GMP Knowledge
for Your Safety.

Data integrity is a key element in the pharmaceutical quality assurance system which has gained importance in recent years, especially from the viewpoint of the authorities. In GxP-regulated companies, managers are responsible for identifying and minimising risks to data integrity (“data governance”).

The revised ISO 14644-5:2025 “Cleanrooms and Associated Controlled Environments – Part 5: Operations” replaces the previous 2005 edition. It sets out the basic requirements for planning, operating and controlling cleanrooms, as referenced in regulations such as EU GMP Annex 1.

Starting 1 October 2025, the European Medicines Agency (EMA) has begun accepting FDA inspection findings for manufacturing sites located outside the United States. The decision follows a successful pilot under the EU–US Mutual Recognition Agreement (MRA).

The FDA has issued guidance on how alternative tools can be used alongside or instead of traditional on-site inspections to assess manufacturing facilities named in pending applications. 

The Medical Device Coordination Group (MDCG) has updated its manual on the classification of products that are on the borderlines between medtech and other regulatory categories (Version 4).

During this year‘s Regulatory Conference, the Parental Drug Association (PDA) announced that a comprehensive AI glossary is available on its website.

The European Commission (EC) has published a call for evidence on the medical device and in vitro diagnostic regulations (MDR/IVDR). The initiative aims to simplify and streamline the regulatory framework, and make it more cost-efficient and proportionate. The overall structure of the current regulatory framework will be maintained.

Appendix 1 of EMA’s Questions and Answers on nitrosamine impurities has been updated. This appendix contains acceptable intakes (AIs) established for N-nitrosamines.

MedTech Europe is calling on EU lawmakers to align cross-sector digital legislation – the AI Act, Cybersecurity Act, Data Act and the European Health Data Space (EHDS) – with medical-device requirements to avoid duplicative or conflicting obligations.

Today, the European Commission published the revised Chapter 1, Pharmaceutical Quality System, of the EU GMP Guide. The public consultation phase closes on December 3, 2025.

The guideline on Good Agricultural and Collection Practice (GACP) for herbal starting materials has been in place since 2006 to ensure consistent quality of herbal substances. The newly released Revision 1 updates the document to current standards, reflecting developments over the past decade such as the growing use of indoor cultivation technologies and published legal interpretations. In addition, Annex 1 introduces specific requirements for indoor cultivation practices.

POWTECH TECHNOPHARM will once again take place in Nuremberg from 23 – 25 September 2025. In line with the new focus on the GxP-compliant production of pharmaceuticals, GMP-Verlag will also be there this year.

How does subjectivity impact quality risk management? Martin Mayer discusses the dos and don'ts for an objective quality risk management.

On 26 June 2025, Implementing Regulation (EU) 2025/1234 was published in the Official Journal of the EU, entering into force on 16 July 2025. It amends Implementing Regulation (EU) 2021/2226, which sets out the requirements for the electronic provision of instructions for use for medical devices. The regulations have been expanded. Switzerland is adopting these requirements immediately, initially without any additional amendments to the Swiss MepV (Medical Devices Ordinance).

On 7 August 2025, the World Health Organization (WHO) officially designated Health Canada, Japan's MHLW/PMDA (Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency), and the United Kingdom's MHRA (Medicines and Healthcare Products Regulatory Agency) as WHO-listed authorities (WLAs).

On 1 August 2025, the International Council for Harmonisation (ICH) endorsed the draft version of the ICH Q3E Guideline for Extractables and Leachables and made it available for public consultation. The guideline addresses a gap in the ICH's current guidelines on impurities and comes along with a supporting document on Class 3 leachable monographs.

The European Medicines Agency (EMA) and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) have jointly published a comprehensive report on nitrosamine impurities in human medicines, summarising key regulatory and scientific developments since their discovery in 2018.

What are the key considerations for gas distribution systems for pharmaceutical gases?

What are the important aspects of effective change management from an authorities' point of view?

Dr. Michael Hiob gives an overview on the relevant topics to observe when implementing changes in drug manufacturing. A detailed discussion of the change management procedure can be found in the chapter ‘Change Management’ of the GMP Compliance Adviser.

How does the draft ICH Q1 guideline affect the stability study design and conduct of drug products and drug substances? Joachim Ermer, PhD, summarises the most important changes and comments on critical aspects. 

The Association of German Engineers (VDI) has updated and published for comment its cleanroom standards, VDI 2083 Part 4.1 and Part 4.2. Part 4.1 covers the planning, construction, and initial commissioning of cleanrooms, and Part 4.2 covers the energy efficiency of cleanrooms.

At its June 2025 session, the European Pharmacopoeia Commission (EPC) adopted three revised texts on pharmaceutical waters. This is an important step towards achieving international harmonisation with the pharmacopoeias of India, Japan and the US.

The European Pharmacopoeia (Ph. Eur.) has published a significantly revised version of general chapter 3.2.1 Glass containers for pharmaceutical use in Pharmeuropa 37.3, marking the first major update since 2019 (Ph. Eur. Supplement 9.6).

ISPE has released the new GAMP^® Guide: Artificial Intelligence, addressing the use of AI in GxP-regulated areas within the life sciences sector.

The updated 〈1231〉 Water for Pharmaceutical Purposes addresses stakeholder input by clarifying and expanding guidance on water system design, control, and testing.

The BIO INN Laboratories of the Egyptian Drug Authority (EDA) have joined the General European OMCL Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), as an associated member.

The EC has published the long-awaited revised and new documents of the EU GMP Guide for consultation: Chapter 4 Documentation, Annex 11 Computerised Systems and the new Annex 22 Artificial Intelligence. Stakeholder consultations are open until 7 October on the EC website.

Swissmedic has published a new Technical Interpretation based on the guidelines of Good Distribution Practice (GDP). It defines the minimum requirements for wholesalers handling medicinal products returned by retailers, particularly with regard to the time limits that must be observed between delivery and return of the medicinal products.

The Medical Device Coordination Group (MDCG), in collaboration with the Artificial Intelligence Board (AIB), has released MDCG 2025-6, a joint guidance document detailing how the Medical Device Regulation (MDR), In Vitro Diagnostic Regulation (IVDR), and the new Artificial Intelligence Act (AIA) must be applied in tandem to Medical Device Artificial Intelligence (MDAI) systems.

The rapid development of information technology has made computer-based systems indispensable in the pharmaceutical and biotechnology industries. They are crucial for managing and processing sensitive data, controlling and monitoring production, and complying with regulations. With increasing digitalisation, there is a growing need to protect these systems from potential threats and ensure that they meet regulatory requirements. In today's feature, Dennis Sandkühler explains why the implementation and subsequent commissioning of computerised systems require careful planning and continuous monitoring, and which aspects you should consider.

