justification of the study design rationale, including cumulative in-use hold times that account for preparation, storage, and administration phases and microbiological safety justifications that address the risk of contamination.
Microbiological safety justifications are critical and must address contamination risks differentiated by product configuration: preserved multi-dose formulations that face repeated access contamination risks, while unpreserved single-dose formulations require sterility maintenance throughout the administration window. The summary must explicitly identify all acceptable diluents, validated concentration ranges, and compatibility with administration devices, ensuring these specifications align with intended clinical use and support proposed labeling claims.
Section 3.2.P.8.1 functions as the integration point for the complete in-use evidence package. Detailed protocols, analytical datasets, and time-point results are cross-referenced to Section 3.2.P.8.3 for reviewer verification, while device and material compatibility discussions regarding infusion sets, filters, adsorption, and extractables are documented in Section 3.2.P.2.6. This cross-referencing strategy creates a cohesive regulatory submission that enables efficient review while maintaining complete traceability to supporting data.
Presenting the Proof: 3.2.P.8.3 Stability Data
Section 3.2.P.8.3, Stability Data, functions as the comprehensive repository for stability study results supporting the drug product’s proposed shelf-life and storage conditions. The section must present data from long-term, accelerated, and in-use stability studies through tabular summaries, graphical trend plots, or narrative evaluations. The data must demonstrate that the drug product maintains quality, safety, and efficacy throughout the proposed shelf life under specified storage and in-use conditions.
Regulatory reviewers require detailed study protocols, complete datasets for all CQAs tested at each time point, and cross-references to analytical method validation reports in Section 3.2.P.5.3 demonstrating that stability-indicating procedures were appropriately employed. All CQA data must be tabulated with acceptance criteria and presented graphically to facilitate trend assessment. This includes assay or potency, degradation products, pH, solution appearance, and particulate matter quantified per USP <788> or USP <787>. A robust data package ensures reviewers can verify that in-use claims are scientifically justified and complement the primary stability package.
Microbiological data represents a critical component of Section 3.2.P.8.3. Product configuration dictates distinct testing requirements. Preserved multi-dose products require complete antimicrobial effectiveness testing (AET) datasets per USP <51>, documenting log reduction tables for all challenge organisms (bacteria, yeast, mold) at days 0, 7, 14, and 28 to demonstrate preservative system efficacy throughout repeated access. Unpreserved sterile products must provide sterility testing per USP <71> and bacterial endotoxin testing per USP <85> at the end of the proposed in-use period, demonstrating maintenance of microbiological quality throughout the administration window. These data directly support labeling instructions for multi-dose vial storage duration and single-dose product administration timeframes.
Modality-specific requirements further define Section 3.2.P.8.3 data packages, reflecting the distinct degradation pathways and quality concerns characteristic of different drug classes. For biologics, ICH Q5C mandates datasets demonstrating aggregation profiles via SEC and charge variant distribution via IEX, as protein aggregation and chemical modifications represent the primary degradation mechanisms affecting biological activity and immunogenicity. For small molecules, ICH Q1A(R2) and ICH Q3B require degradation product and impurity profiles via high-performance liquid chromatography (HPLC) or ultra-performance liquid chromatography (UPLC), capturing chemical instability pathways including oxidation, hydrolysis, and photodegradation. Solid oral dosage forms must include dissolution testing per USP <711> or <724> to ensure consistent drug release performance, as physical changes during storage and handling can affect bioavailability even when chemical potency remains acceptable.
In-use Studies Support and Execution Throughout the Commercialization Lifecycle
Synopsis
In-use studies for parenteral biologics and small molecules ensure that drug products remain safe, stable, and effective throughout preparation, handling, and administration at clinical sites. These studies assess compatibility with administration components (IV bags, tubing, filters, syringes) and define hold times that preserve CQAs during dose preparation and patient administration. This section outlines recommendations of a phased approach to in-use studies: (1) pre-clinical risk identification of containers, administration sets, and process parameters; (2) pre-IND amendment flexibility-building through material compatibility screening within stability programs; and (3) execution of a right-first-time definitive study that satisfies regulatory requirements while leveraging prior compatibility risk assessments. Early planning ensures high-quality CTD Module 3 submissions that avoid information requests particularly when comprehensive primary stability protocols that include in-use compatibility requirements are well planned and executed.
