I hasn’t been difficult to notice that a whole lot of biological new drug applications have been rejected in the last few years, many for CMC reasons. Recently CDER Director Patrizia Cavazzoni spoke on the matter at a recent at a Duke University and FDA event at the National Press Club iin the video above.
“Our standards have not changed. We have exactly the same standards as we had in 2018 and 2019,” she said, before going on to talk about how the quality related issues the FDA is seeing: contamination, overall oversight, manufacturing controls or insufficient quality management systems.
Max Van Tassell, a senior pharmaceutical quality assessor in CDER’s Office of Pharmaceutical Quality, provided insights from analyzing 100 complete response letters (CRLs) for Biologics License Applications (BLAs) issued between 2014 and 2024. He noted that facility-related deficiencies in CRLs typically stem from inadequate demonstration that proposed corrective and preventive actions would effectively mitigate risks identified during on-site inspections.
It should be a key takeaway from this presentation that:
Occasionally the FDA writes a Warning Letter that is a succinct lesson in what is important about a quality system. In this Warning Letter they masterfully describe what a CAPA Program is. As this one further describes how to deal with an inadequate cleaning program it is near and dear to my heart.
The ICH, ICMRA, and PIC/S are three important international organizations in the pharmaceutical regulatory space that folks should pay attention to and understand how they shape our profession’s future.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a global initiative that brings together regulatory authorities and the pharmaceutical industry to discuss and establish common guidelines and standards for developing, registering, and post-approval pharmaceutical products.
History and Evolution
Establishment: ICH was established in 1990 by the regulatory authorities and pharmaceutical industry associations from Europe, Japan, and the United States. The goal was to harmonize the regulatory requirements for pharmaceutical product registration across these regions.
Reformation: In 2015, ICH was reformed and became a legal entity under Swiss law, transforming from the International Conference on Harmonisation to the International Council for Harmonisation. This change aimed to create a more robust and transparent governance structure and to expand its global reach.
Objectives and Goals
Harmonization: The primary goal of ICH is to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.
Efficiency: By harmonizing technical requirements, ICH aims to improve the efficiency of the drug development and registration process, reduce duplication of clinical trials, and minimize the use of animal testing without compromising safety and effectiveness.
Structure and Governance
ICH Assembly: This is the overarching governing body, which includes all members and observers. It adopts decisions on guidelines, membership, work plans, and budgets.
ICH Management Committee: This committee oversees the operational aspects, including administrative and financial matters and working group activities.
MedDRA Management Committee: This committee manages the Medical Dictionary for Regulatory Activities (MedDRA), standardizing medical terminology for adverse event reporting and clinical trial data.
ICH Secretariat: Handles the day-to-day management and coordination of ICH activities.
Guidelines and Categories
ICH guidelines are categorized into four main areas:
Quality: Covers topics such as stability testing, analytical validation, and good manufacturing practices (GMP).
Safety: Includes guidelines on genotoxicity, reproductive toxicity, and other safety evaluations.
Efficacy: Focuses on the design, conduct, safety, and reporting of clinical trials, including novel drug classes and pharmacogenetics.
Multidisciplinary: Encompasses cross-cutting topics like the Common Technical Document (CTD) and electronic standards for regulatory information transfer.
Global Impact and Implementation
Membership: ICH includes regulatory authorities and industry associations from around the world. It currently has 20 members and 36 observers.
Implementation: Regulatory members are committed to adopting and implementing ICH guidelines within their jurisdictions, ensuring consistent regulatory standards globally.
Key Activities
Guideline Development: ICH develops harmonized guidelines through a consensus-based process involving regulatory and industry experts.
Training and Support: Provide training materials and support to facilitate the consistent implementation of guidelines across different regions.
The ICH plays a crucial role in the global pharmaceutical regulatory landscape by promoting harmonized standards, improving the efficiency of drug development, and ensuring the safety and efficacy of medicines worldwide.
International Coalition of Medicines Regulatory Authorities (ICMRA)
The International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive-level, strategic coordinating, advocacy, and leadership entity. It brings together heads of national and regional medicines regulatory authorities worldwide to address global and emerging human medicine regulatory and safety challenges.
Objectives and Goals
Global Coordination: ICMRA provides a global architecture to support enhanced communication, information sharing, crisis response, and addressing regulatory science issues.
Strategic Direction: It offers direction for areas and activities common to many regulatory authorities’ missions and identifies areas for potential synergies.
Leveraging Resources: ICMRA leverages existing initiatives, enablers, and resources to maximize the global regulatory impact wherever possible.
Membership
Voluntary Participation: Membership is voluntary and open to all medicines regulatory authorities. It includes prominent entities such as the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and many others worldwide.
Global Representation: The coalition includes regulatory authorities from various regions, with the World Health Organization (WHO) participating as an observer.
Key Activities and Projects
Antimicrobial Resistance (AMR): Developing a coordinated global approach to tackle AMR.
COVID-19 Response: During the COVID-19 pandemic, ICMRA has been pivotal in expediting and streamlining the development, authorization, and availability of COVID-19 treatments and vaccines worldwide.