You might be thinking: “It's clear – GMP applies to manufacturing and GDP to distribution!” But is this distinction always so unambiguous? Unfortunately not, says Simone Ferrante, author of the knowledge portal GMP:KnowHow Pharma Logistics (GDP). From her many years of professional experience, she knows a number of topics where the legal situation is insufficiently harmonized and therefore unclear.
Find out more about the interfaces between GMP and GDP and test your knowledge in today's feature! 

The Active Pharmaceutical Ingredients Committee (APIC) has published the 2^nd revision of its nitrosamine risk management guidance for API manufacturers. This guidance document was first prepared in 2020 by the APIC Nitrosamines Task Force.

The U.S. Food and Drug Administration (FDA) has launched Elsa, a generative AI tool aimed at enhancing the productivity of its employees, from scientists to investigators.

The European Council has adopted its negotiating position on the major reform of EU pharmaceutical laws, the 'Pharma Package', and is now ready to start talks with the European Parliament.

In today’s feature, our editor Sabine Paris reports from the PDA Good Aseptic Manufacturing Conference 2025 in Basel, where Swissmedic's Paula Walser provided valuable regulatory perspective alongside industry experts. The conference revealed that 25 % of companies remain non-compliant with Annex 1, facing challenges from cleanroom upgrades to contamination control strategies. However, speakers from Takeda, Novartis, and Charles River demonstrated how regulatory pressure is driving innovation – from questioning traditional monitoring methods to advancing digital transformation of sterility testing and rapid microbiological methods. The blend of regulatory insight and industry innovation showcased how Annex 1 compliance is reshaping aseptic manufacturing.

Pharmaceutical water plays a distinctive and vital role in the pharmaceutical industry. Unlike raw materials and excipients, which undergo quality control and approval before use, pharmaceutical water is used immediately after production. For this reason, it is considered extremely critical. Three types of water are particularly important: potable source water, purified water (PW) and water for injection (WFI). In this feature we focus on WFI. Two previous LOGFILES have already reported on drinking water as source water and on PW.

The International Council for Harmonisation (ICH) held its Assembly meeting on 13–14 May 2025 in Madrid, Spain, alongside 11 Working Groups and prior meetings of the Management and MedDRA Steering Committees.

Swissmedic has updated its guidance on Good Manufacturing Practice (GMP) compliance for foreign manufacturers, clarifying documentation requirements for various application types (e.g., new authorizations, type IA/IB/II changes for human and veterinary medicines).

The EDQM has released an updated version of the guideline “How to Read a CEP”, offering clear explanations of the information contained in Certificates of Suitability (CEPs) to European Pharmacopoeia monographs.

EMA has updated ist questions and answers for marketing authorisation holders/applicants on nitrosamine impurities in human medicinal products.

Artificial intelligence is developing faster than any previous technology, promising innovation and competitive advantage. Yet, integrating AI while maintaining safety, quality, and trust poses a challenging task for the pharmaceutical industry. It requires an appropriate regulatory framework as a fundamental condition. Today's editorial outlines which role the EU AI Act, the EMA's reflection paper, and various ISO standards play in shaping the regulatory landscape.

Appendix 1 of EMA’s Questions and Answers on nitrosamine impurities has been updated. This appendix contains acceptable intakes (AIs) established for N-nitrosamines.

EMA has updated its FAQ document on the European Shortages Monitoring Platform (ESMP), addressing six new questions – five related to data submission and reporting. 

The U.S. FDA announced its intent to expand the use of unannounced inspections at foreign manufacturing facilities that produce foods, essential medicines, and other medical products intended for American consumers and patients. 

Swissmedic has established the requirement to submit risk assessments relating to nitrosamines in active substances and/or finished medicinal products in the corresponding specification documents.

EMA has published a concept paper on the revision of GMP Guide Part IV on ATMPs for public consultation. 

EMA has published a Q&A on how to reflect third party audit(s) in part C of the QP declaration.

Artificial intelligence is a highly relevant topic, and for good reason. It has the potential to provide innovative solutions to complex challenges. This is particularly true in the pharmaceutical industry, where implementing and using AI can result in significant benefits. Today's editorial explores the potential of AI applications in the GMP environment and the challenges that could come along with it.
The upcoming LOGFILE will tackle the current regulatory framework for AI, focusing on the EU AI Act, relevant ISO standards, and the EMA's reflection paper on the topic. Don’t miss out and benefit from the concise overview!

The WHO has released a series of new and updated guidelines related to pharmaceutical manufacturing, testing, and development, published as part of Technical Report Series No. 1060 (TRS 1060). Annexes 2 through 9 address a range of topics, including nitrosamine control, GMP for excipients, bioanalytical methods and blood establishments.

The European Medicines Agency (EMA) has updated guidance on GMP and GDP. The EMA has added two questions and answers on the basic requirements for active substances used as starting material in relation to third party audits.

Pharmaceutical water occupies a unique position within the pharmaceutical industry. Whereas raw materials and excipients are used only after quality control and approval, pharmaceutical water is used immediately after production. For this reason, it is considered extremely critical. Three types of water are of particular importance: potable source water, purified water (PW) and water for injection (WFI). In this issue we will focus on PW, while a future issue of LOGFILE will cover WFI.

Do you know where your pills come from? They probably have a long journey behind them. Active ingredients from China meet excipients from India to be pressed into tablets in France, which are blister-packed in Italy and packaged in Spain before being imported to Germany – sounds unrealistic? No, because the manufacture and distribution of pharmaceuticals is a global business. Therefore it is important to speak the same language in terms of the underlying regulations. In todays feature you will read a short summary of the WHO GDSP guideline, which is not only the latest, but probably also the most globally oriented guideline on the topic of good storage and distribution.

The Chinese drug authority NMPA has published its long-awaited draft annex to the Chinese GMP for sterile drugs for public review and comment. There is close alignment with the tripartite WHO/EU/PICs GMP Annex that was published in 2022.

EMA has published a draft reflection paper on linking electronic product information (ePI) from medicine packages. This paper describes components to be put in place to realise an EU-wide solution in which ePI could be easily accessed by citizens wherever they are in Europe, in their preferred language when available.

Swissmedic has published an updated version of its technical interpretation for a Product Quality Review (I-SMI.TI.14e).

The 3-year work plan for the EU GMDP Inspectors Working Group (IWG) aligns with Network Strategy goals, emphasising supply chain integrity, product quality, enhancing inspector capacities, and the impact of new manufacturing technologies. 10 documents of the GMP Guide will be revised or newly launched.

The EMA's GMDP Inspectors Working Group (GMPD IWG) has published its 2024 annual report.

