The Molecule That Changed Everything: How Insulin Rewired Drug Manufacturing and Regulatory Thinking

There’s a tendency in our industry to talk about “small molecules versus biologics” as if we woke up one morning and the world had simply divided itself into two neat categories. But the truth is more interesting—and more instructive—than that. The dividing line was drawn by one molecule in particular: insulin. And the story of how insulin moved from animal extraction to recombinant manufacturing didn’t just change how we make one drug. It fundamentally rewired how we think about manufacturing, quality, and regulation across the entire pharmaceutical landscape.

From Pancreases to Plasmids

For the first six decades of its therapeutic life, insulin was an extractive product. Since the 1920s, producing insulin required enormous quantities of animal pancreases—primarily from cows and pigs—sourced from slaughterhouses. Eli Lilly began full-scale animal insulin production in 1923 using isoelectric precipitation to separate and purify the hormone, and that basic approach held for decades. Chromatographic advancements in the 1970s improved purity and reduced the immunogenic reactions that had long plagued patients, but the fundamental dependency on animal tissue remained.

This was, in manufacturing terms, essentially a small-molecule mindset applied to a protein. You sourced your raw material, you extracted, you purified, you tested the final product against a specification, and you released it. The process was relatively well-characterized and reproducible. Quality lived primarily in the finished product testing.

But this model was fragile. Market forces and growing global demand revealed the unsustainable nature of dependency on animal sources. The fear of supply shortages was real. And it was into this gap that recombinant DNA technology arrived.

1982: The Paradigm Breaks Open

In 1978, scientists at City of Hope and Genentech developed a method for producing biosynthetic human insulin (BHI) using recombinant DNA technology, synthesizing the insulin A and B chains separately in E. coli. On October 28, 1982, after only five months of review, the FDA approved Humulin—the first biosynthetic human insulin and the first approved medical product of any kind derived from recombinant DNA technology.

Think about what happened here. Overnight, insulin manufacturing went from:

Animal tissue extraction → Living cell factory production
Sourcing variability tied to agricultural supply chains → Engineered biological systems with defined genetic constructs
Purification of a natural mixture → Directed expression of a specific gene product

The production systems themselves tell the story. Recombinant human insulin is produced predominantly in E. coli (where insulin precursors form inclusion bodies requiring solubilization and refolding) or in Saccharomyces cerevisiae (where soluble precursors are secreted into culture supernatant). Each system brings its own manufacturing challenges—post-translational modification limitations in bacteria, glycosylation considerations in yeast—that simply did not exist in the old extraction paradigm.

This wasn’t just a change in sourcing. It was a change in manufacturing identity.

“The Process Is the Product”

And here is where the real conceptual earthquake happened. With small-molecule drugs, you can fully characterize the molecule. You know every atom, every bond. If two manufacturers produce the same compound by different routes, you can prove equivalence through analytical testing of the finished product. The process matters, but it isn’t definitional.

Biologics are different. As the NIH Regulatory Knowledge Guide puts it directly: “the process is the product”—any changes in the manufacturing process can result in a fundamental change to the biological molecule, impacting the product and its performance, safety, or efficacy. The manufacturing process for biologics—from cell bank to fermentation to purification to formulation—determines the quality of the product in ways that cannot be fully captured by end-product testing alone.

Insulin was the first product to force the industry to confront this reality at commercial scale. When Lilly and Genentech brought Humulin to market, they weren’t just scaling up a chemical reaction. They were scaling up a living system, with all the inherent variability that implies—batch-to-batch differences in cell growth, protein folding, post-translational modifications, and impurity profiles.

This single insight—that for biologics, process control is product control—cascaded through the entire regulatory and quality framework over the next four decades.

The Regulatory Framework Catches Up

Insulin’s journey also exposed a peculiar regulatory gap. Despite being a biologic by any scientific definition, insulin was regulated as a drug under Section 505 of the Federal Food, Drug, and Cosmetic Act (FFDCA), not as a biologic under the Public Health Service Act (PHSA). This was largely a historical accident: when recombinant insulin arrived in 1982, the distinctions between FFDCA and PHSA weren’t particularly consequential, and the relevant FDA expertise happened to reside in the drug review division.

But this classification mismatch had real consequences. Because insulin was regulated as a “drug,” there was no pathway for biosimilar insulins—even after the Hatch-Waxman Act of 1984 created abbreviated pathways for generic small-molecule drugs. The “generic” framework simply doesn’t work for complex biological molecules where “identical” is the wrong standard.

It took decades to resolve this. The Biologics Price Competition and Innovation Act (BPCIA), enacted in 2010 as part of the Affordable Care Act, created an abbreviated regulatory pathway for biosimilars and mandated that insulin—along with certain other protein products—would transition from drug status to biologic status. On March 23, 2020, all insulin products were formally “deemed to be” biologics, licensed under Section 351 of the PHSA.

