Life Sciences Blog

Annex 15 Revision for APIs: What Manufacturers Must Prepare Now

Jo Doucet, Division Head Qualification/Validation at QbD Group — Wed, 25 Feb 2026 12:45:39 GMT

The EMA concept paper on revising Annex 15 sends a clear signal: qualification and validation for active substance (API) manufacturers are moving from supplementary guidance toward a mandatory, risk-based expectation. For many API sites, this will require rethinking how process knowledge, validation strategy, and change control integrate across the lifecycle.

Today, Annex 15 is optional supplementary guidance for active substance manufacturers alongside EudraLex Volume 4 Part II. The concept paper proposes making it formally mandatory for chemical and biological APIs. This shift is largely driven by the nitrosamine crisis in sartans, where investigations revealed insufficient process and product understanding, weak contamination control, and GMP deficiencies at API manufacturers.

The revised Annex 15 is expected to strengthen expectations for process development, clarify concurrent validation, extend third-party validation oversight, and emphasise robust failure investigations and transport validation under a stronger quality risk management (QRM) framework aligned with ICH Q9(R1).

This article outlines what API manufacturers should prepare now to align qualification and validation practices with the forthcoming Annex 15 expectations.

From Guidance to Compliance Anchor

For API manufacturers, the impact is twofold. Regulators will expect a more structured, documented approach to qualification and validation, and they will verify it during inspections of API facilities under EU and PIC/S inspectorates.

Topics such as User Requirement Specifications (URS), FAT/SAT, full qualification stages (DQ/IQ/OQ/PQ), process validation (including solvent recovery), transport verification, and periodic review will become explicit compliance anchors rather than optional good practice. This also implies stronger control over outsourced validation work and clearer, data-driven investigations when acceptance criteria are not met.

Preparing a Risk-Based Validation Lifecycle

QbD Group supports API manufacturers in translating these evolving Annex 15 expectations into a pragmatic, lifecycle-based validation roadmap rather than a last-minute compliance scramble.

Building on experience in Annex 15 and risk-based validation, QbD performs structured gap assessments against the evolving Annex 15 text and Part II, identifying where current qualification, validation, and change control practices fall short. Using QRM tools aligned with ICH Q9(R1), QbD supports redesign of validation master plans, process validation strategies (including continuous process verification or hybrid models), and supplier or third-party validation oversight.

Consultants also help define or refine URS, FAT/SAT, and lifecycle qualification strategies for equipment and systems critical to API quality, embedding risk review and periodic requalification within the Pharmaceutical Quality System.

Building an Inspection-Ready Validation Story

QbD also coaches API manufacturers in building an inspection-ready validation story: how development data, risk assessments, validation protocols, deviation investigations, and transport studies collectively demonstrate control of critical quality attributes and prevention of unexpected impurities such as nitrosamines.

Acting now, during the concept and draft guideline phase, allows API companies to spread workload, pilot updated approaches on selected processes, and enter the final Annex 15 implementation phase with a mature, defensible validation framework rather than reacting to corrective actions after inspections.

Preparing API validation systems for the Annex 15 revision?

QbD Group helps API manufacturers assess gaps, redesign lifecycle validation strategies, and build inspection-ready qualification frameworks aligned with Annex 15 and ICH Q9(R1).

👉Talk to our API validation experts.

EU Expansion Strategy for US Biotechs: What to Get Right Early

Angeles Escartí-Nebot, Global Head Regulatory Affairs at QbD Group — Wed, 18 Feb 2026 14:21:59 GMT

For a US biotech with a proven track record at home, EU and UK expansion is often the next logical growth step. But while Europe offers access to multiple high-value markets and a sophisticated scientific ecosystem, it operates through distinct regulatory pathways, country-level realities, and operational obligations that can catch teams off guard when an FDA-ready strategy is assumed to apply directly.

The opportunity is real. The difference between a smooth market entry and a costly detour usually comes down to one thing: early strategic planning grounded in real European regulatory experience.

In summary: structured EU expansion creates long-term value

Europe is technically demanding, but that is not a barrier. It is an environment where disciplined planning creates an advantage. For late-stage US biotechs, a strong EU and UK roadmap can accelerate value inflection points, open partnering opportunities, and reduce rework by aligning expectations early.