Pharmaceutical water has a unique position in pharmaceutical industry. As raw materials and excipients are only used after quality control and subsequent release, pharmaceutical water is used immediately after production. For this reason, pharmaceutical water is considered extremely critical. Three types of water are of particular interest: Drinking water as source water, purified water (PW) and water for injections (WFI). In today’s feature we report on drinking water as source water. In future LOGFILES, we will report on PW and WFI.

The International Coalition of Medicines Regulatory Authorities (ICMRA) Pharmaceutical Quality Knowledge Management (PQKM) collaborative pilots have been extended until the end of 2025. ICMRA is actively seeking new applications for collaborative review by multiple global regulators. 

The European Commission (EC) has proposed the Critical Medicines Act to enhance the availability of essential medicines in the EU. The regulation aims to diversify supply chains, boost EU pharmaceutical production, and improve access to critical medicines.

Do you trust your pills? Are you sure that nothing went wrong during production? Actually, you should be able to say yes, because medicinal products must be manufactured in such a way that they do not pose any risk to the patient through lack of safety, purity, quality or efficacy.

However, every step in the manufacturing process of medicinal products involves potential risks. Effective management, control and thus minimization of potential patient risks is only possible with the help of effective risk management.

The authoritative guideline for quality risk management, ICH Q9, has been revised. In today's editorial, you will find a summary of the most important changes in ICH Q9(R1).

The International Pharmaceutical Excipients Council (IPEC) Federation has released an update of its position paper advocating for independent third party audits and certification programs. The position paper was first published in September 2015.

In collaboration with the World Health Organization (WHO), the European Medicines Agency (EMA) supports a pilot programme that allows pharmaceutical companies to submit EMA-approved post-authorisation changes (i.e. variations) to multiple non-EU national authorities.

In February 2025, EMA's CHMP adopted a positive opinion approving changes to the manufacturing process for Champix, a smoking cessation medicine.

EMA’s Biologics Working Party has updated the question-and-answer document for biological medicinal products, adding information on nitrogen gas for backfilling, container closure systems and prior knowledge.

The call for Quality Oversight is getting louder – especially in FDA warning letters there is an increasing number of deficiencies observed in the context of quality oversight.

In today’s feature, Christian Gausepohl presents an approach for implementing Quality Oversight at shop floor level as a collaboration between Quality Assurance and Operations. What are the success factors for this model and how could the organisational structure look like?

Swissmedic has updated its medicinal products' portal, introducing a new process for ordering GxP certificates and granting direct access to all pre-registered company administrators. However, Swissmedic acknowledged the absence of a new onboarding process for companies or administrators as a known issue.

Appendix 1 of EMA’s Questions and Answers on nitrosmine impurities has been updated. This appendix contains acceptable intakes (AIs) established for N-nitrosamines.

At the end of December 2023, the Indian Ministry of Health revised the provisions of Schedule M of the Drugs and Cosmetics Act. Schedule M describes good manufacturing practices (GMP) for pharmaceutical products.

The Medical Device Coordination Group (MDCG) has updated its questions and answers document on requirements relating to notified bodies to explain how notified bodies can use previous assessments to avoid unnecessary duplication of work.

Analytical methods are used throughout the development, manufacture and release of pharmaceutical substances and dosage forms. The accuracy and reliability of analytical results are therefore essential. Successful method validation proves that the test procedure is suitable for the defined application. In our last feature, we reported on the regulatory requirements for analytical method validation. Today, you can find out which aspects need to be considered when putting them into practice.

Health Canada and Swissmedic agreed to expand the existing approach to include both the recognition of GMP extra-jurisdictional inspection outcomes (inspections outside Switzerland and Canada) as well as active pharmaceutical ingredient and stable medicinal products derived from human blood or human plasma in the operational scope.

The European Commission (EC) launched a Biotech and Biomanufacturing Hub.

EMA has added three new questions to its guidance on good manufacturing practices to address risks of diethylene and ethylene glycol (DEG/EG) contamination in glycerol and other excipients.

Appendix 1 of EMA’s Questions and Answers on nitrosmine impurities has been updated. This appendix contains acceptable intakes (AIs) established for N-nitrosamines.

From 13 February, the Federal Institute for Drugs and Medical Devices (BfArM) will offer the public part of the drug information system (AMIce) in its entirety for free research.

The EMA has published for consultation a reflection paper on the qualification of non-mutagenic impurities (NMI).

Analytical methods are used throughout the development, manufacture and release of pharmaceutical substances and dosage forms. The accuracy and reliability of analytical results are therefore essential. Successful method validation proves that the test procedure is suitable for the defined application. In today's feature, Joachim Ermer writes about the regulatory requirements for the validation of analytical methods. 

In the next LOGFILE you will learn more about important aspects of putting these requirements into practice.

The PIC/S Committee has granted the African Union Development Agency - New Partnership for Africa's Development (AUDA-NEPAD) the status of Associated Partner Organisation.

The World Health Organization (WHO) has released a draft document titled Points to Consider in Continuous Manufacturing of Pharmaceutical Products for public comment.

The FDA has published Considerations for Complying with 21 CFR 211.110 for comment.

Appendix 1 of EMA’s Questions and Answers on nitrosmine impurities has been updated. This appendix contains acceptable intakes (AIs) established for N-nitrosamines.

The MHRA has published supplementary information for international regulators: export of UK medicines and the new Windsor Framework (Northern Ireland) labelling requirements.
 

Has it ever happened to you that ‘your’ medicine was not available in the pharmacy? It becomes problematic when the re-availability is not foreseeable, the medicine is urgently needed and no alternatives exist. The topic of ‘supply shortages’ is in the public eye and was also discussed at the 30th GMP Conference, which took place in Cologne, Germany, from 6 to 7 November 2024. Doris Borchert, PhD, attended the conference on behalf of GMP-Verlag. Today she reports on a panel discussion on the topic of supply shortages.

The amended Ordinance on In Vitro Diagnostic Medical Devices (IvDO) enters into force on 1 January 2025. Switzerland is implementing extended transitional periods in line with the EU Regulation 2024/1860.

FDA’s CDER has updated the recommended acceptable intake (AI) limits for certain hypothetical nitrosamine drug substance-related impurities (NDSRIs) and other identified nitrosamine impurities (Table 1) as well as the recommended interim AI limits for certain nitrosamine impurities for approved or currently marketed products (Table 3).

The EMA has published two new GDP Q&As for wholesale distributors and brokers on suspicious offers.

The EMA has published a pilot report on the creation and testing of electronic product information (ePI) in regulatory procedures. The findings suggest that the EU regulatory system is ready for ePI and can begin phased implementation, though further development is needed, including additional features and IT system integration.