Pre-Clinical In-Use Studies Considerations
While formal requirements for in-use studies are not mandated for IND submissions, initiating planning during pre-clinical development serves as a critical risk-mitigation strategy that supports the broader stability program. Biologics face unique vulnerabilities during the transition from controlled storage to clinical administration. Dilution factors and exposure to extensive surface areas from IV bags, tubing, infusion pumps, and syringes, create conditions ripe for protein adsorption, aggregation, and potency loss. These interfacial stresses are particularly problematic in Phase 1 dose-escalation studies, where low-dose recovery due to adsorption to inline filters and administration components can compromise dose accuracy and lead to erroneous clinical outcomes. Early characterization and risk assessment of these vulnerabilities informs robust formulation design and avoids the need for late-stage protocol amendments that can delay program timelines.
A foundational step in pre-clinical planning involves establishing a comprehensive inventory of all containers and administration sets that will contact the drug product during preparation and delivery. This inventory spans primary containers, transfer devices, inline filters of varying pore sizes and membrane materials, syringes, IV bags, administration tubing, infusion pumps, fittings, and closure systems. Documenting the materials of construction for each component establishes the foundation for compatibility assessments and extractables-leachable risk evaluations that will be required later in development.
Equally important is the early definition of administration process parameters that govern product exposure and hold conditions. Developing a detailed process description for drug administration at this stage aids in defining the steps and parameterizing the definitive in-use device study. Critical parameters include the selection of diluents and their impact on pH and osmolality, target concentration ranges post-dilution to evaluate adsorption risks, infusion rates that determine shear stress and residence time, filter placement and pore size selection, line priming volumes and associated dead-volume losses, total contact time from preparation through infusion completion, temperature and light exposure profiles, and the potential for air-liquid interface effects during transport that can induce substantial aggregation. Establishing allowable in-use hold times supported by proposed clinical administration protocols ensures that future studies reflect realistic practices.
Critically, this early planning phase must ensure that the drug product can be administered using different commercially available administration devices from multiple vendors. This flexibility is essential to avoid designation as a combination device, which would trigger significant regulatory hurdles under combination product pathways and potentially delay market entry. By proactively demonstrating compatibility across a range of standard administration components during pre-clinical development, sponsors maintain regulatory flexibility and streamline the path through IND to marketing approval.
Building In-Use Studies Flexibility prior to an IND amendment
Formal in-use studies are not mandated for IND amendments. Nonetheless, the clinical development phase presents a strategic opportunity to address two challenges: material compatibility requirements for the definitive in-use device study and combination product designation. Clinical insights on container and administration material diversity inform material compatibility requirements for stability testing and administration device flexibility requirements that address combination product classification. Addressing these requirements early simplifies definitive in-use device study, reduces drug product testing requirements, and avoids the substantial regulatory burdens associated with combination product designation.
As clinical development progresses from Phase 1 through Phase 2, practical insights emerge regarding the flexibility required for diluents, containers, and administration sets across diverse clinical sites and geographies. Clinical operations teams and pharmacy stakeholders provide valuable input on site preferences, supply chain constraints, and regional variations in standard-of-care administration practices. These real-world insights should be systematically incorporated into evolving bill of materials and risk assessments. By maintaining a site flexibility matrix that documents tested components, their materials of construction, identified risks, compatibility evidence sources, and recommended use conditions, sponsors generate robust data packages that address material comparability and combination product challenges.
A forward-thinking approach involves building in-use device material compatibility requirements directly into accelerated and stress stability studies. The generated data will support shelf-life determinations while simultaneously generating compatibility data that informs risk assessments for the definitive in-use device study. Compatibility integration is particularly valuable for programs with limited drug product availability, where efficient use of material can make the difference between timely advancement and costly delays.