This wasn’t a relabeling exercise. It opened insulin to the biosimilar pathway for the first time, culminating in the July 2021 approval of Semglee (insulin glargine-yfgn) as the first interchangeable biosimilar insulin product. That approval—allowing pharmacy-level substitution of a biologic—was a moment the industry had been building toward for decades.

ICH Q5 and the Quality Architecture for Biologics

The regulatory thinking that insulin forced into existence didn’t stay confined to insulin. It spawned an entire framework of ICH guidelines specifically addressing the quality of biotechnological products:

ICH Q5A – Viral safety evaluation of biotech products derived from cell lines
ICH Q5B – Analysis of the expression construct in cell lines
ICH Q5C – Stability testing of biotechnological/biological products
ICH Q5D – Derivation and characterization of cell substrates
ICH Q5E – Comparability of biotechnological/biological products subject to changes in their manufacturing process

ICH Q5E deserves particular attention because it codifies the “process is the product” principle into an operational framework. It states that changes to manufacturing processes are “normal and expected” but insists that manufacturers demonstrate comparability—proving that post-change product has “highly similar quality attributes” and that no adverse impact on safety or efficacy has occurred. The guideline explicitly acknowledges that even “minor” changes can have unpredictable impacts on quality, safety, and efficacy.

This is fundamentally different from the small-molecule world, where a process change can often be managed through updated specifications and finished-product testing. For biologics, comparability exercises can involve extensive analytical characterization, in-process testing, stability studies, and potentially nonclinical or clinical assessments.

How This Changed Industry Thinking

The ripple effects of insulin’s transition from extraction to biologics manufacturing reshaped the entire pharmaceutical industry in several concrete ways:

1. Process Development Became a Core Competency, Not a Support Function.
When “the process is the product,” process development scientists aren’t just optimizing yield—they’re defining the drug. The extensive process characterization, design space definition, and control strategy work enshrined in ICH Q8 (Pharmaceutical Development) and ICH Q11 (Development and Manufacture of Drug Substances) grew directly from the recognition that biologics manufacturing demands a fundamentally deeper understanding of process-product relationships.

2. Cell Banks Became the Crown Jewels.
The master cell bank concept—maintaining a characterized, qualified starting point for all future production—became the foundational control strategy for biologics. Every batch traces back to a defined, banked cell line. This was a completely new paradigm compared to sourcing animal pancreases from slaughterhouses.

3. Comparability Became a Lifecycle Discipline.
In the small-molecule world, process changes are managed through supplements and updated batch records. In biologics, every significant process change triggers a comparability exercise that can take months and cost millions. This has made change control for biologics a far more rigorous discipline and has elevated the role of quality and regulatory functions in manufacturing decisions.

4. The Biosimilar Paradigm Created New Quality Standards.
Unlike generics, biosimilars cannot be “identical” to the reference product. The FDA requires a demonstration that the biosimilar is “highly similar” with “no clinically meaningful differences” in safety, purity, and potency. This “totality of evidence” approach, developed for the BPCIA pathway, requires sophisticated analytical, functional, and clinical comparisons that go well beyond the bioequivalence studies used for generic drugs.

5. Manufacturing Cost and Complexity Became Strategic Variables.
Biologics manufacturing requires living cell systems, specialized bioreactors, extensive purification trains (including viral clearance steps), and facility designs with stringent contamination controls. The average cost to develop an approved biologic is estimated at $2.6–2.8 billion, compared to significantly lower costs for small molecules. This manufacturing complexity has driven the growth of the CDMO industry and made facility design, tech transfer, and manufacturing strategy central to business planning.

The Broader Industry Shift

Insulin was the leading edge of a massive transformation. By 2023, the global pharmaceutical market was $1.34 trillion, with biologics representing 42% of sales (up from 31% in 2018) and growing three times faster than small molecules. Some analysts predict biologics will outstrip small molecule sales by 2027.

This growth has been enabled by the manufacturing and regulatory infrastructure that insulin’s transition helped build. The expression systems first commercialized for insulin—E. coli and yeast—remain workhorses, while mammalian cell lines (especially CHO cells) now dominate monoclonal antibody production. The quality frameworks (ICH Q5 series, Q6B specifications, Q8–Q11 development and manufacturing guidelines) provide the regulatory architecture that makes all of this possible.

Even the regulatory structure itself—the distinction between 21 CFR Parts 210/211 (drug CGMP) and 21 CFR Parts 600–680 (biologics)—reflects this historical evolution. Biologics manufacturers must often comply with both frameworks simultaneously, maintaining drug CGMP baselines while layering on biologics-specific controls for establishment licensing, lot release, and biological product deviation reporting.