Innovation and Pharmacovigilance: Ongoing investigations and case studies relating to emerging regulatory challenges and working on real-world evidence, adverse event reporting, and vaccine confidence.
Supply Chain Integrity: Ensuring the integrity of the global supply chain for medicines.
Strategic Importance
Enhanced Collaboration: ICMRA fosters international collaboration among medicine regulatory authorities to ensure the safety, quality, and efficacy of medicinal products globally.
Regulatory Agility: The coalition promotes regulatory agility and rapid response to global health emergencies, ensuring patients have timely access to safe and effective medical products.
The ICMRA plays a crucial role in the global regulatory landscape by enhancing communication and cooperation among medicines regulatory authorities, addressing shared challenges, and promoting the safety and efficacy of medicinal products worldwide.
Pharmaceutical Inspection Co-operation Scheme.
PIC/S stands for the Pharmaceutical Inspection Co-operation Scheme, a non-binding, informal co-operative arrangement between regulatory authorities in Good Manufacturing Practice (GMP) of medicinal products for human or veterinary use. Its main purpose is to lead the international development, implementation, and maintenance of harmonized GMP standards and quality systems of inspectorates in the pharmaceutical field.
History: PIC/S was established in 1995 as an extension to the Pharmaceutical Inspection Convention (PIC) of 1970. It was created to overcome legal limitations that prevented new countries from joining the original PIC due to incompatibilities with European law.
Membership: PIC/S is open to any regulatory authority with a comparable GMP inspection system. As of 2023, it comprises 56 participating authorities worldwide, including Europe, Africa, America, Asia, and Australasia.
Structure: PIC/S operates as an association under Swiss law, registered in Geneva, Switzerland. It has a committee, an executive bureau, and various working groups.
Relationship with Other Organizations: PIC/S works closely with other international bodies, including the European Medicines Agency (EMA), to promote GMP harmonization and share resources.
Objectives
Harmonizing inspection procedures worldwide
Providing training opportunities for inspectors
Developing common standards in GMP
Facilitating cooperation between competent authorities and international organizations
Activities
Developing and promoting harmonized GMP standards and guidance documents
Training competent authorities, particularly inspectors
Assessing and reassessing inspectorates
Facilitating networking among regulatory authorities
Benefits
Ensures high standards among members
Provides training and networking opportunities
May facilitate pharmaceutical exports indirectly
Increases confidence in medicines manufactured in member countries
PIC/S plays a crucial role in global pharmaceutical regulation by promoting harmonized standards, facilitating cooperation between regulatory authorities, and working towards ensuring the quality and safety of medicinal products worldwide.
The Three in Overview
Aspect
ICH
ICMRA
PIC/S
Full Name
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
International Coalition of Medicines Regulatory Authorities
Pharmaceutical Inspection Co-operation Scheme
Established
1990 (reformed in 2015)
2013
1995
Primary Focus
Harmonization of technical requirements for drug development and registration
Strategic coordination and leadership in global human medicine regulation
Harmonization of Good Manufacturing Practice (GMP) standards and inspections
Main Objectives
Develop harmonized guidelines for drug development, registration, and post-approval
Enhance communication, information sharing, and crisis response among regulators
Develop common GMP standards and train inspectors
Membership
20 members, 36 observers (regulatory authorities and industry associations)
Heads of medicines regulatory authorities worldwide
Guideline development, training, and implementation support
Scope
Global, with emphasis on technical aspects of drug development
Global, focusing on high-level strategic issues
Global, concentrating on GMP and quality systems
Key Activities
Guideline development, training, implementation support
Strategic initiatives, position papers, statements
GMP guidelines, inspection reports, training programs
This table highlights the distinct roles and focuses of these three important international pharmaceutical regulatory organizations. While they all contribute to global harmonization and cooperation in pharmaceutical regulation, each has a unique emphasis:
ICH primarily develops technical guidelines for drug development and registration.
ICMRA focuses on high-level strategic coordination among regulatory authorities.
PIC/S concentrates on harmonizing GMP standards and inspection practices.
Their complementary roles contribute to a more cohesive global regulatory environment for pharmaceuticals.
How to Monitor
Organization
What to Monitor
How to Monitor
Frequency
ICMRA
– COVID-19 updates and guidance – Statements on regulatory issues – Reports on emerging topics (e.g., AI, RWE) – Strategic meetings and workshops
– Check ICMRA website regularly – Subscribe to ICMRA newsletter – Follow ICMRA on social media – Attend public workshops when possible
Monthly
ICH
– New and updated guidelines – Ongoing harmonization efforts – Implementation status of guidelines – Training materials and events
– Monitor ICH website for updates – Subscribe to ICH news alerts – Participate in public consultations – Attend ICH training programs
Bi-weekly
PIC/S
– GMP guide updates – New guidance documents – Training events and seminars – Inspection trends and focus areas
– Check PIC/S website regularly – Subscribe to PIC/S newsletter – Review annual reports – Participate in PIC/S seminars if eligible
Monthly
Key points for monitoring:
Set up automated alerts or RSS feeds where available
Create a calendar reminder for regular check-ins on each organization’s website
Collaborate with regulatory affairs colleagues to share insights and updates
Implement a system to disseminate relevant information within your organization
Consider joining industry associations that actively engage with these organizations
Assure data integrity in the context of GMP. This would be in parallel with similar consideration of Annex 11 (Computerised Systems).