Successful EU expansion is typically driven by three principles:

Selecting the right pathway based on product characteristics and ambition
Designing EU and UK plans that acknowledge regional differences
Building an execution model that fits organisational size and maturity

When these elements are in place, EU expansion becomes what it should be: a structured path toward sustainable growth.

From EU expansion strategy to execution

Successful EU and UK expansion requires more than regulatory knowledge; it requires an integrated strategy that connects pathway selection, clinical planning, CMC readiness, and operational governance.

QbD Group supports US biotechs in planning and executing EU expansion strategies that are realistic, scalable, and aligned with European regulatory expectations. 👉 Get in touch to discuss how to build a robust EU and UK expansion roadmap

Get in touch to discuss how to build a robust EU and UK expansion roadmap.

The Role of Residual Solvent Testing in Pharmaceuticals | QbD Group

Yves Peeraer, Division Head Lab Services at QbD Group — Wed, 18 Feb 2026 13:25:58 GMT

Patient safety is a foundational responsibility of the pharmaceutical industry, and residual solvent testing is a critical element in safeguarding that responsibility.

Organic solvents are widely used during the manufacture of drug substances and drug products, yet many are associated with acute toxicity, long-term health risks, or environmental concerns. Even at low levels, residual solvents can pose unacceptable risks if patient exposure exceeds established safety thresholds.

Regulatory authorities, therefore, require pharmaceutical manufacturers to demonstrate, through robust residual solvent testing, that solvent residues are consistently controlled throughout a product’s lifecycle. This testing provides the analytical evidence that manufacturing processes, purification steps, and control strategies effectively minimize patient exposure.

By verifying compliance with toxicological limits defined in ICH Q3C and related pharmacopeial standards, residual solvent testing helps ensure that medicines are not only effective, but also safe for both short-term and chronic use.

Regulatory expectations for residual solvent testing

Pharmaceutical manufacturers are expected to monitor and control residual solvents in accordance with ICH Q3C and applicable pharmacopeial requirements, including USP <467>, Ph. Eur., and the Japanese Pharmacopoeia. Across regions, regulators expect a risk-based, scientifically justified approach that includes:

Use of validated and stability-indicating analytical methods
Sufficient sensitivity to meet permitted daily exposure (PDE) limits
Demonstrated specificity for target solvents
Robustness and reproducibility suitable for routine GMP testing

Gas chromatography is the preferred analytical technique for residual solvent analysis, due to its ability to separate and detect volatile compounds at low concentrations in complex pharmaceutical matrices.

Gas chromatography for residual solvent analysis

Gas chromatography methods for residual solvent testing typically employ headspace sampling. This technique allows volatile solvents to partition into the gasphase, while minimizing interference from non-volatile sample components. As a result, headspace GC improves method reproducibility and reduces the risk of contamination or carryover within chromatographic systems.

Within pharmaceutical laboratories, two detection techniques are most commonly used: Flame Ionization Detection and Mass Spectrometry.

Conclusion

Residual solvent testing plays a direct role in protecting patients by ensuring that pharmaceutical products comply with established safety thresholds for solvent exposure.

Through the complementary use of GC-FID and GC-MS, manufacturers can both quantify known residual solvents and confidently identify unexpected compounds.

These analytical techniques remain essential tools for supporting regulatory compliance, process understanding, and the industry’s broader responsibility to deliver safe, high-quality medicines.

Need support with residual solvent strategy or analytical testing?

QbD Group supports pharmaceutical and biotech companies with method development, validation, and GMP-compliant residual solvent testing, aligned with ICH Q3C and global pharmacopeial expectations.

Don’t hesitate to get in touch.

Scaling PV Governance in Europe: Keeping Oversight as Organizations Grow

Fri, 13 Feb 2026 13:43:42 GMT

For many European SMEs and biotechs, pharmacovigilance typically begins as a lean setup. A small internal team, a focused geographic scope, and one or two trusted partners are often sufficient to remain compliant and keep operations running smoothly. This model is practical and efficient in the early stages of growth. As the organization expands, however, the same setup can start to show its limits.

Growth brings new countries, partners, higher case volumes, and increasing regulatory expectations. Pharmacovigilance no longer simply means handling more work; it involves managing greater system complexity across an expanding PV network. This is often where governance starts to feel like a burden, but it does not have to.

When designed with scalability in mind, PV governance can become a practical enabler of growth rather than a constraint.

This article discusses how PV governance needs to evolve as European SMEs and biotechs scale, and how to maintain EU-QPPV oversight and inspection readiness in a growing pharmacovigilance system.