Where We Are Now

Today, insulin sits at a fascinating intersection. It’s a relatively small, well-characterized protein—analytically simpler than a monoclonal antibody—but it carries the full regulatory weight of a biologic. The USP maintains five drug substance monographs and thirteen drug product monographs for insulin. Manufacturers must hold Biologics License Applications, comply with CGMP for both drugs and biologics, and submit to pre-approval inspections.

Meanwhile, the manufacturing technology continues to evolve. Animal-free recombinant insulin is now a critical component of cell culture media used in the production of other biologics, supporting CHO cell growth in monoclonal antibody manufacturing—a kind of recursive loop where the first recombinant biologic enables the manufacture of subsequent generations.

And the biosimilar pathway that insulin’s reclassification finally opened is beginning to deliver on its promise. Multiple biosimilar and interchangeable insulin products are now reaching patients at lower costs. The framework developed for insulin biosimilars is being applied across the biologics landscape—from adalimumab to trastuzumab to bevacizumab.

The Lesson for Quality Professionals

If there’s a single takeaway from insulin’s manufacturing evolution, it’s this: the way we make a drug is inseparable from what the drug is. This was always true for biologics, but it took insulin—the first recombinant product to reach commercial scale—to force the industry and regulators to internalize that principle.

Every comparability study you run, every cell bank qualification you perform, every process validation protocol you execute for a biologic product exists because of the conceptual framework that insulin’s journey established. The ICH Q5E comparability exercise, the Q5D cell substrate characterization, the Q5A viral safety evaluation—these aren’t bureaucratic requirements imposed from outside. They’re the rational response to a fundamental truth about biological manufacturing that insulin made impossible to ignore.

The molecule that changed everything didn’t just save millions of lives. It rewired how an entire industry thinks about the relationship between process and product. And in doing so, it set the stage for every biologic that followed.

The Draft ICH Q3E: Transforming Extractables and Leachables Assessment in Pharmaceutical Manufacturing

The recently released draft of ICH Q3E addresses a critical gap that has persisted in pharmaceutical regulation for over two decades. Since the FDA’s 1999 Container Closure Systems guidance and the EMA’s 2005 Plastic Immediate Packaging Materials guideline, the regulatory landscape for extractables and leachables has remained fragmented across regions and dosage forms. This fragmentation has created significant challenges for global pharmaceutical companies, leading to inconsistent approaches, variable interpretation of requirements, and substantial regulatory uncertainty that ultimately impacts patient access to medicines.

The ICH Q3E guideline emerges from recognition that modern pharmaceutical development increasingly relies on complex drug-device combinations, novel delivery systems, and sophisticated manufacturing technologies that transcend traditional regulatory boundaries. Biologics, cell and gene therapies, combination products, and single-use manufacturing systems have created E&L challenges that existing guidance documents were never designed to address. The guideline’s comprehensive scope encompasses chemical entities, biologics, biotechnological products, and drug-device combinations across all dosage forms, establishing a unified framework that reflects the reality of contemporary pharmaceutical manufacturing.

The harmonization achieved through ICH Q3E extends beyond mere procedural alignment to establish fundamental scientific principles that can be applied consistently regardless of geographical location or specific regulatory jurisdiction. This represents a significant evolution from the current patchwork of guidance documents, each with distinct requirements and safety thresholds that often conflict or create unnecessary redundancy in global development programs.

Comprehensive Risk Management Framework Integration

The most transformative aspect of ICH Q3E lies in its integration of comprehensive risk management principles derived from ICH Q9 throughout the entire E&L assessment process. This represents a fundamental departure from the prescriptive, one-size-fits-all approaches that have characterized previous guidance documents. The risk management framework encompasses four critical stages: hazard identification, risk assessment, risk control, and lifecycle management.

The hazard identification phase requires systematic evaluation of all materials of construction, manufacturing processes, and storage conditions that could contribute to extractables formation or leachables migration. This includes not only primary packaging components but also manufacturing equipment, single-use systems, filters, tubing, and any other materials that contact the drug substance or drug product during production, storage, or administration. The guideline recognizes that modern pharmaceutical manufacturing involves complex material interactions that require comprehensive evaluation beyond traditional container-closure system assessments.

Risk assessment under ICH Q3E employs a multi-dimensional approach that considers both the probability of extractables/leachables occurrence and the potential impact on product quality and patient safety. This assessment integrates factors such as contact time, temperature, pH, chemical compatibility, route of administration, patient population, and treatment duration. The framework explicitly acknowledges that risk varies significantly across different scenarios and requires tailored approaches rather than uniform requirements.

The risk control strategies outlined in ICH Q3E provide multiple pathways for managing identified risks, including material selection optimization, process parameter control, analytical monitoring, and specification limits. This flexibility enables pharmaceutical companies to develop cost-effective control strategies that are proportionate to the actual risks identified rather than applying maximum controls uniformly across all situations.