PIC/S has published two guidance documents for inspectors: "Guidance on Remote Assessments" (PI 056-1) and "Aide Memoire on Remote Assessments" (PI 057-1). These documents will enter into force on 1 January 2025.

The EMA has published the three-year rolling work plan for the Quality Innovation Group (QIG) for the period 2025-2027. QIG supports the translation of innovative approaches to the design, manufacture and quality control of medicines.

The ICH has published the updated Q9(R1) Annex 1: Q8/Q9/Q10 Questions & Answers (R5) related to ICH Q9(R1) Quality Risk Management (QRM).

The World Health Organisation (WHO) announced that Senegal had became the 7th country and Rwanda the 8th country to achieve the status of a stable, well-functioning regulatory authority for the regulation of medicines in Africa.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has published further guidance for the preparation of dossiers to obtain a Certificate of Suitability (CEP) for a sterile substance.

The Brazilian health regulatory authority, ANVISA, has decided to consider evaluation reports from international regulatory bodies in their decision-making process.

The Pharmacopoeial Discussion Group (PDG) signed off on the harmonised general chapter “Elemental Impurities (G-07)” on 19 June 2024. The PDG, which includes the European Pharmacopoeia (Ph. Eur.), Indian Pharmacopoeia Commission (IPC), Japanese Pharmacopoeia (JP), and United States Pharmacopeia (USP), worked on this chapter to align elemental impurity requirements across regions based on the ICH Q3D Guideline.

The ICH has published the ICH Q13 IWG "Continuous Manufacturing of Drug Substances and Drug Products" Modules 1–12 video training material.

Pharmaceutical water is used in the manufacture of medicines, vaccines and other pharmaceutical products. High water quality is essential to ensure the safety and efficacy of the final products. In order to ensure that the quality is maintained at all times, there are many parameters that need to be monitored. In today's article, we look at the importance of physicochemical monitoring of pharmaceutical water.

The EMA has revised the Q&As on good manufacturing and distribution practices (GMPs/GDPs). A new question and answer on the documentation of supply chain traceability has been added to the section about EU GMP Guide Annex 16 certification by a qualified person and batch release.

The European Commission (EC) has published a Q&A on practical aspects related to the implementation of the gradual roll-out of Eudamed pursuant to the MDR and IVDR, as amended by Regulation (EU) 2024/1860 as regards a gradual roll-out of Eudamed, the obligation to inform in case of interruption or discontinuation of supply, and transitional provisions for certain in vitro diagnostic medical devices.

Looking at Annex 1, the use of barrier systems such as RABS or isolators is very common. Since Contamination Control Strategy (CCS) requirements are an important part of selecting the appropriate barrier technology, closed RABS or isolators should be preferred. As isolators have the additional feature of automatic surface decontamination with vaporized or finely nebulized H2O2 compared to a closed RABS and can be installed in a grade C/D cleanroom area, isolator technology is more commonly used. It also offers the highest level of safety and is more sustainable, as it requires fewer cleanroom zones and associated airlocks with the energy-intensive room air technology they require.

The International Council for Harmonisation (ICH) held its Assembly Meeting in Montréal, Canada on November 5-6, 2024.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) will launch the online-only European Pharmacopoeia (Ph. Eur.) in June 2025, transitioning to a more environmentally friendly format. The new platform will enhance user experience with a modern interface and improved search tools.

The PMDA has established an office in Washington, D.C. This is the PMDA's second overseas office, following the establishment of the Asia office in Thailand in July.

The Analysis and Control Laboratories Department of the Turkish Medicines and Medical Devices Agency has become a full member of the General European OMCL Network (GEON), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM).

Filters in safety cabinets: The filters are the most important part of a safety cabinet. To ensure comprehensive protection of the product and personnel, HEPA filters of at least class H13 must be used, usually H14 filters are used.

ICH has published the updated training materials related to ICH Q9(R1) Quality Risk Management (QRM). These materials, include a Q9(R1) Introduction Presentation replacing 5 presentations in the current ICH Q9 Briefing Pack and updated ICH Q8/Q9/Q10 Training Material which replaces 12 presentations developed in 2006-2010.

The European Commission has published a Q&A on practical aspects related to the implementation of the Article 10a obligation in case of interruption or discontinuation of supply of certain devices as introduced by Regulation (EU) 2024/1860 amending Regulations (EU) 2017/745 (MDR) and (EU) 2017/746 (IVDR).

On 23 October, the European Parliament has adopted a resolution to revise the Medical Devices Regulation (MDR) and In Vitro Diagnostic Medical Devices Regulation (IVDR) to address ongoing implementation challenges and support patient access to essential medical devices by 2025.

The European Commission (EC) Medical Device Coordination Group (MDCG) has published guidance on qualification of in vitro diagnostic medical devices (IVDs) (MDCG 2024-11). The guidance determines which products fall under the scope of Regulation (EU) 2017/746 (IVDR) as IVD.

When establishing the basic design of equipment, containers, components and machines for pharmaceutical use, a wide variety of materials is required. These are typically subdivided into materials of construction and adjuvants or production aids.

The ICH has published the 2024 Implementation Survey Report. It contains the results of a study aimed to monitor the adequacy of implementation and adherence to ICH Guidelines by regulatory authorities – continuing the assessment initiated in 2019 and repeated in 2021.

The EMA has published for consultation the draft guideline on risk management requirements for elemental impurities in veterinary medicinal products (VMPs). As the Ph. Eur. General Monograph 2619 on pharmaceutical preparations applies to all VMPs, risk management of elemental impurities in all VMPs in the EU market is expected.

Brasil‘s Anvisa has launched a new tool, a dashboard, which allows you to consult the list of active ingredients in medicinal products for which registration applications are being assessed by the agency.

Swissmedic has launched the SwissGMDP database, which gives public access to GMP and GDP certificates of all authorised Swiss pharmaceutical companies.

The manufacture of sterile products involves a wide range of product types, primary packaging materials and technologies. The sterilisation process used must be appropriate and effective for the application. The specified sterilisation conditions must be consistently achieved in all parts of the load or over the entire surface of the system, equipment and components. In today's article, we look at the general requirements for sterilisation processes and the important definitions that go with them.

Reading SOPs is not Training! This powerful statement was echoed in several sessions with the PDA/FDA Joint Regulatory Conference 2024. It highlights a critical point: training is more than just reading procedures – it requires performance evaluation. Sabine Paris and Thomas Peither attended the event and have highlighted some of the other key takeaways in today’s feature.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) has issued new guidance for wholesalers and manufacturers in response to the Windsor Framework, which updated the terms of Brexit.

The EMA has published for consultation new Q&As for co-processed excipients (CoPEs) used in solid oral dosage forms. The document outlines the quality requirements for CoPEs used in solid oral dosage forms in both human and veterinary medicinal products.