Building a Scalable Governance Structure

Why governance needs to change as your organization evolves

In earlier stages, oversight is often informal, with decisions taken quickly, roles overlapping, and communication flowing naturally because everyone is close to the work. As organizations grow, that same informality starts to create risk. Responsibilities blur, assumptions replace clarity, and issues are identified later than they should be.

Scaling governance is not about adding bureaucracy, but about creating a clear and proportionate framework that ensures accountability, transparency, and control across an increasingly distributed PV system. Done well, it allows companies to scale faster, onboard vendors more confidently, and respond to regulatory expectations without constantly reinventing the wheel.

The role of the EU-QPPV and structured oversight

A scalable governance model ensures that the EU-QPPV has access to the right information at the right time, supported by clear escalation pathways, defined governance forums, and agreed decision thresholds that guide how and when key issues are addressed, in line with EU GVP Module I expectations for QPPV oversight.

This structure helps avoid the common trap of having a QPPV “on paper” while critical PV activities are managed elsewhere without sufficient visibility or control. For SMEs and biotechs, this level of clarity is empowering.

It allows senior PV roles to focus on risk management and informed decision-making rather than chasing fragmented information or resolving misalignments that could have been prevented through better coordination.

Aligning internal teams and external partners

Outsourcing is often a strategic necessity when scaling PV. However, adding vendors without adapting governance can increase complexity rather than reduce it. A scalable governance framework clarifies how internal teams, vendors, and local partners interact, defining who is responsible for what, how performance is monitored, and how issues are escalated and resolved.

Importantly, it establishes clear expectations not only at the contractual level but in day-to-day collaboration. Mechanisms such as vendor oversight models, safety governance meetings, and defined performance indicators help teams and partners operate in a consistent and controlled way as the PV system expands.

From Operational Control to Inspection Readiness

Moving from reactive oversight to proactive control

One of the main advantages of scaling governance early is the ability to move from reacting to problems to anticipating them. Organizations gain regular insight into how their PV system performs instead of discovering issues during audits or inspections.

Simple governance mechanisms such as periodic safety governance meetings, defined performance indicators, and structured management reviews provide early signals that support informed decision-making and continuous improvement, without the need for heavy technical infrastructure.

Inspection readiness as a natural outcome, not the main objective

A scalable governance model supports inspection readiness as part of normal operations, with clearly documented roles, traceable oversight activities, and consistently recorded decisions. This allows the PV system to present a coherent picture of how safety is managed as the company grows.

For SMEs and biotechs, this represents a significant advantage. It reduces stress, builds confidence, and allows teams to focus on their core mission rather than constantly responding to urgent compliance issues.

Conclusion: Scaling with the Right Foundations for Long-Term Growth

The key message is simple. Scaling your PV system is not a sign that something has gone wrong; it is a clear indication that your business is moving forward andentering a new stage of maturity.

When governance is designed with scalability in mind, it enables sustainable growth, supports flexible outsourcing strategies, and strengthens long-term compliance by connecting operating models, systems, people, and regulatory expectations into a coherent framework.

In practice, this is much easier to achieve when companies work from an early stage with specialized pharmacovigilance partners who understand both regulatory expectations and scalable operating models, helping to design governance structures that evolve smoothly as the organization expands.

Scaling pharmacovigilance operations across Europe?

QbD Group helps SMEs and biotechs design scalable PV governance models that maintain EU-QPPV oversight, vendor control, and inspection readiness as organizations grow.

Don’t hesitate to get in touch.

Annex 1 Cleanrooms, Isolators & RABS: Designing for Aseptic Compliance

Jo Doucet, Division Head Qualification/Validation at QbD Group — Fri, 13 Feb 2026 13:22:12 GMT

EU GMP Annex 1 has accelerated a shift that many manufacturers were already moving toward. Regulators increasingly expect contamination control to be engineered into the facility and process design, not managed through procedural workarounds.

In practice, that means cleanroom performance, airflow protection, and barrier technologies are now assessed as part of a single contaminationcontrol strategy, rather than as independent compliance topics.

This article explains how Annex 1 expectations reshape cleanroom and barrier design decisions, and what manufacturers need to demonstrate during inspection.

