EMA GMP Plans for Regulation Updates

Like one does, I watch upcoming regulations like a hawk. Here are a few of the forthcoming GMP changes coming from the 3-year work plan for the Inspectors Working Group.

Document	Intended Changes	When	My Thoughts
GMP Guide: Chapter 4 (Documentation)	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.

Regulatory Requirements for Contamination Control

A list of Regulatory documents that apply to contamination control.

European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Chapter 3: Premises and Equipment, (2014)
European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Chapter 5: Production, (2014)
European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Part II: Basic Requirements for Active Substances used as Starting Materials, (2014)
European Union, Guidelines of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use, Official Journal of the European Union, (2015/C 95/02), (2015)
European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Annex 2: Manufacture of Biological active substances and Medicinal Products for Human Use, (2018)
European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Annex 3 Manufacture of Radiopharmaceuticals, (2008)
European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Annex 14 Manufacture of Medicinal Products Derived from Human Blood or Plasma, (2011)
European Commission, EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines, Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products, (2017)
European Union, Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use, Official Journal of the European Union, (2013/C 343/01), (2013),
European Union, Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use, Official Journal of the European Union, (2015/C 95/01), (2015)
EMA Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (20 November 2014)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, subpart C = Building and Facilities, sec. 211.42 Design and construction features (b), (c)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart F – Production and Process Controls, sec. 211.113 Control of microbial contamination (a), (b)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart B – Organization and Personnel, sec.211.28 Personnel responsibilities (a)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart E – Control of Components and Drug Product Containers and Closures, sec. 211.80 General requirements. (b)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart E – Control of Components and Drug Product Containers and Closures, sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures (d)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart D – Equipment, sec. 211.67 Equipment cleaning and maintenance (a)
U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current good manufacturing practice for finished pharmaceuticals, Subpart C – Buildings and Facilities, sec. 211.56 Sanitation (c)
U.S. Food & Drug Administration, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, (2004)
U.S. Food & Drug Administration, Guidance for Industry – Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing, (2020)
U.S. Food & Drug Administration, Guidance for Industry – Guidance for Industry Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross Contamination, (2013)
U.S. Food & Drug Administrationn, Guidance for Industry Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, Draft Guidance. https://www.fda.gov/media/88905/download (accessed Mar 6, 2022)
Pharmaceutical Inspection Co-operation Scheme gmp guide, 2nd targeted consultation document on revision of annex 1
Pharmaceutical Inspection Co-operation Schemepharmaceutical inspection co-operation scheme gmp guide, ps inf 25 2019 (rev. 1) draft, manufacture of advanced therapy medicinal products for human use
Pharmaceutical Inspection Co-operation Scheme gmp guide, ps inf 26 2019 (rev. 1) draft, manufacture of biological medicinal substances and products for human use
Pharmaceutical Inspection Co-operation Scheme gmp guide, pe 009-15 (part i), guide to good manufacturing practice for medicinal products part i
Pharmaceutical Inspection Co-operation Scheme gmp guide, pe 009-15 (part ii), guide to good manufacturing practice for medicinal products part ii
Pharmaceutical Inspection Co-operation Scheme gmp guide, pe 009-15 (annexes), guide to good manufacturing practice for medicinal products annexes
World Health Organisation, good manufacturing practices for pharmaceutical products: main principles, annex 2, who technical report series 986, 2014,
World Health Organisation, who good manufacturing practices for active pharmaceutical ingredients (bulk drug substances), annex 2, who technical report series 957, 2010
World Health Organisation, points to consider for manufacturers and inspectors: environmental aspects of manufacturing for the prevention of antimicrobial resistance annex 6, who technical report series 1025, 2020
World Health Organisation, WHO good manufacturing practices for sterile pharmaceutical products, annex 6, who technical report series 961, 2011
World Health Organisation, WHO good manufacturing practices for biological products, annex 3, who technical report series 996, 2016
World Health Organisation, WHO good manufacturing practices for the manufacture of investigational pharmaceutical products for clinical trials in humans, annex 7, who technical report series 863, 1996
World Health Organisation, WHO good manufacturing practices for radiopharmaceutical products annex 2, who technical report series 1025, 2020
World Health Organisation, WHO GMP for Pharmaceutical Products containing Hazardous Substances, TRS 957, Annex-3 (2010)
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, Quality Risk Management, Q8 (R2), Pharmaceutical Development, August 2009. https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf (Accessed Mar 06, 2022)
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, Quality Risk Management Q9, November. https://database.ich.org/sites/default/files/Q9%20Guideline.pdf (accessed Mar 06, 2022).
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use, pharmaceutical quality system Q10. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf (accessed Mar 06, 2022).

Escalation of Critical Events

Event management systems need to have an escalation mechanism to ensure critical events are quickly elevated to a senior level to ensure organization-wide timely reactions.

There are many reasons for a fast escalation.