EMA published the revision 6 of the Appendix 1 (“Acceptable intakes (AIs) established for N-nitrosamines”) of the EMA Questions and answers for marketing authorization 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 (EMA/409815/2020 Rev.21).

The FDA published the second revision to the industry guidance on "Control of Nitrosamine Impurities in Human Drugs".

During the press conference of the PDA/FDA Joint Regulatory Conference 2024, PDA (Parenteral Drug Association) announced interesting new publications and the formation of the new D/A/CH Chapter to support local members.

On 5 September 2024 the EMA and the Heads of Medicine Agencies HMA, published guiding principles that set how EU medicine regulators can use large language models (LLMs), a form of generative AI, focusing on text generation in regulatory science and for regulatory activities. The 10-page document provides high-level recommendations to facilitate LLMs' safe, responsible, and effective use, being of interest to anyone who uses or would like to use such AI models in the future.

Swissmedic published an updated version of Technical Interpretation 17: Responsible Person: requirements on 26 August 2024. The document outlines the Swiss Inspectorate’s understanding of an RP in accordance with the Medicinal Products Licensing Ordinance (MPLO). It can also serve as a reference for companies to assess whether an individual meets the criteria for applying to Swissmedic to act as an RP.

This guideline is an essential reading for all regulatory professionals involved in preparing MAAs. It describes the revised requirements for assessing the potential environmental risks of human medicinal products. The guideline was adopted on 15 February 2024 and will enter into force on 1 September 2024. The changes and extended requirements for environmental risk assessment will be mandatory for all pharmaceutical companies placing their medicines on the EU market.

The Drug Regulatory Authority of Pakistan (DRAP) issued a Rapid Alert on 22 August 2024 regarding counterfeit batches of Propylene Glycol. The batches are tagged with Dow Chemical labels, and some are declared to be from 'Dow Europe GmbH, Made in Germany'.

The Central Drugs Standard Control Organization (CDSCO), the Ministry of Health, and the Government of India have released a 25-page document Draft Guidelines on GDP for Pharmaceutical Products. The guidelines have been developed following WHO TRS 1025 – Annex 7: Good Storage and Distribution Practices for Medical Products, with a broader focus on pharmaceutical product storage.

Swissmedic has issued an update regarding non-standardized medicinal products, revising an information sheet and the list of products impacted by a specific manufacturing regulation. This product category addresses patient-specific preparations.

A pressure cascade is required between cleanrooms of different cleanliness levels to prevent cross contamination. Annex 1 of the EU GMP Guide requires a pressure difference of at least 10 Pascal between two different cleanliness classes. Today’s feature explains how these pressure differences can be achieved and maintained for two different types of pressure cascade systems. 

The EMA has published an updated Q&A on the impact of MRA between the EU and the US. Since last year, the US has confirmed the capability of 4 additional EU Member States for veterinary product inspections.

The Therapeutic Goods Administration (TGA) has initiated a consultation phase to harmonise the basic principles for medical devices in Australia with the EU Medical Device Regulations. A comparison of the two regulatory systems revealed that the EU MDR and IVDR regulations impose additional safety and performance requirements, e.g. for clinical evidence or the information to be provided for medical devices. The keywords here are risk minimisation, risk management systems, and measures to reduce risks due to user error.

The term "PUPSIT", which stands for the Pre-Use Post-Sterilization Integrity Test, has been included in the revised Annex 1. While the term is new, the requirement to check the integrity of a sterilizing filter after it has been sterilized and before it is used for sterile filtration is not new. This has been included in Annex 1 since 1998.

The new "swissdamed" medical devices platform has been gradually rolled out since 6 August 2024. The first release of the "Actors" module enables economic operators to register online.

The Australian TGA has introduced temporary 'surveillance inspections' for domestic and overseas manufacturers of medicines, Active Pharmaceutical Ingredients (APIs), biologicals, and blood products.

The EMA published for consultation an update of the guideline on the chemistry of active substances. The need for revision was identified in the report on “Lessons learnt from presence of N-nitrosamine impurities in sartan medicines” (LLE), which makes recommendations to reduce the risk of N-nitrosamines being present in human medicines and to help the European medicines regulatory network to be better prepared to deal with future cases of unexpected impurities.

The EMA has updated its Q&A document on nitrosamine impurities in human medicinal products. In collaboration with the Heads of Medicines Agencies (HMA) responses to six questions were revised. Specifically, EMA updated one answer to reflect its position on the acceptability of the Ames test and another to clarify responsibilities concerning active substance master files and the certification of suitability.

The US Food and Drug Administration (FDA) released a draft guidance detailing how manufacturers should report postapproval manufacturing changes for licensed biosimilar and interchangeable products.

Empty shelves, incorrectly sorted goods and food that has passed its sell-by-date. A supermarket with such problems would have no chance of success. Materials management would have failed across the board. Fortunately, this scenario is rather unlikely. However, it illustrates the importance of efficient and reliable processes to ensure that the right material from the right source arrives at the right place in the right packaging and under the right storage conditions. The same holds true for pharmaceutical operations. Read more about the key requirements for material storage and internal logistics in this week’s brief extract.

Carrying out quality testing internally may be a complex process, but it also has many advantages. A solid knowledge of product properties, stability and degradation products is built up over time in a laboratory and can be particularly valuable when carrying out quality risk analysis. However, some tests can be outsourced to external partners.

The European Commission has published a new Regulation (2024/1938) providing new rules on standards of quality and safety for substances of human origin (SoHO).

Regulation (EU) 2024/1860 amending the MDR and the IVDR was published in the Official Journal of the EU on 9 July and entered into force immediately.

The European Medicines Agency (EMA) updated Appendix 1 (EMA/307633/2024 /Rev. 5) of the Nitrosamine Q&As, listing nitrosamines with established Acceptable Intake (AI) values.

The Japanese Ministry of Health, Labour and Welfare (MHLW) has published an updated English translation of the Ministerial Order on the Standard of Manufacturing Control and Quality Control for Pharmaceuticals and Quasi-Pharmaceuticals.

The Medical Device Coordination Group (MDCG) has updated its guidance on standardisation for medical devices, including topics such as the European Pharmacopoeia and common specifications.

While the European Pharmacopoeia (Ph. Eur.) already includes parts of the ICH Q3D guideline on elemental impurities in the general chapter on Elemental impurities (5.20), the requirements for extractable elements from plastic containers for pharmaceutical use and closures are legally binding.

The European Commission (EC) launched an online public consultation on cooperation with the European Medicines Agency (EMA) under the Health Technology Assessment (HTA) Regulation. The cooperation, which is outlined in a draft implementing act, includes the exchange of information between the Coordination Group on Health Technology Assessment (Member States), the Commission and the EMA.