Why cleanroom and barrier decisions now drive inspection outcomes

Annex 1 makes clear that sterile operations must be performed in an environment appropriate to the activity, using defined cleanroom grades and controls. It also explicitly positions Restricted Access Barrier Systems and isolators as beneficial for minimizing contamination linked to direct human intervention in the critical zone, and it expects alternative approaches to be justified within the CCS.

This has two direct implications for manufacturers who are still operating conventional Grade A and B cleanrooms without robust separation principles.

First, inspectors are less concerned with whether a room complies with particle limits under static conditions and more focused on whether the process remains protected during real operations.
Second, regulators increasingly focus on the points where the cleanroom concept breaks down, such as open manipulations, frequent interventions, weak separation, and poorly controlled material and personnel flows.

Barrier technologies are not a standalone solution, but they significantly reduce one of the most persistent sources of aseptic risk: human intervention.

FDA has made a similar point for years, highlighting that isolator systems separate the aseptic process from the surrounding cleanroom and minimize exposure to personnel, provided they are well-designed and adequately maintained, monitored, and controlled.

What Annex 1 Really Expects from Facility and Barrier Improvements

A cleanroom or barrier upgrade is often misunderstood as a single capital project. In reality, Annex 1 pushes manufacturers to treat facility and barrier decisions as part of an integrated risk control approach. That includes:

the background environment,
the interface between critical and surrounding zones,
decontamination approaches,
glove management for barrier systems,
and how the overall design limits the need for interventions.

In practical terms, upgrades typically fall into three categories:

Inspection Expectations and Supporting Documentation

One recurring theme across Annex 1 and long-standing FDA expectations is that sterile manufacturing control must be demonstrated, not assumed. For cleanrooms and barrier systems, that demonstration often comes down to three types of evidence:

Where Remediation Projects Commonly Get Delayed

In our experience, the most common delays and cost escalations do not come from deciding to implement barrier technology. They come from treating cleanroom upgrades, barrier selection, and qualification evidence as separate workstreams.

For example, airflow visualization is sometimes planned late, after equipment is installed and operating procedures are already fixed. When smoke studies reveal airflow disruption or contamination pathways, the remediation becomes expensive because the facility and line configuration are already locked.

Similarly, facility design changes are sometimes made without a clear link to CCS logic, which creates a documentation gap that regulators will challenge.

A Practical Approach to Planning Annex 1 Upgrades

A strong approach starts with defining the risk drivers of the operation and the intervention profile, then selecting the barrier and background strategy that best controls those risks. The CCS should capture this rationale, and the qualification plan should be built to demonstrate protection under real operating conditions.

This is also where an integrated support model adds value. Facility design and qualification activities must align with the barrier strategy. Airflow visualization must be planned as evidence, not as a late-stage test. Technology decisions should be anchored to contamination control logic rather than vendor preferences.

Conclusion

Annex 1 has raised the bar for how cleanroom design and barrier technologies are justified and demonstrated. Manufacturers that treat cleanroom classification, barrier selection, and qualification evidence as one coherent program are better positioned to avoid late remediation, inspection surprises, and credibility loss.

The most efficient path is not necessarily the most complex technology; it is the one that reduces interventions, demonstrates protection in operation, and fits into a well-structured contamination control strategy.

Planning Annex 1 cleanroom or barrier upgrades?

QbD Group supports manufacturers with integrated facility, barrier, and CCS strategies, from concept through qualification and inspection readiness.

Talk to our aseptic manufacturing experts.

Early Orphan Strategy: Regulatory & Commercial Considerations Across EU, US & UK

Angeles Escartí-Nebot, Global Head Regulatory Affairs at QbD Group — Fri, 13 Feb 2026 11:09:20 GMT

Deciding whether an orphan strategy fits a development program requires more than assessing headline incentives. Differences in regulatory definitions, evidentiary thresholds, timing, exclusivity, and incentives across regions can materially influence both development planning and long-term commercial value. For early-stage biotech teams, these considerations belong in early strategic decision-making, not as a late regulatory exercise.

Regulatory definitions shape feasibility

Orphan eligibility is not defined uniformly across regions. In the EU and UK, designation depends not only on rarity but also on disease severity. The condition must be life-threatening or seriously debilitating and affect no more than 5 in 10,000 people.

In the US, orphan status is primarily prevalence-driven, focusing on conditions affecting fewer than 200,000 patients nationally, with an alternative pathway where development costs are unlikely to be recovered.