Lifecycle management ensures that E&L considerations remain integrated throughout product development, commercialization, and post-market surveillance. This includes provisions for managing material changes, process modifications, and the incorporation of new scientific knowledge as it becomes available. The lifecycle approach recognizes that E&L assessment is not a one-time activity but an ongoing process that must evolve with the product and available scientific understanding.

Safety Threshold Harmonization

ICH Q3E introduces a sophisticated threshold framework that harmonizes and extends the safety assessment principles developed through industry initiatives while addressing critical gaps in current approaches. The guideline establishes a risk-based threshold system that considers both mutagenic and non-mutagenic compounds while providing clear decision-making criteria for safety assessment.

For mutagenic compounds, ICH Q3E adopts a Threshold of Toxicological Concern (TTC) approach aligned with ICH M7 principles, establishing 1.5 μg/day as the default threshold for compounds with mutagenic potential. This represents harmonization with existing approaches while extending application to extractables and leachables that was previously addressed only through analogy or extrapolation.

For non-mutagenic compounds, the guideline introduces a tiered threshold system that considers route of administration, treatment duration, and patient population. The Safety Concern Threshold (SCT) varies based on these factors, with more conservative thresholds applied to high-risk scenarios such as parenteral administration or pediatric populations. This approach represents a significant advancement over current practice, which often applies uniform thresholds regardless of actual exposure scenarios or patient risk factors.

The Analytical Evaluation Threshold (AET) calculation methodology has been standardized and refined to provide consistent application across different analytical techniques and product configurations. The AET serves as the practical threshold for analytical identification and reporting, incorporating analytical uncertainty factors that ensure appropriate sensitivity for detecting compounds of potential safety concern.

The qualification threshold framework establishes clear decision points for when additional toxicological evaluation is required, reducing uncertainty and providing predictable pathways for safety assessment. Compounds below the SCT require no additional evaluation unless structural alerts are present, while compounds above the qualification threshold require comprehensive toxicological assessment using established methodologies.

Advanced Analytical Methodology Requirements

ICH Q3E establishes sophisticated analytical requirements that reflect advances in analytical chemistry and the increasing complexity of pharmaceutical products and manufacturing systems. The guideline requires fit-for-purpose analytical methods that are appropriately validated for their intended use, with particular emphasis on method capability to detect and quantify compounds at relevant safety thresholds.

The extraction study requirements have been standardized to ensure consistent generation of extractables profiles while allowing flexibility for product-specific optimization. The guideline establishes principles for solvent selection, extraction conditions, and extraction ratios that provide meaningful worst-case scenarios without introducing artifacts or irrelevant compounds. This standardization addresses a major source of variability in current practice, where different companies often use dramatically different extraction conditions that produce incomparable results.

Leachables assessment requirements emphasize the need for methods capable of detecting both known and unknown compounds in complex product matrices. The guideline recognizes the challenges associated with detecting low-level leachables in pharmaceutical formulations and provides guidance on method development strategies, including the use of placebo formulations, matrix subtraction approaches, and accelerated testing conditions that enhance detection capability.

The analytical uncertainty framework provides specific guidance on incorporating analytical variability into safety assessments, ensuring that measurement uncertainty does not compromise patient safety. This includes requirements for response factor databases, analytical uncertainty calculations, and the application of appropriate safety factors that account for analytical limitations.

Method validation requirements are tailored to the specific challenges of E&L analysis, including considerations for selectivity in complex matrices, detection limit requirements based on safety thresholds, and precision requirements that support reliable safety assessment. The guideline acknowledges that traditional pharmaceutical analytical validation approaches may not be directly applicable to E&L analysis and provides modified requirements that reflect the unique challenges of this application.

Material Science Integration and Innovation

ICH Q3E represents a significant advancement in the integration of material science principles into pharmaceutical quality systems. The guideline requires comprehensive material characterization that goes beyond simple compositional analysis to include understanding of manufacturing processes, potential degradation pathways, and interaction mechanisms that could lead to extractables formation.

The material selection guidance emphasizes proactive risk assessment during early development stages, enabling pharmaceutical companies to make informed material choices that minimize E&L risks rather than simply characterizing risks after materials have been selected. This approach aligns with Quality by Design principles and can significantly reduce development timelines and costs by avoiding late-stage material changes necessitated by unacceptable E&L profiles.

Single-use system assessment requirements reflect the increasing adoption of disposable manufacturing technologies in pharmaceutical production. The guideline provides specific frameworks for evaluating complex single-use assemblies that may contain multiple materials of construction and require additive risk assessment approaches. This addresses a critical gap in current guidance documents that were developed primarily for traditional reusable manufacturing equipment.