EMA releases templates to assist marketing authorisation holders (MAHs) in creating plans to prevent and mitigate shortages. The EMA is urging MAHs in the EU/EEA Area to develop a plan to prevent shortages and minimise the likelihood of shortages for their marketed medicines.

The Medical Device Coordination Group (MDCG) has revised its guidance regarding the designation, re-assessment, and notification of conformity assessment bodies and notified bodies.

What do you associate with the word “culture”? 
It’s likely to be literature, fine art, or music, but not necessarily GMP. Yet, the term culture has found its place in our professional world in recent years, especially when it comes to quality. Today's editorial by Doris Borchert, PhD, highlights the striking connections between quality culture and a symphony orchestra.

Do you know the difference between “clean up period” and “recovery time”? Both terms are often used to describe the same procedure, but they are completely different from each other. 
Today's feature clearly explains the differences between test methods for determining the clean-up phase (Annex 1) and the recovery time (ISO 14644-3), using real-world examples.

The International Council for Harmonisation (ICH) held its Assembly on 4-5 June 2024 in Fukuoka, Japan, alongside meetings of 13 Working Groups, the ICH Management Committee, and the MedDRA Management Committee. ICH welcomed new members ANMAT (Argentina) and JFDA (Jordan), expanding to 23 Members and 35 Observers.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published details of what its members are doing to improve the environmental sustainability of the pharma industry. EFPIA aims to adopt innovative practices that reduce environmental impact, exceeding EU Green Deal targets under the Zero Pollution, Circular Economy, and Climate Action plans.

In 2015, with the revision of Chapters 3 and 5 and Annex 15 of the EU GMP Guide and with the publication of the EMA PDE Guideline a paradigm shift occurred in the setting of limits for the validation of cleaning processes. Instead of the previously used criteria, such as 10 ppm or 1/1000 of the therapeutic dose of the foregoing product, the only acceptable criterion is now a toxicological risk assessment based on PDE values.

Process validation is ubiquitous and always an important issue in GMP manufacturing and packing. In our today’s feature you can get a first insight into the basics of process validation and learn that only validated processes lead to consistently high quality products.

The Medical Device Coordination Group (MDCG) issued a second revision to its surveillance guidance for medical devices. The changes align the guidance with EU regulations on transitional provisions for certain medical devices and in vitro diagnostic devices (IVDs).

The Q2(R2)/Q14 EWG developed a new ICH Quality Guideline, ICH Q14, on Analytical Procedure Development, and revised the ICH Q2(R1) Guideline on Validation of Analytical Procedures. The ICH Q2(R2) revised Guideline and the Q14 Guideline reached Step 4 of the ICH process on 1 November 2023. A Step 4 introductory training presentation has now been developed by the Q2(R2)/Q14 Expert Working Group.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has drafted a guideline ‘Content of the dossier for sterile substances’ (PA/PH/CEP (23) 54). The draft document is now available for public consultation until 15 August 2024.

The European Commission (EC) has published a new version 21 of its Q&As on safety features for medicinal products for human use. Four new questions have been added.

The EMA has published a new revision of the guidance available to applicants, marketing authorisation holders and notified bodies of medical devices. This question-and-answer document provides practical considerations on the implementation of the medical devices and in vitro diagnostic regulations (MDR and IVDR) for combinations of medicinal products and medical devices.

The Contamination Control Strategy (CCS) is one of the few genuinely new requirements in the revised Annex 1. While Annex 1 provides quite comprehensive information on the content, the formal structure is not prescribed. In today’s feature you will read about an inspector’s point of view concerning the creation of this document, the responsibilities for review and approval, and the expectations for the first inspections to come.

An update of the Appendix 1 (“Acceptable intakes established for N-nitrosamines”) of the Questions and answers for marketing authorization 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 has just been published by the EMA.

The GMP/GDP Inspectors Working Group has amended their FAQs on GDP. Two new questions deal with the possibility and conditions for remote activities of the resposible person (RP) for GDP.

The FDA has issued final guidance clarifying "remanufacturing" for reusable medical devices needing maintenace or repair, aiming for consistency and better understanding of federal laws.

In its Q&A section on GMP and GDP, EMA has added questions and answers on additional guidance to Annex 8 on sampling excipients at risk of glycol contamination, emphasising stringent measures for high-risk substances. In seven key questions, EMA highlights the risks of diethylene glycol (DEG) and ethylene glycol (EG) contamination, emphasising the responsibilities of manufacturers and supply chain management.

On 29 April, the Food and Drug Administration (FDA) issued a final rule that will phase out its general enforcement discretion approach for laboratory developed tests (LDTs) over a four-year period.

The WHO has published a new draft guideline on considerations for the prevention and control of nitrosamine contamination in pharmaceutical products. This guideline applies to all manufacturers of excipients, active pharmaceutical ingredients and finished pharmaceutical products.

The 3-year work plan for the EU GMDP Inspectors Working Group (IWG) aligns with Network Strategy and Regulatory Science Strategy (RSS) goals, emphasising supply chain integrity, product quality, and the impact of new manufacturing technologies. 10 documents of the GMP Guide will be revised or newly launched.

On 18 April, the EMA launched a new draft version of the Guideline on Good Agricultural and Collection Practice (GACP) for starting materials of herbal origin. This update brings the document up to date with current standards, incorporates the increased development of indoor growing technologies and also covers best practice and legal interpretations published over the last 10 years.

To address the specific requirements for manufacturing ATMPs, separate GMP regulations were published as Part IV of the EU GMP Guidelines in late 2017.

The Japanese Pharmacopoeia (JP) and the European Pharmacopoeia (Ph. Eur.) are launching a joint project to harmonise pharmacopoeial standards for active substances and medicinal products. This initiative aims to reduce the burden on manufacturers by aligning pharmacopoeial standards across different regulatory regions.

On 10 April, the EU Parliament approved a legislative package to reform the EU‘s pharmaceutical legislation, with the aim of boosting innovation and improving the accessibility and affordability of medicines. The package, which includes a new directive and a regulation, recieved strong support from Members of the European Parliament (MEPs).

Advanced therapy medicinal products (ATMPs) are an innovative class of medicinal products characterised by the use of advanced technologies.They target the underlying genetic, cellular, or tissue-based abnormalities of diseases and thus offer the potential for cure or at least a long-term therapeutic benefit.

On 27 March 2024, Japan's PMDA (Pharmaceuticals and Medical Devices Agency) published an English-language version of its updated recommendations on the quality, safety, and efficacy of biosimilars. The 14-page document, Questions and Answers on Guideline for Ensuring the Quality, Safety, and Efficacy of Biosimilars, has been updated to reflect the current state of scientific knowledge. The revised sections of the document are indicated and relate to Q&As 9, 10, and 11.