The strategy centers on leveraging ICH Q5C-mandated accelerated and stress-condition stability studies as vehicles for screening compatibility with clinically informed diluents, containers, administration components. The analytical panel for these integrated studies should evaluate critical parameters including drug product recovery to detect adsorption, aggregation, particulate formation, visual appearance changes, and targeted leachable and extractables based on risk assessments. Establishing acceptance criteria linked to CQAs ensures that the data generated will support both stability claims and compatibility assertions in future regulatory filings.
Under FDA’s combination product regulations, products that are co-packaged with or require specific devices for administration may be designated as combination products, subjecting them to additional regulatory pathways and requirements. By systematically demonstrating through administration device compatibility studies that the drug product maintains its quality attributes, sponsors build evidence that the product is device-agnostic. The documentation generated supports the position that the drug product’s primary mode of action does not depend on a specific device, helping to maintain classification as a standalone drug product. The clinical insights gathered during development, regarding which devices are routinely used across sites, directly inform which materials should be tested.
Although a comprehensive in-use device study is not required at the IND amendment stage, having an established framework for the in-use device study becomes invaluable as programs advance toward marketing approval. Sponsors who have integrated compatibility screening into primary stability studies while systematically documenting administration device flexibility find themselves in a significantly stronger position. The proactive approach simplifies the in-use device study execution and provides a defensible regulatory classification as a drug product, rather than a combination product. The definitive in-use device study will have a narrow scope of pre-qualified pathways rather than broad exploration work. The result is a more efficient path to market that balances regulatory requirements with practical constraints on material availability and development timelines, while ensuring clinical sites retain flexibility to use preferred administration components without triggering protocol amendments or regulatory delays.
Executing the In-Use Device Study Right-First-Time Prior to Marketing Approval
As programs advance toward marketing approval submission, the definitive in-use device study becomes a critical supporting element of the overall stability package, complementing required shelf-life stability studies by demonstrating that the drug product maintains quality throughout real-world preparation, storage, and administration conditions. This study is distinct from but complementary to primary drug product stability information, focusing specifically on the product journey from pharmacy preparation through patient administration. When prior development work has systematically addressed material compatibility through accelerated studies and risk assessments, the definitive study can be streamlined to confirm pre-qualified pathways rather than conducting broad material comparability investigations, significantly reducing material requirements and study complexity.
The protocol design must be informed by and explicitly reference all prior compatibility data, including accelerated and stress studies, extractables and leachables assessments, and adsorption screening results accumulated during pre-clinical and clinical development phases. This risk-based approach allows the study to focus on worst-case and representative conditions that reflect intended use: the longest allowable hold time at ambient temperature, the lowest clinically relevant concentration where adsorption risk peaks, maximum tubing length and contact surface area, and inline filter use if specified in labeling. Industry best practice emphasizes incorporating these worst-case scenarios while ensuring that study conditions genuinely mirror clinical administration practices. Batch selection should follow regulatory guidance recommending a minimum of two batches at pilot scale or larger, with at least one batch tested at or near its end of shelf-life to demonstrate robustness across the product lifecycle.
The analytical methods deployed must be validated and constitute a comprehensive stability-indicating panel aligned with product CQAs, including assay or potency measurements to assess dose recovery, purity analysis through SEC to detect aggregation, particulate testing meeting USP requirements for subvisible particles, visual appearance inspection, pH and osmolality verification, and when applicable for multi-dose or extended-hold scenarios, sterility or endotoxin testing. Acceptance criteria should be rigorously linked to both product specifications and clinical relevance, ensuring that patients receive the intended dose with maintained safety and efficacy profiles.
The study outputs must populate three distinct sections of the Common Technical Document with precision and traceability. Section 3.2.P.2.6 requires a comprehensive compatibility narrative that summarizes device and consumable selection rationale, presents a detailed compatibility matrix documenting all tested components with their materials of construction and use conditions, provides extractables and leachables justifications, and specifies clear instructions for use that will ultimately appear in product labeling. Section 3.2.P.8.1 demands a concise stability summary and conclusions that synthesize study objectives, design, key findings, and trends analysis, culminating in definitive statements of supported in-use hold times and conditions with appropriate cross-references to detailed data. Section 3.2.P.8.3 houses the detailed stability data tables presenting time-point results across all analytical methods, conditions, and batches, complete with method references and batch genealogy information. By maintaining rigorous traceability back through clinical development risk assessments to pre-clinical compatibility screening, sponsors demonstrate a systematic, science-based approach that enhances regulatory confidence and positions the application for efficient review and approval.