The guideline also addresses emerging materials and manufacturing technologies, including 3D-printed components, advanced polymer systems, and novel coating technologies. Provisions for evaluating innovative materials ensure that regulatory frameworks can accommodate technological advancement without compromising patient safety.

Comparison with Current Regulatory Frameworks

The transformative nature of ICH Q3E becomes evident when compared with existing regulatory approaches across different jurisdictions and application areas. The FDA’s 1999 Container Closure Systems guidance, while foundational, provides limited specific requirements and relies heavily on case-by-case assessment. This approach has led to significant variability in regulatory expectations and industry practice, creating uncertainty for both applicants and reviewers.

The EMA’s 2005 Plastic Immediate Packaging Materials guideline focuses specifically on plastic packaging materials and does not address the broader range of materials and applications covered by ICH Q3E. Additionally, the EMA guideline lacks specific safety thresholds, requiring product-specific risk assessment that can lead to inconsistent outcomes.

USP chapters <1663> and <1664> provide valuable technical guidance on extraction and leachables testing methodologies but do not establish safety thresholds or comprehensive risk assessment frameworks. These chapters serve as important technical references but require supplementation with safety assessment approaches from other sources.

The PQRI recommendations for orally inhaled and nasal drug products (OINDP) and parenteral and ophthalmic drug products (PODP) have provided industry-leading approaches to threshold-based safety assessment. However, these recommendations are limited to specific dosage forms and have not been formally adopted as regulatory requirements. ICH Q3E harmonizes and extends these approaches across all dosage forms while incorporating them into a formal regulatory framework.

Current European Pharmacopoeia requirements focus primarily on elemental extractables and do not address organic compounds comprehensively. The new EP chapter 2.4.35 on extractable elements represents an important advance but remains limited in scope compared to the comprehensive approach established by ICH Q3E.

ICH Q3E represents not merely an update or harmonization of existing approaches but a fundamental reconceptualization of E&L assessment that integrates the best elements of current practice while addressing critical gaps and inconsistencies.

Manufacturing Process Integration and Single-Use Systems

ICH Q3E places unprecedented emphasis on manufacturing process-related extractables and leachables, recognizing that modern pharmaceutical production increasingly relies on single-use systems, filters, tubing, and other disposable components that can contribute significantly to the overall E&L burden. This represents a major expansion from traditional container-closure system focus to encompass the entire manufacturing process.

The guideline establishes risk-based approaches for evaluating manufacturing equipment that consider factors such as contact time, process conditions, downstream processing steps, and the cumulative impact of multiple single-use components. This additive assessment approach acknowledges that even individually low-risk components can contribute to significant overall E&L levels when multiple components are used in series.

Single-use system assessment requirements address the complexity of modern bioprocessing equipment that may contain dozens of different materials of construction in a single assembly. The guideline provides frameworks for component-level assessment, assembly-level evaluation, and process-level integration that enable comprehensive risk assessment while maintaining practical feasibility.

The integration of manufacturing process E&L assessment with traditional container-closure system evaluation provides a holistic view of potential patient exposure that reflects the reality of modern pharmaceutical manufacturing. This comprehensive approach ensures that all sources of potential extractables and leachables are identified and appropriately controlled.

Biological Product Considerations and Specialized Applications

ICH Q3E provides specific considerations for biological products that reflect the unique challenges associated with protein stability, immunogenicity risk, and complex formulation requirements. Biological products often require specialized container-closure systems, delivery devices, and manufacturing processes that create distinct E&L challenges not adequately addressed by approaches developed for small molecule drugs.

The guideline addresses the potential for extractables and leachables to impact protein stability, aggregation, and biological activity through mechanisms that may not be captured by traditional chemical analytical approaches. This includes consideration of subvisible particle formation, protein adsorption, and catalytic degradation pathways that can be initiated by trace levels of extractables or leachables.

Immunogenicity considerations are explicitly addressed, recognizing that even very low levels of certain extractables or leachables could potentially trigger immune responses in sensitive patient populations. The guideline provides frameworks for assessing immunogenic risk that consider both the chemical nature of potential leachables and the clinical context of the biological product.

Cell and gene therapy applications receive special attention due to their unique manufacturing requirements, complex delivery systems, and often highly vulnerable patient populations. The guideline provides tailored approaches for these emerging therapeutic modalities that reflect their distinct risk profiles and manufacturing challenges.

Analytical Method Development and Validation Evolution

The analytical requirements established by ICH Q3E requires method capabilities that extend beyond traditional pharmaceutical analysis to encompass broad-spectrum unknown identification and quantification in complex matrices. This creates both challenges and opportunities for analytical laboratories and method development organizations.

