Cover story GMP Update 2022/2023
2022 saw a lot of new developments in the GMP environment. The following article summarizes a few selected highlights.
New veterinary medicines legislation
Regulation 2019/6, commonly known as the new veterinary regulation ("NVR"), governs the authorization, use and supervision of veterinary medicinal products in the European Union. The legislation entered into force on January 28, 2019, and has been applied in all EU member states since January 28, 2022. The aim was to develop a fit-for-purpose veterinary medicines legislation that is no longer based on the corresponding requirements for human medicinesRegulation 2019/6, commonly known as the new veterinary regulation ("NVR"), governs the authorization, use and supervision of veterinary medicinal products in the European Union. The legislation entered into force on January 28, 2019, and has been applied in all EU member states since January 28, 2022. The aim was to develop a fit-for-purpose veterinary medicines legislation that is no longer based on the corresponding requirements for human medicines.
As an EU regulation, the EU Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) applies directly in the member states and replaces the previously applicable Veterinary Medicinal Products Directive 2001/82/EC. As an EU regulation, the EU Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) applies directly in the member states and replaces the previously applicable Veterinary Medicinal Products Directive 2001/82/EC.
In this context, the European Medicines Agency (EMA) has adapted the answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP)1 on its website. The new chapter deals with requirements for active substances used as starting materials for the manufacture of veterinary medicinal products. In this context, the European Medicines Agency (EMA) has adapted the answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP)1 on its website. The new chapter deals with requirements for active substances used as starting materials for the manufacture of veterinary medicinal products.
After more than five years and two public drafts for comment, the European Commission published the final version of the new Annex 1 to the EU GMP Guidelines in August 2022. The new Annex 1, entitled "Manufacture of Sterile Medicinal Products", will enter into force on August 25, 2023, one year after publication in Eudralex Volume 4. Only with regard to Chapter 8.123 "Product transfer / loading/unloading areas for freeze dryers", the deadline is two years and ends on August 25, 2024.
Which changes/additions compared to the second draft version of 2020 are obvious?
Annex 1 has become even more extensive. The number of pages has increased from 52 to 58.
In addition to the increased importance of Quality Risk Management (QRM) and the discussion of Pre-Use, Post-Sterilization Integrity Testing (PUPSIT) of filters, it is particularly striking that for the first time, an overarching recording and coordinated management of contamination control measures is required, called "Contamination Control Strategy" (CCS) in the draft. The CCS is intended to link various measures such as personnel hygiene, clothing specifications, cleaning and disinfection processes, environmental monitoring and ventilation technology.
Barcelona, Spain12 March 2024
Pre-Course Session: What you need to know about Suppliers in China and India
Furthermore, there are a few deletions in addition to rewordings in many chapters.
The final version of Annex 21 to the EU GMP Guidelines ("Importation of medicinal products") was published in EudraLex Vol. 4 in February2. The new annex has been valid since August 21, 2022.
Besides editorial changes and adaptations to Annex 16, there were a few important additions and clarifications:
- Clinical investigational medicinal products are now explicitly included. Advanced Therapeutic Medicinal Products (ATMPs) and medicinal products that do not have a marketing authorization in the EU / EEA and are directly re-exported were not included.
- "Fiscal transactions" (physical retention of the product in the EU but change of ownership to a third country and vice versa) remain explicitly excluded.
- Full batch documentation must be available to the MIA holder responsible for QP certification or confirmation of the batch, as appropriate, at the time of certification or confirmation of the batch.
- QP certification or confirmation of the batch now also requires a packing list, shipping documents or an import customs declaration. The certification of a batch can therefore only take place after the physical import and customs clearance.
Guidance on quality and specifications for herbal medicinal products
The European Medicines Agency (EMA) has published final guidelines (Revision 3) on quality and specifications for herbal medicinal products (HMPs). Among other things, a written GACP confirmation for the herbal starting material is to be submitted. In addition, the EMA's Committee on Herbal Medicinal Products (HMPC) recently published a concept paper on revising the GACP guidance. The deadline for comments was June 1, 2022.
In May, the EMA opened a brief, one-month public consultation on a draft question and answer document on remote batch release (remote certification) by the Qualified Person (QP): "Public Consultation concerning the Physical Attendance and the Location of Personal Residency of The Qualified Person" (EMA/INS/169000/2022).
Questions to be clarified here are:
- Is remote batch certification by the QP routinely permitted?
- What conditions should apply?
- Does the QP need to be located in the Member State where the approved site is located?
- What are the technical requirements for remote access and signature?
Nitrosamine impurities: further update of EMA's question-andanswer document
The question-answer document developed by EMA and CMDh is updated at irregular intervals to reflect the latest knowledge. On October 12, 2022, the EMA published a new update of the Q&A document "Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products"3 on its "What's new" website - the 14th revision. New issues discussed are current limits and novel nitrosamine impurities.
Clinical investigational medicinal products
Validity of the Clinical Trials Regulation
On January 31, 2022, the Clinical Trials Regulation 536/2014 (CTR) became applicable for the first time. For clinical trials in Europe, there were thus some significant changes with regard to the processes and procedures for authorizing, conducting and terminating clinical trials. A total transition period of three years is now ongoing, during which both the contents of the CTR and the current legislation for clinical trials apply.