Q1 2026
An update is needed to align with current thinking. Data Integrity has advanced significantly in the last five years, and Chapter 4 could benefit from alignment with the PIC/S guidance.
GMP Guide: Annex 11 (Computerised Systems)
Assure data integrity in the context of GMP. This would be in parallel with similar consideration of Chapter 4 (Documentation).
Q1 2026
A necessary update. Will be curious to see how it aligns with the FDA’s CSA approach (which isn’t really all that new).
We pretty much know what will be in it from the concept paper. At least it will solidify this requirement for cloud systems “Regulated users should 26 have access to the complete documentation for validation and safe operation of a system and be able to present this during regulatory inspections, e.g. with the help of the service provider.”
Guidelines on GMP specific to ATMPS
Review the Guidelines in collaboration with CAT and the European Commission following the publication of a new regulation on standards of quality and safety for substances of human origin intended for human application and need to update legal references and definitions. Review the Guidelines in the light of new Annex 1 Manufacture of Sterile Medicinal Products and consider whether any updates are necessary.
Q4 2026
This is a fast area of change, and this update is called for.
Aligning to Annex 1 is overdue.
GMP Guide: Annex 3 Manufacture of Radiopharmaceuticals
A review and update of the Annex to reflect current state of the art.
Q4 2026
I’ve never worked in radiopharmaceuticals. Maybe someday.
GMP Guide: Annex 15 Qualification and Validation
In the context of new technology in facilities, products and processes and following up on LLE recommendations, and extend the scope to APIs.
Q4 2025
LLE is the EMA’s lessons learnt report (LLE) on Nitrosamines.
I’d love to see significant changes to finally align with ATSM E2500 and other recent challenges in validation.
GMP Guide: Annex 16 Certification by a Qualified Person and Batch Release
Following up on LLE recommendations.
Q4 2025
I’m not a massive fan of QPs as structured. Not expecting that to change.
GMP and Marketing Authorisation Holders
To revise the paper in line with recommendations from the Nitrosamines LLE, to strengthen guidance for MAHs in terms of having adequate quality agreement with manufactures.
Q4 2025
Anything to strengthen quality agreements is probably a good thing.
Anytime we see a major chapter update in the Eudralex Volume 4 is an exciting year, and the next few promise to be big. Maybe not Annex 1 big, but maybe the EMA and PIC/S will surprise us.
I often get asked why I moved from a broader senior role in Quality Management to a particular but deep role in Quality Engineering and Validation. There are many answers, but the biggest is that validation is poised for some exciting shifts due to navigating a complex validation landscape characterized by rapid technological advancements, evolving regulatory standards, and the development of novel therapies. Addressing these challenges requires innovation, collaboration, and a proactive approach to risk management and data integration. Topics near and dear to me.
Today’s Challenges in Biotech Validation
1. Rapid Technological Advancements
The biotech industry is experiencing rapid technological advancements such as AI, machine learning, and automation. Integrating these technologies into validation processes can be challenging due to the need for new validation frameworks and methodologies.
2. Regulatory Compliance
Maintaining compliance with evolving regulatory standards is a significant challenge. Regulatory bodies like the FDA continuously update guidelines for technological advancements.
3. Complexity of New Therapies
Developing novel therapies, such as cell and gene therapies, introduces additional complexity to the validation process. These therapies often require redesigned facilities and equipment to accommodate their sensitive and sterile nature. Ensuring sterility and product quality at each process stage is crucial but challenging.
4. Data Management and Integration
Managing and integrating vast amounts of data has become challenging with the increasing use of digital tools and platforms. Effective data management is essential for predictive modeling and risk management in validation processes. Organizations must adopt robust data analytics and machine learning tools to handle this data efficiently.
Validation processes often require collaboration among various stakeholders, including validation teams, developers, and regulatory bodies. Ensuring real-time communication and data sharing can be challenging but is essential for streamlining validation efforts and aligning goals.
6. Resource Constraints
Smaller biotech companies, in particular, face resource constraints regarding funding, personnel, and expertise. These constraints can hinder their ability to implement advanced validation techniques and maintain compliance with regulatory standards.
Adopting a risk-based approach to validation is essential but challenging. Companies must identify and mitigate risks throughout the product lifecycle, which requires a thorough understanding of potential risks and effective risk management strategies.
Let’s Avoid the Term Validation 4.0
Let’s avoid the 4.0 term. We are constantly evolving, and adding a current ‘buzziness’ to it does no one any favors. We are shifting from traditional, paper-heavy validation methods to a more dynamic, data-driven, and digitalized process. Yes, we are leveraging modern technologies such as automation, data analytics, artificial intelligence (AI), and the Internet of Things (IoT) to enhance validation processes’ efficiency, flexibility, and reliability. But we don’t need buzziness, we just need to give it some thought, experiment, and refine.
Investigations of a Dog 