Method development requirements emphasize systematic approaches to achieving required detection limits while maintaining selectivity in complex product matrices. The guideline provides specific guidance on extraction efficiency verification, matrix effect assessment, and the development of appropriate reference standards for quantification. These requirements ensure that analytical methods provide reliable data for safety assessment while maintaining practical feasibility.

Validation requirements are tailored to the unique challenges of E&L analysis, including considerations for compound identification confidence, quantification accuracy across diverse chemical structures, and method robustness across different product matrices. The guideline acknowledges that traditional pharmaceutical validation approaches may not be appropriate for E&L methods and provides modified requirements that reflect the specific challenges of this application.

The requirement for analytical uncertainty assessment and incorporation into safety evaluation represents a significant advancement in analytical quality assurance. Methods must not only provide accurate results but must also provide reliable estimates of measurement uncertainty that can be incorporated into risk assessment calculations.

Global Implementation Challenges and Opportunities

The implementation of ICH Q3E will require significant changes in pharmaceutical company practices, analytical capabilities, and regulatory review processes across all ICH regions. The comprehensive nature of the guideline means that virtually all pharmaceutical products will be impacted to some degree, creating both implementation challenges and opportunities for improved efficiency.

Training requirements will be substantial, as the guideline requires expertise in materials science, analytical chemistry, toxicology, and risk assessment that may not currently exist within all pharmaceutical organizations. The development of specialized E&L expertise will become increasingly important as companies seek to implement the guideline effectively.

Analytical infrastructure requirements may necessitate significant investments in instrumentation, method development capabilities, and reference standards. Smaller pharmaceutical companies may need to partner with specialized contract laboratories to access the required analytical capabilities.

Regulatory review processes will need to evolve to accommodate the risk-based approaches and comprehensive documentation requirements established by the guideline. Regulatory authorities will need to develop expertise in E&L assessment and establish consistent review practices across different therapeutic areas and product types.

The opportunities created by ICH Q3E implementation include improved regulatory predictability, reduced development timelines through early risk identification, and enhanced patient safety through more comprehensive E&L assessment. The harmonized approach should reduce the regulatory burden associated with multi-regional submissions while improving the overall quality of E&L assessments.

Future Evolution and Emerging Technologies

ICH Q3E has been designed with sufficient flexibility to accommodate emerging technologies and evolving scientific understanding. The risk-based framework can be adapted to new materials, manufacturing processes, and delivery systems as they are developed and implemented.

The guideline’s emphasis on scientific principles rather than prescriptive requirements enables adaptation to technological advances such as continuous manufacturing, advanced drug delivery systems, and personalized medicine approaches. This forward-looking design ensures that the guideline will remain relevant as pharmaceutical technology continues to evolve.

Provisions for incorporating new toxicological data and analytical methodologies ensure that the guideline can evolve with advancing scientific understanding. The lifecycle management approach enables updates and refinements based on accumulated experience and emerging scientific knowledge.

The integration with other ICH guidelines creates synergies that will facilitate future development of related guidance documents and ensure consistency across the broader ICH framework. This systematic approach to guideline development enhances the overall effectiveness of international pharmaceutical regulation.

Economic Impact and Industry Transformation

The implementation of ICH Q3E will have significant economic implications for the pharmaceutical industry, both in terms of implementation costs and long-term benefits. Initial implementation will require substantial investments in analytical capabilities, personnel training, and process modifications. However, the long-term benefits of harmonized requirements, improved regulatory predictability, and enhanced product quality are expected to provide significant value.

The harmonized approach should reduce the overall cost of global product development by eliminating duplicate testing requirements and reducing regulatory review timelines. Companies will be able to develop single global E&L strategies rather than maintaining multiple region-specific approaches.

Contract research organizations and analytical service providers will need to develop specialized capabilities to support pharmaceutical company implementation efforts. This will create new market opportunities while requiring significant investments in infrastructure and expertise.

The enhanced focus on risk-based assessment should enable more efficient allocation of resources to genuine safety concerns while reducing unnecessary testing and evaluation activities. This optimization of effort should improve overall industry efficiency while enhancing patient safety.

Patient Safety Enhancement and Risk Mitigation

The ultimate objective of ICH Q3E is enhanced patient safety through more comprehensive and scientifically rigorous assessment of extractables and leachables risks. The guideline achieves this objective through multiple mechanisms that address current gaps and limitations in E&L assessment practice.

The comprehensive material assessment requirements ensure that all potential sources of extractables and leachables are identified and evaluated. This includes not only traditional packaging materials but also manufacturing equipment, delivery device components, and any other materials that could contribute to patient exposure.

The harmonized safety threshold framework provides consistent and scientifically defensible criteria for safety assessment across all product types and administration routes. This eliminates the variability and uncertainty that can arise from inconsistent threshold application in current practice.

The risk-based approach enables appropriate allocation of assessment effort to genuine safety concerns while avoiding unnecessary evaluation of trivial risks. This optimization ensures that resources are focused on protecting patient safety rather than simply meeting regulatory requirements.