Events that trigger reporting to Regulatory Agencies (e.g. Serious Breach, Urgent Safety Measures (UK), Field Alerts, Biological Product Deviation, Medical Device Report)
Events that require immediate action to prevent additional harm from across the organization
Events that require marshalling resources from large parts of the organization

GMP	GCP	GPVP	GLP	Research	IT
• Impact to data integrity • Impact to product quality/supply	• Impact to data integrity • Data/privacy breach	• Event impacting on-time compliance rates (not isolated/steady state)	• Impact to data integrity	• Impact to data integrity	• Reference GxP area for Impact resulting from/linked to system error/failure
• Product Quality/ CMC events in accordance with MRB criteria (or other events of similar scope of impact)	• Impact to study integrity • Impact to subject’s safety, rights or welfare	• Gaps in reporting/ collection of potential AEs	• Impact to study integrity	• Impact to study integrity	• System design, testing, deployment, upgrade, etc. event impacting GxP data integrity or regulatory compliance
• Recurring event with broad scope of impact	• Recurring event with broad scope of impact	• Recurring event with broad scope of impact	• Recurring event with broad scope of impact	• Recurring event with broad scope of impact	• Recurring event with broad scope of impact
• Impact to program milestones & corporate goals	• Impact to program milestones & corporate goals	• Impact to program milestones & corporate goals	• Impact to program milestones & corporate goals	• Impact to program milestones & corporate goals
• Potential Falsified or Counterfeit Product				• Potential Fraud or Misconduct	• Potential Fraud or Misconduct
• Credible Risk of Product Shortage				• Quality event with patient safety risk/gap	• GxP Data Breach
• Potential Product Recall				• Significant Quality Event Notified to Regulatory Authority	• System error or failure with significant GxP compliance impact
· Potential Critical Finding Resulting from Regulatory Authority Inspection or Audit by External Body/Third Party · Quality Event/Observation Classified as Critical (Event or Internal Audit) Notification from Regulatory Authority or other External Authority of Findings of Significant/Critical Quality Deficiency (inspection or other than through inspection) o e.g.; Refusal to File, Notification of Inadequate Response to Inspection Findings (e.g.; Other Action Indicated (FDA classification), Warning Letter

You can drill down to a lower, more practical level, like this

Escalation Criteria	Examples of Quality Events for Escalation
Potential to adversely affect quality, safety, efficacy, performance or compliance of product (commercial or clinical)	• Contamination (product, raw material, equipment, micro; environmental) • Product defect/deviation from process parameters or specification (on file with agencies) • Significant GMP deviations • Incorrect/deficient labeling • Product complaints (significant PC, trends in PCs) • OOS/OOT (e.g., stability)
Product counterfeiting, tampering, theft	• Product counterfeiting, tampering, theft reportable to Health Authority (HA) • Lost/stolen IMP • Fraud or misconduct associated with counterfeiting, tampering, theft • Potential to impact product supply (e.g., removal, correction, recall)
Product shortage likely to disrupt patient care and/or reportable to HA	• Disruption of product supply due to product quality events, natural disasters (business continuity disruption), OOS impact, capacity constraints
Potential to cause patient harm associated with a product quality event	• Urgent Safety Measure, Serious Breach, Significant Product Compliant, Safety Signal that are determined associated with a product quality event
Significant GMP non-compliance/event	• Non-compliance or non-conformance event with potential to impact product performance meeting specification, safety efficacy or regulatory requirements
Regulatory Compliance Event	• Significant (critical, repeat) regulatory inspection findings, lack of commitment adherence • Notification of directed/for cause inspection • Notification of HA correspondence indicating potential regulatory action

An updated and expanded version of this is found here.

Quality Escalation Best Practices: Ensuring GxP Compliance and Patient Safety

The Great Man Fallacy and Pharmaceutical Quality

Primary Investigator, Study Director, Qualified Person, Responsible Person – the pharmaceutical regulations are rife with a series of positions that are charged with achieving compliance and quality results. I tend to think of them as a giant Achilles heel created by the regulations.

The concept of an individual having all the accountability is nowhere near universal, for example, the term Quality Unit is a nice inclusive we – though I do have some quibbles on how it can end up placing the quality unit within the organization.

This is an application of the great man fallacy – the idea that one person by the brunt of education, experience, and stunning good looks can ensure product safety, efficacy and quality, and all the other aspects of patient and data integrity of trials.

That is, frankly, poppycock.

People only perform successfully when they are in a well-built system. Process drives success and leverages the right people at the right time making the right decisions with the right information. No one person can do that, and frankly thinking someone can is setting them up for failure. Which we see, a lot in the regulatory space.

Sure, the requirement exists, we need to meet it failing the agencies waking up and realizing the regulations are setting us up for failure. But we don’t need to buy into it. We build our processes to leverage the team, to democratize decisions, and to drive for reliable results.

Let’s leave the great man theory in the dustbins where it belongs.

The stick is broken, regulatory agencies are toothless

Admit it, we’ve all been through GxP training that utilizes the stick. I’m assuming many of you have designed it. It might have looked like this:

Perhaps you have went over the hundred-and-fifty-plus years history of regulatory action, discussing Elixir Sulfanilamide, thalidomide, and a dozen other noteworthy cases that shared the modern regulatory environment.

Or perhaps you just like to show a slide with recent headlines on it.

Let’s put aside all the excellent research about the power of positive messaging etc. Valid stuff but not the point I’m trying to make.

The point I want to make in this post is that the regulatory stick has long been broken. Companies suffer at most a slap on the wrist, fines that are weeks or months of profit. But real repercussions are absent.

The Sackler family walks away with billions, MacKenzie gets a slap on the wrist, and other companies are all protected from their deliberate actions in fueling the opioid epidemic.

J&J avoids all real accountability for knowingly causing cancer.

The list goes on.

Frankly, I think this is really bad for our industry. If the price of being caught is pennies to the dollar earned, it has become merely a cost of doing business.

This erodes trust in the safety of our drug supply. And if the last year hasn’t brought home the importance of that trust, you may be hiding under a rock.

We need more perp walks. We need a real system of deterrence that involves arrests and punishments that match the crimes. We can’t even count on the one form of deterrence left, liability lawsuits because companies are playing shenanigans with bankruptcy laws.

We talk about how quality culture starts at the top. But as we see again and again, the top only cares about profit.

That makes me fundamentally worry about the safety of our drugs and medical devices. And if I someone who has dear friends who work at large and small pharma worry, I must admit I can understand why people start to hold suspicions.