Best Practices for Robust Device Compatibility Programs
Study Design Principles That Satisfy Regulators
Successful device compatibility programs share common design principles that ensure regulatory acceptance while optimizing resource utilization. These principles include comprehensive risk assessment driving study design with focus on administration device interactions, statistically robust protocols with appropriate controls for sorption and precipitation, analytical methods validated specifically for compatibility assessment of biologics with containers and administration sets, clear acceptance criteria tied to product specifications and labeling requirements, and systematic evaluation of all proposed diluents and procedures.
Documentation Templates and Quality Standards
Standardized documentation approaches ensure consistency and completeness across your device compatibility program. Templates should address study objectives and rationale specific to administration device compatibility, detailed experimental protocols for sorption, precipitation, and stability testing, analytical methods and validation for device interaction assessment, statistical analysis plans with appropriate power calculations, and clear conclusions with regulatory implications for product labeling and commercial device selection.
Vendor Management for Device Testing Partnerships
Many companies rely on CDMOs for device compatibility testing, requiring careful vendor management to ensure data quality and regulatory acceptability. Key considerations include vendor qualification and audit programs with expertise in biologic-device interactions, clear specifications for study conduct and documentation focusing on administration device compatibility, regular communication and project management ensuring regulatory compliance, and quality agreements covering regulatory requirements specific to 3.2.P.2.6 compatibility documentation.
Avoiding Common Pitfalls in Device Compatibility Studies
Inadequate Statistical Power in Study Design
One of the most frequent causes of regulatory delays involves insufficient statistical power to detect clinically meaningful compatibility issues, particularly sorption effects that could impact bioavailability. This problem typically stems from underestimating variability in device materials and manufacturing tolerances, using sample sizes appropriate for stability studies rather than compatibility assessment, failing to account for multiple comparison adjustments when testing multiple devices, inadequate consideration of regulatory acceptance criteria for sorption limits, and insufficient power to detect precipitation in reconstitution studies.
Insufficient Device Diversity in Testing Protocols
Regulatory agencies expect device compatibility programs to reflect real-world administration diversity across different administration devices and reconstitution scenarios. Insufficient diversity often results from testing only preferred commercial devices rather than representative alternatives, neglecting regional differences in device preferences and materials, overlooking device material variations that might occur during commercial supply, failing to consider reconstitution diluent variations across different clinical sites, and inadequate evaluation of device evolution over the product lifecycle.
Poor Documentation That Triggers Information Requests
Even excellent science can fail regulatory review if poorly documented. Common documentation issues include unclear study objectives and acceptance criteria specific to device compatibility, inadequate statistical analysis and interpretation of sorption data, missing correlation between device studies and clinical administration procedures, insufficient risk assessment and mitigation planning for compatibility failures, unclear linkage between compatibility data and proposed product labeling, and inadequate justification for administration device selection and reconstitution procedures.
Future-Proofing Your Device Compatibility Strategy
Emerging Regulatory Trends and Expectations
Regulatory expectations for device compatibility continue to evolve, driven by increased focus on patient-centric drug development and administration convenience, growing emphasis on real-world evidence for device performance, enhanced understanding of sorption risks and bioavailability impact, improving analytical capabilities for compatibility assessment of biologics, and expanding recognition of reconstitution procedure variability in clinical practice.
Companies investing in advanced compatibility assessment capabilities and comprehensive documentation standards position themselves advantageously for future regulatory requirements while supporting commercial differentiation through superior device compatibility profiles.
Technology Considerations for Next-Generation Biologics
Emerging biologic modalities present unique device compatibility challenges requiring innovative approaches. Gene therapies with specialized delivery requirements and catheter compatibility needs, cell therapies with complex handling needs and specialized injection vessels, combination products integrating drugs and devices with unique compatibility considerations, and personalized biologics requiring flexible reconstitution and administration options each demand tailored compatibility assessment strategies that address their specific administration device interaction profiles.