The lifecycle management requirements ensure that E&L considerations remain current throughout product development and commercialization. This ongoing attention to E&L issues helps identify and address emerging risks that might not be apparent during initial assessment.

Conclusion

ICH Q3E represents far more than an incremental improvement in extractables and leachables guidance; it establishes a new paradigm for pharmaceutical quality assurance that integrates materials science, analytical chemistry, toxicology, and risk management into a comprehensive framework that reflects the complexity of modern pharmaceutical development and manufacturing.

The guideline’s emphasis on scientific principles over prescriptive requirements creates a flexible framework that can accommodate the diverse and evolving landscape of pharmaceutical products while maintaining rigorous safety standards. This approach represents a significant maturation of regulatory science that moves beyond one-size-fits-all requirements to embrace risk-based, scientifically defensible assessment approaches.

The global harmonization achieved through ICH Q3E addresses one of the most significant challenges facing the pharmaceutical industry by providing consistent requirements and expectations across all major regulatory jurisdictions. This harmonization will facilitate more efficient global product development while enhancing patient safety through improved assessment practices.

The comprehensive scope of ICH Q3E ensures that extractables and leachables assessment evolves from a specialized concern for specific dosage forms to an integral component of pharmaceutical quality assurance across all products and therapeutic modalities. This integration reflects the reality that E&L considerations impact virtually all pharmaceutical products and must be systematically addressed throughout development and commercialization.

As the pharmaceutical industry prepares for ICH Q3E implementation, the focus must be on building the scientific expertise, analytical capabilities, and quality systems necessary to realize the guideline’s potential for enhancing patient safety while improving development efficiency. The successful implementation of ICH Q3E will mark a new era in pharmaceutical quality assurance that better serves patients, regulators, and the pharmaceutical industry through more rigorous, consistent, and scientifically defensible approaches to extractables and leachables assessment.

The transformation initiated by ICH Q3E extends beyond technical requirements to encompass fundamental changes in how pharmaceutical companies approach material selection, process design, analytical strategy, and risk management. This holistic transformation will ultimately deliver safer, higher-quality pharmaceutical products to patients worldwide while establishing a more efficient and predictable regulatory environment that facilitates innovation and global access to medicines.

Six stages:

Material Selection (beaker)

Hazard Identification (warning triangle)

Risk Assessment (scale)

Risk Control (shield)

Lifecycle Management (circular arrows)

Post-Market Surveillance (radar/monitoring icon)

WHO Points to Consider on Continuous Manufacturing

The World Health Organization (WHO) has recently released draft guidelines on continuous manufacturing (CM) in the pharmaceutical industry, marking a significant step towards global harmonization of this innovative manufacturing approach. This guidance comes a few years after the International Council for Harmonisation’s (ICH) Q13 guideline, which was finalized in 2023. Let’s explore the main points of the WHO draft guidance and how it compares to ICH Q13.

Key Points of WHO Draft Guidance on Continuous Manufacturing

Risk Management

The document emphasizes the importance of robust risk management strategies in CM processes. Manufacturers are expected to identify, assess, and mitigate potential risks associated with the continuous nature of production.

Control Strategies

WHO outlines best practices for developing and implementing effective control strategies in CM. This includes real-time monitoring and control of critical process parameters and quality attributes.

Process Dynamics

The guidance addresses the unique challenges of managing process dynamics in continuous systems, including strategies for handling transient states and disturbances.

Validation of Computerized Systems

Given the heavy reliance on automation and digital systems in CM, the WHO document provides specific guidance on validating computerized systems used in continuous manufacturing processes.

Batch Definition and Traceability

The guidance offers recommendations on defining batches in a continuous process and ensuring traceability throughout the manufacturing chain.

Comparison with ICH Q13

While the WHO draft guidance and ICH Q13 share many common elements, there are some notable differences and complementary aspects:

Scope and Applicability

ICH Q13: Applies to CM of drug substances and drug products for chemical entities and therapeutic proteins, including biosimilars.
WHO Guidance: Likely to have a broader scope, covering even excipient manufacturing.

Regulatory Approach

ICH Q13: Provides a harmonized approach for regulatory submissions and assessments across ICH member countries.
WHO Guidance: Aims to provide a global framework that can be adopted by regulatory authorities worldwide, especially in countries not part of ICH.

Technical Detail

ICH Q13: Offers in-depth technical guidance, including annexes for specific types of products and manufacturing scenarios.
WHO Guidance: May provide more general principles and best practices that can be adapted to various regulatory and manufacturing contexts.

Implementation Focus

ICH Q13: Emphasizes scientific and regulatory considerations for development, implementation, and lifecycle management of CM.
WHO Guidance: Likely to include more practical considerations for implementing CM in diverse manufacturing environments, including resource-limited settings.