For global programs, this means that a product may clearly qualify as an orphan in the US, while requiring a more robust and carefully justified case in Europe and the UK that addresses epidemiology, disease burden, and unmet medical need in parallel.

Existing therapies raise the evidentiary bar

The presence of authorised therapies directly affects orphan positioning, particularly in Europe. In the EU and UK, if satisfactory methods of diagnosis, prevention, or treatment already exist, orphan designation can only be granted if the product demonstrates a significant benefit, such as a clinically relevant advantage or a major contribution to patient care.

This concept sits at the core of the European orphan framework and has practical implications for early development choices, including endpoint selection, comparator strategy, and overall clinical positioning. In the US, orphan designation does not rely on an equivalent structured significant-benefit assessment at the designation stage, resulting in a different regulatory dynamic even when the clinical context appears similar.

Timing matters and differs by region

Timing is a critical strategic variable. In the EU, orphan designation may be requested at any point prior to submission of the marketing authorisation application, including early development stages, provided sufficient justification is available.

Importantly, orphan criteria must not only be met at designation but must also be maintained and re-assessed at the time of approval to secure exclusivity. Early designation, therefore, represents a long-term strategic commitment rather than a single regulatory milestone.

In the US, orphan designation can similarly be requested at any time before NDA or BLA submission, including during preclinical or early clinical development. The UK follows a different model.

There is no standalone early orphan designation procedure, and orphan status is assessed as part of the marketing authorisation process itself. As a result, UK orphan strategy is inherently linked to the strength, consistency, and maturity of the full dossier rather than to an earlier designation decision.

Exclusivity differences affect lifecycle planning

Market exclusivity provisions further influence strategic planning. In the EU, orphan designation can confer 10 years of post-approval market exclusivity, with potential extensions linked to paediatric obligations.

The UK similarly offers up to 10 years of exclusivity, although this may be reduced in specific circumstances. In contrast, the US provides seven years of exclusivity for the approved orphan indication.

These differences can meaningfully affect lifecycle management, follow-on indications, and geographic launch sequencing, and should be factored into early commercial, clinical, and investment decisions.

Incentives are real but not equivalent

The tangible value of orphan designation varies by region. In the EU, orphan status provides access to regulatory incentives such as fee reductions for Protocol Assistance and other regulatory interactions, directly influencing development costs and agency engagement strategy.

In the US, the orphan framework is more financially oriented, offering incentives such as tax credits for qualified clinical trials and exemptions from certain FDA user fees. The UK provides its own fee incentives and refunds, but these differ in scope and structure from those available in the EU.

As a result, the point at which orphan designation delivers meaningful value, and how that value supports development, is highly region-dependent.

A strategic decision with long-term impact

Taken together, these differences reinforce a key conclusion. Deciding early whether an orphan strategy fits is a strategic developer decision, not merely a regulatory one.

Definitions, evidentiary expectations, timing constraints, exclusivity periods, and incentives differ across the EU, US, and UK, and each can shape development design, risk exposure, investment priorities, and long-term program value.

Teams that assess these dimensions early are better positioned to build a coherent, globally aligned orphan strategy that supports regulatory success while enabling sustainable development and informed decision-making.

Need support defining your orphan strategy early?

QbD Group supports biotech teams in translating scientific potential into a regulator-ready, globally coherent orphan strategy, from early positioning and designation planning to evidence generation and lifecycle optimisation.

Speak with our regulatory and development experts to de-risk your path forward.

Nitrosamine Impurities in Medicinal Products: Risks and Regulatory Insights | QbD Group

Pablo Palomar, Senior Toxicology Officer at QbD Group — Mon, 09 Feb 2026 14:00:00 GMT

The emergence of nitrosamine impurities

In June 2018, regulatory authorities worldwide became aware of the presence of the nitrosamine N-nitrosodimethylamine (NDMA) in valsartan, an active pharmaceutical ingredient (API) manufactured by a specific producer.

Subsequently, another nitrosamine, N-nitrosodiethylamine (NDEA), was also detected in valsartan and other sartan-containing APIs from additional manufacturers.

NDMA and NDEA are classified as probable human carcinogens, and their unexpected presence in sartans was concerning. Since then, nitrosamine impurities have been identified in several other medicinal products containing diverse APIs, such as ranitidine, metformin, and pioglitazone.

This widespread detection of nitrosamine contaminants has prompted regulatory bodies, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), to take action and address the issue.