References
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (2002). The Common Technical Document for the registration of pharmaceuticals for human use: Quality – M4Q (R1) – Quality overall summary of Module 2, Module 3: Quality (ICH Harmonised Tripartite Guideline, Step 4 version). https://database.ich.org/sites/default/files/M4Q_R1_Guideline.pdf
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (1995, November 30). Q5C: Stability testing of biotechnological/biological products (ICH Harmonised Tripartite Guideline, Current Step 4 version). https://database.ich.org/sites/default/files/Q5C%20Guideline.pdf
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (2025, April 11). ICH Q1: Stability testing of drug substances and drug products (Draft Guideline, Step 2). https://database.ich.org/sites/default/files/ICH_Q1EWG_Step2_Draft_Guideline_2025_0411.pdf
- Federal Register. (2025, June 24). Q1 Stability Testing of Drug Substances and Drug Products; International Council for Harmonisation; Draft Guidance for Industry; Availability, 90(120), 26821-26822. https://www.federalregister.gov/documents/2025/06/24/2025-11552/q1-stability-testing-of-drug-substances-and-drug-products-international-council-for-harmonisation
- U.S. Food and Drug Administration. (2003, November). Q1A(R2) Stability Testing of New Drug Substances and Products (Guidance for industry, Revision 2). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-products
- United States Pharmacopeial Convention. (2013). <788> Particulate matter in injections. In United States Pharmacopeia and National Formulary (USP 36-NF 31, Revision). https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisionGeneralChapter788.pdf
- United States Pharmacopeial Convention. (2016). <790> Visible particulates in injections. In United States Pharmacopeia and National Formulary (USP 39-NF 34). https://www.pharmout.net/wp-content/uploads/2018/02/NGVF-2016-USP-790-Visible-particles-USP37.pdf
- United States Pharmacopeial Convention. (2021). <1790> Visual inspection of injections. In United States Pharmacopeia and National Formulary (USP 44-NF 39).
- United States Pharmacopeial Convention. (n.d.). <787> Subvisible particulate matter in therapeutic protein injections. In United States Pharmacopeia and National Formulary.
External Reference Links:
- International Council for Harmonisation (ICH). Framework for post-approval change management protocols (PACMP), established conditions, and lifecycle management strategies for compatibility programs. https://database.ich.org/sites/default/files/Q12_Guideline_Step4_2019_1119.pdf
- International Council for Harmonisation (ICH). Quality by Design (QbD) principles including QTPP→CQA→CPP linkages, design space, and proven acceptable ranges underpinning compatibility study design. https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf
- U.S. Food and Drug Administration. Comprehensive guidance on holistic, risk-based approach to visible particulate control including development, manufacturing, inspection, and corrective actions. https://www.fda.gov/media/154868/download
- U.S. Code of Federal Regulations. CGMP regulations establishing manufacturing, quality control, and testing requirements including visual inspection (§211.194) and specifications (§211.160). https://www.ecfr.gov/current/title-21/part-211
- U.S. Code of Federal Regulations. FDA requirements for electronic records and electronic signatures applicable to automated particulate counting systems and stability data management. https://www.ecfr.gov/current/title-21/part-11
- BioProcess International. Industry perspective on navigating Module 3 (CMC) complexity with strategies for submission readiness and documentation consistency. https://www.bioprocessonline.com/doc/demystifying-the-common-technical-document-for-global-submissions-0001
Appendix
Acronyms Table
| Acronym | Definition |
|---|---|
| AET | Antimicrobial Effectiveness Testing |
| BLA | Biologics License Application |
| CDMO | Contract Development and Manufacturing Organization |
| CQA | Critical Quality Attribute |
| CTD | Common Technical Document |
| EMA | European Medicines Agency |
| EU | European Union |
| EWG | Expert Working Group |
| FDA | U.S. Food and Drug Administration |
| HPLC | High-Performance Liquid Chromatography |
| ICH | International Council for Harmonisation |
| IEX | Ion-Exchange Chromatography |
| NDA | New Drug Application |
| SEC | Size-Exclusion Chromatography |
| UPLC | Ultra-Performance Liquid Chromatography |
| USP | United States Pharmacopeia |