Appendix 3 of the EMA’s Nitrosamine Q&A has been updated. The Appendix deals with the enhanced Ames test conditions for N-nitrosamines.

Thomas Peither started his GMP journey nearly three decades ago. Throughout this period, he gained an in-depth understanding of the inner workings of GMP in the pharmaceutical sector. Now Thomas Peither – one of the founders of the GMP-Verlag – has stepped down from the board while still maintaining his role as a writer for the publishing house. Today's editorial offers his personal view on the development of GMP, highlighting important shifts and obstacles. He emphasizes the significance of employees in achieving GMP compliance and reflects on why his enthusiasm and confidence in GMP remains unwavering after 30 years.

On 22 March, the German Cannabis Law was passed by the Bundesrat. The law will therefore come into force on 1 April as planned.

The European Commission adopted two implementing decisions on the sterilisation of medical devices. These decisions were made in accordance with the regulations governing medical devices and in vitro diagnostics (IVDs) in the EU.

Ensuring a clean production environment – sounds simple enough.However, in the pharmaceutical context, cleanliness and contamination are clearly defined, delineated and, of course, regulated, particularly in the manufacture of active ingredients and medicinal products.

The European Court of Justice (ECJ) has ruled that harmonised technical standards are part of EU law and should therefore be freely accessible to EU citizens (Judgment of 05.03.2024, ref. C-588/21 P).

An update of the EMA's Appendix 1 to the questions and answers for marketing authorisation holders/applicants on nitrosamine impurities in human medicinal products has just been published (EMA/72902/2024 /Rev. 3).

The monograph on Cannabis flower (3028) has been published in Ph. Eur. Supplement 11.5 in January 2024, with an implementation date of 1 July 2024. 
All member states of the European Pharmacopoeia are required to replace their national monographs with this new Ph. Eur. Monograph. 

On 23 February, the German Bundestag approved the government's bill on the "controlled use of cannabis". The law allows adults to possess up to 50 grams of cannabis in private and up to 25 grams in public.

The ICH Q3C “Guideline for Residual Solvents” has undergone revision to become finalised as version R9 using the Minor Revision Procedure. This revised document was published on 24 January 2024 and reached Step 4 of the ICH Process, which is the adoption of a harmonised guideline.

The ICH Q12 Implementation Working Group (IWG) "Regulatory and Technical Considerations for Pharmaceutical Product Lifecycle Management" Module 8 Training Material is now accessible on the ICH website.

The European Directorate for the Quality of Medicines and HealthCare (EDQM) has published the top 10 deficiencies identified in 2023 following the initial evaluation of new applications for Certificates of Suitability (CEP).

The World Health Organization (WHO) has published the 10^th edition of the "Quality Assurance of Pharmaceuticals: a Compendium of Guidelines and Related Materials, Volume 2, Good manufacturing practices (GMP) and inspection".

On 31 January 2024, the Medicines and Healthcare products Regulatory Agency (MHRA) announced the designation of two new UK Approved Bodies (UKAB) to increase the capacity to certify the performance and safety of medical devices.

The US Food and Drug Administration (FDA) has released its Quality Management System Regulation (QMSR) final rule after years of development. It is a rework of the Quality System Regulation (QSR) – 21 CFR Part 820.

Swissmedic has further specified risk assessment measures for Nitrosamine Drug Substance-Related Impurities (NDSRI). Initially identified in 2018, nitrosamine impurities, including those in antihypertensives, prompted ongoing evaluations and measures by Swissmedic to prevent such impurities.

The Indian Health Ministry has introduced revised rules under Schedule M of the Drugs and Cosmetics Rules, aimed at ensuring robust quality control for pharmaceutical and biopharmaceutical products. Schedule M outlines Good Manufacturing Practices (GMP) for pharmaceutical products.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has elaborated a document describing the principles for the declassification of documents pertaining to the CEP (Certificate of Suitability to the Monographs of the European Pharmacopoeia) procedure while ensuring when necessary, the confidentiality of information.

On 9 January 2024, the Swiss Medicines Agency Swissmedic informed about critical deficits in the system of medical device regulation. 

The EMA has published 3 new or updated questions and answers on Annex 1 of the EU GMP Guide. They deal with bioburden levels and sampling, and open versus closed isolators. The answers are summarised below:

The European Medicines Agency (EMA) has added 7 Q&As to their quality of medicines questions and answers. They refer to EMA‘s 1998 guidance on the shelf-life of sterile products for human use after opening or reconstitution (CPMP/QWP/159/96 corr).

The pace of digitalisation is accelerating. And it is presenting us with new opportunities at ever shorter intervals. This means that all GMP professionals need to be informed and make risk-based decisions! This also applies to data storage in the cloud. What are the opportunities and risks? Which cloud and service models exist? 
In today’s feature, GMP expert Thomas Peither summarises the key points.

The European Medicines Agency (EMA) has answered nine questions on the application of revised Brexit rules to centrally authorised medicinal products for human use in Northern Ireland (Regulation (EU) 2023/1182).

The EDQM informs that the standards cannabis flower for system suitability HRS (Herbal Reference Standard) and cannabidiol for cannabis CRS (Chemical Reference Substance) that are described in the newly adopted monograph on Cannabis flower (3028) are now available for users under catalogue code Y0002440 and Y0002422 respectively.

On 11 December, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) announced a validity extension of GMP and GDP certificates.

On 5 December 2023, the European Commission (EC) announced that it has adopted an implementing act to designate five EU reference laboratories (EURLs) for class D in vitro diagnostic medical devices (IVDs).

On 7 December 2023, the European Medicines Agency (EMA) published an important update on the validity of GMP certificates after COVID-19 on its Good Manufacturing Practice website:

The validity of GMP and GDP certificates, which were automatically extended to the end of 2023 under COVID-19, will be extended until 2024. Either the validity date until 2024 or the conclusion of the next on-site inspection applies, whichever comes first unless stated otherwise in the relevant document. The working group of GMP/GDP inspectors decided to continue the extension.

The EDQM pre-published the revised monograph on Propylene glycol (0430) adopted by the European Pharmacopoeia Commission (EPC) at its 177th session held on 21 and 22 November 2023. The revision took part as a response to the public health risk posed by the discovery of ethylene glycol (EG) and diethylene glycol (DEG) contamination in several medicinal products in Africa and Asia and confirmed cases of propylene glycol adulterated with EG with over 190 fatalities in Indonesia.

On 9 November 2023, the EMA published a 5-page document with three Q&As on the extended interpretation of Annex 12 of the EU GMP Guideline "Manufacture of medicinal products using ionising radiation" for X-ray sterilisation processes. The questions relate to the use of X-ray sterilisation for single-use systems (SUS) in pharmaceutical manufacturing. These processes are becoming increasingly established.