Regulatory guidance and risk evaluation

In accordance with:

the CHMP opinion under Article 5(3) of Regulation (EC) No. 726/2004, “Questions and Answers for marketing authorization holders/applicants on the CHMP Opinion for Article 5(3) of Regulation (EC) No. 726/2004 referral on nitrosamine impurities in human medicinal products” (EMA/409815/2020)
and the FDA’s Guidance for Industry, “Control of Nitrosamine Impurities in Human Drugs,”

Marketing Authorisation Holders (MAHs), together with API and finished product manufacturers, are required to perform risk evaluations using quality risk management principles, as outlined in the ICH Q9 guideline.

These risk evaluations must consider the potential for nitrosamine impurities to form not only from NDMA and NDEA but also from any other nitrosamine impurity that might occur, such as NMBA, DIPNA, or EIPNA, among others.

Identifying root causes

The current “Questions and Answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral” and the FDA’s Guidance for Industry have identified several potential root causes for the presence of nitrosamine impurities:

Comprehensive evaluation and mitigation strategies

To address the issue of nitrosamine impurities, a comprehensive evaluation of the entire manufacturing process, from the API synthesis to the finished product, is required.

This evaluation must consider all potential sources of nitrosamine formation, including the use of chemicals, equipment, and packaging materials.

Based on the identified risks, appropriate mitigation strategies must be implemented to ensure the quality and safety of the medicinal products.

These strategies may include process modifications, the use of alternative reagents or solvents, the implementation of robust control measures, and the development of sensitive analytical methods to detect and quantify nitrosamine impurities.

Current trends in nitrosamine regulation

Since the emergence of nitrosamine impurities in pharmaceuticals, the relevant regulatory agencies have been updating their guidance on risk analysis for these contaminants.

In particular, the focus has recently shifted to the assessment of the possible formation of Nitrosamine Drug Substance Related Impurities (NDSRIs).

The updates to the EMA/409815/2020 guideline and the FDA’s Guidance for Industry, “Control of Nitrosamine Impurities in Human Drugs,” published in the summer of 2023, are noteworthy in this regard.

These updates introduced the Carcinogenic Potency Categorisation Approach (CPCA) for the establishment of an Acceptable Intake (AI) value for NDSRIs without robust carcinogenic data. CPCA enables the determination of an AI based on the structure of the nitrosamine, eliminating the need for comparison with structural analogues.

This method assumes that the α-hydroxylation mechanism of metabolic activation is responsible for the observed mutagenic and carcinogenic response in many N-nitrosamines. Using the CPCA also establishes a Potency Category from 1 to 5 for NDRSIs, with category 1 and 2 nitrosamines being of most concern.

These regulatory updates reflect the ongoing efforts by authorities to address the issue of nitrosamine impurities in a comprehensive and scientifically robust way.

As of December 2025, the European Medicines Agency (EMA) published an update to Appendix 1 (EMA/42261/2025/Rev. 11) of the Nitrosamines Guideline, which establishes Acceptable Intake (AI) values for additional nitrosamine drug substance–related impurities (NDSRIs) associated with several active substances and process-related sources. These updated AIs add clarity on acceptable exposure levels for certain NDSRIs and may impact existing risk conclusions, particularly for APIs such as levodropropizine, cytisine, lumefantrine, mifepristone, tapentadol and selumetinib. Sponsors are advised to review whether these updated intake values affect their previous evaluations and confirmatory analyses.

Our commitment to nitrosamine risk assessments

At the QbD Group, we are committed to ensuring the quality and safety of pharmaceutical products by conducting comprehensive Risk Assessment Reports for nitrosamine impurities in compliance with all relevant regulations, as well as laboratory analysis for their determination and quantification.

Our team of experts works closely with clients to identify potential sources of nitrosamine formation, calculate acceptable limits, and help them address any agency responses or concerns.

We are dedicated to staying at the forefront of the latest regulatory developments and providing you with the guidance you need to navigate the complex landscape of nitrosamine impurity control.

Contact us today to learn how we can help you ensure the safety and quality of your medicinal products.

Early Biotech Strategy: Key Choices Before First-in-Human

Angeles Escartí-Nebot, Global Head Regulatory Affairs at QbD Group — Wed, 04 Feb 2026 17:01:11 GMT

For early-stage biotech teams, the most consequential decisions are rarely the ones made just before first-in-human (FIH). They’re made much earlier, when the science is promising, resources are tight, and every month of runway matters.