Implications for the Pharmaceutical Industry

The release of the WHO draft guidance on continuous manufacturing, following ICH Q13, signifies a growing global consensus on the importance and potential of CM in pharmaceutical production. This alignment between major global health organizations is expected to:

Accelerate the adoption of continuous manufacturing technologies worldwide.
Provide clearer pathways for regulatory approval of CM processes, especially in non-ICH countries.
Encourage innovation in pharmaceutical manufacturing, potentially leading to more efficient and flexible production of essential medicines.
Improve global supply chain resilience by enabling more localized and adaptable manufacturing capabilities.

As the pharmaceutical industry continues to evolve, the harmonization of guidance documents from WHO and ICH on continuous manufacturing will play a crucial role in shaping the future of drug production. Manufacturers, regulators, and other stakeholders should closely follow the finalization of these guidelines and prepare for a new era of pharmaceutical manufacturing that promises improved quality, efficiency, and accessibility of medicines worldwide.

Requirements for Knowledge Management

I was recently reviewing the updated Q9(R1) Annex 1- Q8/Q9/Q10 Questions & Answers (R5) related to ICH Q9(R1) Quality Risk Management (QRM) that were approved on 30 October 2024 and what they say about knowledge management. While there are some fun new questions asked, I particularly like “Do regulatory agencies expect to see a formal knowledge management approach during inspections?”

To which the answer was: “No. There is no regulatory requirement for a formal knowledge management system. However. it is expected that knowledge from different processes and
systems is appropriately utilised. Note: ‘formal’ in this context means a structured approach using a recognised methodology or (IT-) tool, executing and documenting something in a transparent and detailed manner.”

What does appropriately utilized mean? What is the standard for determining it? The agencies are quite willing to leave that to you to figure out.

As usual I think it is valuable to agree upon a few core assumptions for what appropriate utilization of knowledge management might look like.

Accessibility and Sharing

Knowledge should be easily accessible to those who need it within the organization. This means:

Implementing centralized knowledge repositories or databases
Ensuring information is structured and organized for easy retrieval
Fostering a culture of knowledge sharing among employees

Relevance and Accuracy

Appropriately utilized knowledge is:

Up-to-date and accurate
Relevant to the specific needs of the organization and its employees
Regularly reviewed and updated to maintain its value

Integration into Processes

Knowledge should be integrated into the organization’s workflows and decision-making processes:

Incorporated into standard operating procedures
Used to inform strategic planning and problem-solving
Applied to improve efficiency and productivity

Measurable Impact

Appropriate utilization of knowledge should result in tangible benefits:

Improved decision-making
Increased productivity and efficiency
Enhanced innovation and problem-solving capabilities
Reduced duplication of efforts

Continuous Improvement

Appropriate utilization of knowledge includes a commitment to ongoing improvement:

Regular assessment of knowledge management processes
Gathering feedback from users
Adapting strategies based on changing organizational needs

ICH Document Structure, a Call for Change

The International Conference for Harmonization (ICH) has guidelines categorized into four main categories:

Quality (Q) Guidelines focus on the chemical, pharmaceutical, and biological quality standards, including stability testing protocols to ensure the longevity and consistency of drug products.
Safety (S) Guidelines address non-clinical and preclinical safety evaluations, guiding the toxicological assessments necessary to protect patients’ health.
Efficacy (E) Guidelines cover the clinical aspects of pharmaceutical development, providing standards for designing, conducting, and analyzing clinical trials to ensure therapeutic benefits.
Multidisciplinary (M) Guidelines encompass guidelines that do not fit neatly into the other categories, dealing with genomics, terminologies, and technical aspects of drug registration.

Any Q document is instantly and rightly viewed as a GMP guideline. This includes the quality trio, which, while they have a good philosophy, are still written specifically for GMP purposes. So, if you write your paper, good practice guide, standard, article, or what-have-you and refer heavily to the Q trio, you are either writing a GMP-centered piece or losing most of your audience.

The frustrating thing is that quality-by-design (Q8), risk management (Q9), and quality system management (Q10) are core concepts that apply across the pharmaceutical lifecycle, and there are best practices across all three that can and should be universal, especially Q9(r1), which can really better define risk management as defined in E6, and Q10, which can really shore up parts of E8.

What I would love to see the ICH do is write a technical reference document on risk management. Then, E6 and Q9 would have specific implementation aspects related to their focus. Put all the shared approaches in one place and build on them. The amusing thing is that they are already doing that. For example, Q13 applies the Q trio to continuous manufacturing, and Q14 applies it to the analytical lifecycle.

But for now, if you are writing and just referring to Q9 and Q10 don’t be surprised when all your clinical and safety colleagues tune you out.