In parallel, the European Commission has published an updated version of the draft Questions and Answers (Q&As) to the Clinical Trials Regulation (EU) No. 536/2014 (CTR). However, certain sections of the Q&A document are not yet complete and updated versions of the Q&As will be published gradually4.
Final EMA Guidance on Quality Requirements for IMPs
The final EMA Guidelines (Rev. 2) on Quality Requirements for Investigational Medicinal Products ("IMPs") have been published on the EMA website, together with an overview of comments received on the draft guidelines published last year5. The coming-into-force date has been set for January 31, 2022, same as for Regulation (EU) No. 536/2014 on clinical trials (CTR).
According to the EMA, a clear distinction should be made between the requirements for an investigational medicinal product dossier ("IMPD") for a clinical trial ("CT") and for a marketing authorization dossier. For further information, please refer to the two EMA Guidelines (Rev. 2) on chemical and pharmaceutical quality documentation requirements for investigational medicinal products6 and on quality documentation requirements for investigational biological products7.
News from the FDANews from the FDA
New Guidance on Out-of-Specification (OOS) Findings
In May 2022, the U.S. Food and Drug Administration (FDA) released a new version (Revision 1) of its Guidance for Industry titled "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production"8. The original version of the document was issued nearly 16 years earlier, in October 2006.
Compared to the 2006 version, the following adjustments were made, among others:
- Editorial changes.
- The term "quality control unit (QCU)" was replaced by "quality unit (QU)".
- Addition or updating of references in the main text and footnotes to refer to the latest version of other relevant guidance, USP chapters, CFR paragraphs, etc.
- Additions to "Outlier Tests" and "Averaging results from same final sample preparation".
New Guidance on Recalls
FDA has finalized its guidance on voluntary recalls to assist industry in promptly initiating recalls of defective products ("Initiation of Voluntary Recalls Under 21 CFR Part 7, Subpart C")9. The guidance applies to voluntary recalls of food, drugs, medical devices, cosmetics, biological, and tobacco products. The agency has made only minor changes from the draft version published in April 2019.
The document includes recommendations in the following three key areas:
- Proper training of personnel
- Record keeping
- Written procedures for initiating recalls
How many FDA inspections are still taking place in Germany?
Since July 2019, the MRA (Mutual Recognition Agreement) between the EU and the FDA has been fully in force. One of the main goals was to mutually recognize each other's GMP inspection systems and reduce the number of mutual inspections.
But has the number of FDA inspections actually decreased? A very good source is provided by the FDA Data Dashboard10. This detailed overview of FDA activities performed provides easy-to-use and understandable tables and graphs for comprehensive analysis.
According to the dashboard, for example, ten "drug quality assurance" inspections of German companies were completed in 2021 alone - despite the pandemic and MRA. And pre-approval inspections aren't even listed here. The year before (2020), there were 27, and in 2019 there were 68. No warning letters were issued in this regard.
In addition to on-site inspections, FDA has also conducted socalled "Remote Interactive Evaluations" (RIE). While these remote evaluations do not meet the legal definition of an inspection, according to FDA, and effectively serve only as a supplement to an inspection, a Warning Letter was issued in early 2022 to a firm in Poland11. And this happened after a purely remote inspection. In fact, according to the FDA Dashboard, no on-site inspection has ever been conducted there. The company manufactures over-the-counter drug products (OTC) and distributes a homeopathic cream in the USA. FDA reviewed documents submitted in response to a June 2021 agency request as part of the remote assessment described in the warning letter.
FDA expands remote assessments - even after the pandemic
The FDA wants to use Remote Regulatory Assessments (RRAs) not only during the COVID-19 pandemic, but also beyond it to evaluate sites and regulatory applications and has published a Draft Guidance for Industry "Conducting Remote Regulatory Assessments - Questions and Answers"12.
FDA has also updated two Compliance Program Guides (CPGs) on GMP inspections13. CPGs are primarily for FDA staff and assist them in evaluating and enforcing regulations for industry. Many details and interpretations found there that are not covered by existing FDA laws, regulations or guidances. Chapter 46 - New Drug Evaluation addresses pre-approval inspections (PAIs) and Chapter 56 Drug Quality Assurance addresses routine surveillance inspections.
FDA plans evaluation system for companies
FDA's CDER continues to work on its vision for 21st century pharmaceutical quality and supply chain assurance. To that end, it has produced a white paper titled "Quality Management Maturity (QMM): Essential for Stable U.S. Supply Chains of Quality Pharmaceuticals."14 In principle, this paper deals with ways of objectively assessing the "quality management maturity" of pharmaceutical production sites. A central aspect of this is a so-called "QMM Rating System", a program for evaluating and rating the QMM of production sites using monitoring data and the participation of the companies.
Central elements of the program are:
- Quality Culture as a basis with common business and quality objectives.