Across the EU, UK, and US, different regulatory pathways, expectations, and market realities mean those early choices shape not just what you develop, but where and how you can realistically bring it to the clinic. What looks like optional planning at the preclinical stage often turns into delays, rework, or lost credibility later.

Below are the key questions developers should be asking well before FIH, not to slow progress, but to enter the clinic with intent, reduce avoidable risk, and protect long-term value.

In summary

Taken together, these principles highlight a simple reality: successful entry into the clinic is shaped well before the first subject is dosed. Developers who address these questions early don’t just reach first-in-human; they arrive prepared, credible, and positioned to progress with confidence.

If you’re at this stage and want to sense-check your development strategy, QbD Group works with biotech teams to translate early decisions into regulatory-ready execution. From regulatory strategy and scientific advice to CMC, quality, clinical operations, and safety, our experts help build coherent, scalable pathways toward first-in-human and beyond.

Let’s talk about how we can support your team.

Contamination Control Strategy and Aseptic Process Design Under Annex 1

Wed, 28 Jan 2026 15:36:04 GMT

The EU GMP Annex 1 has made one message unmistakably clear: in sterile manufacturing, compliance is no longer demonstrated by isolated controls. Regulators expect manufacturers to show a joined-up system that prevents contamination, detects weaknesses early, and continuously improves.

The practical vehicle for that system is the Contamination Control Strategy (CCS), supported by an aseptic process design grounded in Quality Risk Management (QRM) and proven in routine operation.

Why does CCS play a central role in Annex 1?

Annex 1 describes the CCS as an overarching strategy that links Contamination Controls across facility design, equipment, utilities, procedures, personnel, and monitoring. CCS ensures contamination risks are managed throughout the entire lifecycle.

A CCS is not a document prepared for inspection. It is the documented explanation of how a sterile process remains in control of contaminations and how the organization demonstrates that control over time.

A strong CCS also addresses a common organizational challenge: sterility assurance responsibilities are often fragmented across QA, Engineering, Manufacturing, Validation, and Microbiology. While each function may manage its own contamination controls, no single view connects the full picture. A CCS forces that integration, making gaps visible, responsibilities clear, and remediation priorities defensible.

Aseptic process design: where strategy meets physics

The CCS is only effective if the underlying process is designed to minimize contamination risk from the outset. Annex 1, therefore, pushes manufacturers toward risk-based aseptic process design, where high-risk steps are engineered out, isolated, or robustly protected through barriers and airflow control.

In practice, this requires a clear definition of:

Inspection findings frequently arise when there is a weak link between intended process design and what a site can actually demonstrate in practice.

What regulators look for and what enforcement trends reveal

Regulatory authorities demand that contamination control be both demonstrable and effective. However, enforcement trends and warning letters frequently reveal recurring failures. Common issues include weak aseptic process controls, insufficient validation of critical steps, poor oversight of interventions, and inadequate corrective actions following sterility breaches.

While challenges differ for each site, the underlying pattern is consistent: without a coherent, risk-based CCS, organizations rely on fragmented controls and reactive responses instead of proactive, risk-based prevention and continuous control.

What should a usable CCS contain?

A practical CCS enables technical leaders to answer three fundamental questions: What are our risks? What are the controls that mitigate them? How do we prove that those controls remain effective?

A concise and usable CCS typically includes:

Connecting CCS to Annex 1 remediation

Annex 1 describes the CCS functions as the most effective organizing framework because it naturally prioritizes effort. The different gaps identified in remediation programs will enhance your compliance level:

This is why CCS works so well as an entry point. It replaces checklist-driven remediation with a shared, risk-based structure that helps decision-makers determine what to fix first.

In summary

Annex 1 raises expectations from simply having controls to proving that controls are integrated, risk-based, and effective over time and a well-constructed CCS, anchored in robust aseptic process design, is the most practical way to meet that expectation.

It transforms regulatory requirements into an operational system that can be improved, defended, and scaled as sterile manufacturing operations evolve.

From Annex 1 requirements to practical implementation

Meeting Annex 1 expectations requires more than documentation; it requires a CCS that truly reflects how your process works in practice. QbD Group supports manufacturers in assessing, designing, and operationalizing Contamination Control Strategies that align aseptic process design, quality risk management, and regulatory expectations.

Get in touch to discuss how your CCS supports Annex 1 compliance in real life.

Designing Meaningful Dissolution Tests in Pharma | QbD Group

Yves Peeraer, Division Head Lab Services at QbD Group — Wed, 17 Dec 2025 14:51:16 GMT

Designing a dissolution test is rarely a purely theoretical exercise. In practice, teams must balance scientific relevance, regulatory expectations, and operational robustness, often under tight development timelines and with limited material. A dissolution method that looks sound on paper can quickly become problematic if it fails to discriminate, lacks robustness, or proves difficult to transfer between laboratories.

Meaningful dissolution testing goes beyond meeting pharmacopeial requirements. It plays a critical role in:

understanding formulation behavior,
controlling manufacturing variability,
and supporting confident regulatory decision-making across the product lifecycle.

Building on these practical realities, this article explores how dissolution tests are designed, executed, and interpreted in day-to-day pharmaceutical development, quality control, and regulatory contexts.

It also complements our earlier blog, “The Evolution and Future of Dissolution Testing in Pharmaceutical Development,” which examined the historical and technological drivers that shaped modern dissolution approaches.

Achieving Meaningful Dissolution Testing

At its core, dissolution testing aims to establish a method that can reliably differentiate between factors influencing drug release and, ultimately, in vivo performance.

A meaningful dissolution method must be sufficiently sensitive to detect variations in critical manufacturing and formulation parameters, such as drug substance particle size, compression force, or tablet hardness, while clearly distinguishing between products manufactured under optimal conditions and those with clinically or technically relevant deviations.

Equally important, the method must be robust, reproducible, and suitable for routine use. It should be transferable between laboratories without introducing variability that could compromise data integrity, regulatory confidence, or batch release decisions.

Practical Foundations of Dissolution Testing

Dissolution Medium and Test Conditions

The dissolution process begins with selecting an appropriate liquid medium, which is introduced into the vessels of the dissolution apparatus. Depending on the product and its intended use, this medium may range from degassed deionized water to buffered solutions with defined pH values or surfactant-containing formulations.

In many cases, the dissolution medium is water- or water-based, with a pH typically between 5 and 7 and a controlled temperature of 37 °C, in line with pharmacopeial requirements and physiological relevance.

Proper degassing of the medium - often achieved through sonication or other validated techniques - is essential, as dissolved gases can interfere with hydrodynamics and affect dissolution results.

Once the medium has reached the specified temperature, the dosage form is introduced into the vessel and the dissolution apparatus is activated under controlled conditions.

Sampling and Analytical Evaluation

Samples collected during dissolution testing are commonly analyzed using High-Performance Liquid Chromatography (HPLC) or Ultraviolet–Visible (UV-Vis) spectroscopy. Results are assessed against predefined release specifications, both at the individual unit level and as an overall average.

A central parameter in dissolution testing is Q, which represents the specified percentage of active ingredient that must be dissolved within a defined timeframe, as described in the product monograph.

If Stage 1 (S1) testing does not meet the Q requirement, additional units are tested in Stage 2 (S2). Failure at S2 triggers Stage 3 (S3) testing. Persistent failure to meet Q at S3 typically leads to an Out-of-Specification (OOS) investigation to identify root causes and assess product impact.

The Role of Dissolution Testing in Pharmaceutical Development

Conclusion

When designed and applied thoughtfully, dissolution testing becomes far more than a routine analytical requirement. It provides critical insight into

formulation behavior,
manufacturing variability,
and product performance,

supporting informed decisions throughout development, registration, and lifecycle management.

By approaching dissolution testing as part of a broader Quality by Design strategy, teams can reduce development risk, strengthen regulatory confidence, and avoid late-stage rework. This requires methods that are scientifically justified, sufficiently discriminatory, robust for routine use, and transferable across laboratories and manufacturing sites.

QbD Group supports pharmaceutical and biotech organizations in designing and implementing dissolution strategies that meet these objectives. Combining analytical expertise, regulatory insight, and practical development experience, our teams help ensure dissolution testing supports sound decision-making.

This includes support from early formulation development and method validation through to regulatory submissions, troubleshooting, and lifecycle management.

If you are looking to strengthen your dissolution approach or address specific method development or transfer challenges, QbD Group’s experts are ready to support you with tailored scientific and regulatory guidance.

Don’t hesitate to get in touch.