- Objectivity of the QMM assessment tool
- Incentives for the industry o Transparency
Draft Guidance on Computer Software Assurance (CSA)
In September 2022, FDA published the draft Guidance for Industry "Computer Software Assurance for Production and Quality System Software"15. The comment period already ended on November 14, 2022. According to FDA, the document will describe "Computer Software Assurance" as a risk-based approach in the course of advancing automation in production or quality systems. When finalized, this Guidance for Industry will complement the FDA Guidance "General Principles of Software Validation." The section on "Validation of Automated Process Equipment and Quality System Software" will be replaced.
News from ICH
Draft revision of ICH Q9 Quality Risk Management Guideline published in 2022
With 33 pages, the draft was significantly more extensive than the previous version with 19 pages16. However, this is due to the fact that each line is numbered for better commenting and the line spacing has thus become larger. However, there are also new passages. This is partly reflected in the table of contents, which contains new elements in the form of subchapters 5.1 Formalities in quality risk management and 5.2 Risk-based decision making and II.9 Quality risk management as part of supply chain control/management.
The most extensive changes are also pointed out in the introduction. For example, the issue of "subjectivity" is addressed in the context of risk management activities and the resulting decisions. Furthermore, appropriate risk-based decision-making during the product lifecycle and formality aspects related to quality risk management are addressed in the introduction.
Then, on June 14, 2022, FDA also published the draft document as "Draft Guidance for Industry" on its website. Comments could be submitted online or in writing to the FDA. In the meantime, the revision (R1) was published on the ICH website.
ICH Q13: Guideline on Continuous Production
As early as 2018, ICH had begun work on a Guideline entitled "Continuous Manufacturing of Drug Substances and Drug Products," which describes the requirements for the continuous manufacturing of medicinal products. A draft was published in mid-2021. In 2022, ICH adopted the final version17.
Guideline ICH Q13 describes scientific and regulatory considerations for the development, implementation, operation, and life cycle management of continuous manufacturing. ICH Q13 is applicable to the manufacture of active pharmaceutical ingredients and drug products (small and large molecules). It applies to new products (e.g., new drugs, generics, biosimilars) and the conversion of conventional batch manufacturing to continuous manufacturing for existing products. Aspects of development, GMP and regulatory affairs are addressed.
News from the PIC/S
Annex 1 (Manufacture of Sterile Medicinal Products)
Almost simultaneously with the EU Commission, the PIC/S (Pharmaceutical Inspection Co-operation Scheme) also published the revised Annex 1, which is identical to the new Annex 1 of the EU GMP Guideline, with the exception of a few minor corrections in the wording.
The PIC/S has also adopted EU-GMP Annex 16 (Certification by a Competent Person and Batch Release) and refers to it as "Certification by the Authorised Person and Batch Release".
Previously, PIC/S had not adopted EU Annex 16, even in an adapted form. Initially, PIC/S felt that the Annex was too EU-specific and difficult to implement for PIC/S purposes. However, after a consultation with the participating PIC/S authorities in 2017, it was then decided to proceed with an implementation of EU Annex 16. The background was also the international harmonization efforts.
The Annex was adopted by the PIC/S Committee on January 26, 2022 (together with an adapted Annex 13 for investigational medicinal products) and entered into force on February 1, 2022. All authorities in the PIC/S (outside the EU and EEA) were encouraged to adopt the annexes into their own GMP guidance documents. It will be interesting to see how these authorities (which include, for example, the US FDA) approach possible implementation.
The EMA has published a three-year plan18. A large part of the IWG's work plan is derived from the experience with nitrosamine contamination issues ("Nitrosamines Lessons Learnt Exercise" - LLE) and includes plans to revise the EU GMP guidelines:
Chapter 1 (Pharmaceutical Quality System)
Submit final text for the revised chapter to the European Commission to encourage industry to adopt risk-based approaches to prevent shortages, taking into account initiatives such as the HMAEMA Taskforce and industry inter-association guidance.
Barcelona, Spain13/14 March 2024
Efficient Supplier Qualification
Chapter 4 (Documentation) and Annex 11 (Computerized Systems)
Submit final texts for the amended chapter and annex to the European Commission to ensure data integrity related to GMP.
Then on November 16, 2022, EMA published a 5-page "Concept- Paper on the revision of Annex 11 of the guidelines on Good Manufacturing Practice for medicinal products - Computerised Systems" (comment period until January 16, 2023)19. This is not yet a new draft, that should probably come in 2025. In 33 points, based on the structure and chapters of the existing Annex 11, new points to be included and topics to be updated are presented.
Annex 4 (Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products)
Review comments received during stakeholder consultation on the concept paper and draft updated text.
Annex 15 (Qualification and Validation)
Review the Annex in light of new technologies in facilities, products, and processes and consider whether updates are needed. Also reviewing whether the scope can be expanded to include APIs.
Annex 16 (Qualified Person Certification and Batch Release)
Following the LLE recommendations, consider revising the Annex to provide additional guidance on batch traceability.
GMP and Marketing Authorization Holders
Revise paper in line with LLE recommendations to align guidance for MAHs regarding appropriate quality agreement with manufacturers.
About the Author
Wolfgang Schmitt is Vice President at CONCEPT HEIDELBERG and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP. He is also Administration Manager of the European QP Association.