From 6 to 7 November 2023, the PIC/S Committee Meeting took place in Bangkok, Thailand, chaired by Paul Gustafson from Health Canada. The Ministry of Public Health of the Thai Food and Drug Administration (Thai FDA) hosted the meeting.

The meeting was attended by 37 of the 56 Participating Authorities (PAs) as well as various applicants, pre-applicants and partner organisations.

The life cycle approach to cleaning validation simply means that control of cleaning effectiveness must be maintained on an ongoing basis.

On 31 October 2023, Swissmedic published a Q&A with the title "Interpretation of GMP Annex 1 2022 (Rev. 1)". In the 25-page document, the Swiss Agency for Therapeutic Products provides key answers to questions related to Annex 1, which came into force in August 2023, and to repeatedly asked questions from the previous version.

Every week we publish interesting questions and answers about GMP in our column GMP Question of the Week. Today we have compiled the most clicked questions of this year (as of November 2023). Browse the Top 15 and refresh your knowledge! Detailed information on each topic can be found in the GMP Compliance Adviser, the world's largest reference work on quality management in the pharmaceutical industry.

On 7 November 2023, MedTech Europe published a position paper on the Medical Devices Regulation (MDR (EU) 2017/745) and the In Vitro Diagnostic Medical Devices Regulation (IVDR (EU) 2017/746). In the report, the association presents its vision for a regulated legal framework and outlines possible solutions to the ongoing challenges, which have not been overcome after the implementation phase of the MDR and IVDR.

The Assembly of the International Council for Harmonisation (ICH) has adopted the revised Q5A(R2) Guideline on the Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. The guideline describes a general approach to testing and assessing the viral safety of those products and sets out the data that should be submitted in marketing authorisation applications and registration packages. These products include biotherapeutics and biological products derived from characterised cell cultures of human or animal origin (mammals, birds, insects). The term "virus" used therein does not include non-conventionally transmissible pathogens, such as mammalian prion-associated pathogens.

On 30 October 2023, the World Health Organization (WHO) recognized regulatory authorities as "WHO-Listed Authorities" for the first time. WHO-Listed Authorities (WLA) are regulatory authorities that operate in accordance with international standards and fulfil the requirements based on an established benchmarking and performance evaluation process.

The Assembly of the International Council for Harmonisation (ICH) adopted the revised Q2(R2) Guideline on the Validation of Analytical Procedures and the new Q14 Guideline on Analytical Procedure Development. They jointly describe the development and validation activities that should be applied during the life cycle of an analytical procedure to assess the quality of medicinal substances and products.

The stability of a medicinal product or an active substance is defined as the maintenance of certain quality characteristics (specification) over a fixed period of time under defined conditions.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) has announced that it is planning to establish a new AI-based "regulatory sandbox" to help artificial intelligence (AI) developers test and provide evidence for their technologies in a virtual space under regulatory monitoring. The so-called AI-Airlock is expected to go into operation in April 2024.

Every year since 2008, the International Criminal Police Organisation (INTERPOL) has carried out large-scale operations to combat the illegal trade in medicines, known as Operation Pangea.

Team-NB, the European association of Notified Bodies, strongly recommends that medical device manufacturers of Class D devices submit applications for In Vitro Diagnostic Regulation (IVDR) certification this year to ensure timely processing.

On 24 October 2023, the European Commission adopted steps to prevent drug shortages and increase the security of supply in the European Union.

‘Hygiene programmes adapted to the activities to be carried out shall be established and observed. These programmes shall, in particular, include procedures relating to health, hygiene practice and clothing of personnel.‘ This is explicitly stated in the EU GMP Directive 2017/1572.

The new monograph on Cannabis flower (3028) will be published in Ph. Eur. Supplement 11.5 in January 2024. Given the exceptionally high interest from stakeholders in having access to the new text as soon as possible, the Ph. Eur. decided to make the monograph immediately available on the EDQM website for information.

A new part of the ISO 14644 cleanroom series has been published: ISO/TR 14644-21:2023 Cleanrooms and associated controlled environments — Part 21: Airborne particle sampling techniques.

On 25 September 2023, Swissmedic expanded a list of frequently asked questions for marketing authorisation holders submitting adverse drug reaction (ADR) reports under the authority's pharmacovigilance program. The Swiss surveillance authority is thereby preparing manufacturers in its area of application for the additional documentation requirements in individual case reports, which will be mandatory from 1 January 2024.

The EMA Q&A on nitrosamine impurities has been updated on 2 October 2023 and is now available as Revision 18. The update concerns Q&A 3 regarding the “call of review” and how to report steps 1 and 2 to the competent authorities. The update highlights the responsibilities of MAH(s) to control, report, and mitigate the detection of Nitrosamine impurities throughout the product life cycle, using the established procedure.

Subjectivity in QRM should be addressed in every organisation. I had the opportunity to attend a very stimulating presentation by Alex Viehmann, Division Director at OPQ, CDER, U.S. FDA, who shared insights into the new ICH Q9 Guideline on Quality Risk Management (QRM) at the PDA/FDA Joint Regulatory Conference 2023, 18-20 September in Washington.

The EMA has published 14 questions and answers for biological products on its website. The CHMP Biologics Working Party developed the page that provides their agreed positions on issues that typically arise from discussions or correspondence during assessment procedures of biological human medicinal products.

MedTech Europe, along with 34 national associations, published an open letter to EU Health Commissioner Stella Kyriakides on 14 September 2023.

According to Swissmedic, the independent SwissGMDP database will be launched in the first quarter of 2024. The database will be maintained similar to the European EudraGMDP database of the EMA. The GMP or GDP certificates of every company in Switzerland that has a valid Swissmedic operating licence will be listed. Contrary to the EudraGMDP, the SwissGMDP certificates contain all approved activities, i.e. the GDP activities and Switzerland-specific GMP activities of the Swiss companies will also be listed in the certificates.

The WHO has recently published a draft document that will be of interest to all GMP practitioners in the field of pharmaceutical quality control laboratories: WHO good practices for pharmaceutical quality control laboratories. It provides recommendations for a Quality Management System (QMS) within which analyses of pharmaceutical products should be performed by quality control laboratories. The aim is to ensure accurate and reliable analytical results.

To err is human - and is only too willingly used as the most probable cause for deviations of all kinds. It is also temptingly easy to look for the cause of error in individual (mis)behaviour. Everyone has a bad day, is distracted or unfocused, forgets or mixes things up and makes mistakes, even though they "actually" know how to do it correctly.

On 9 August 2023, Swissmedic announced its accreditation for GMP/GDP inspections in the field of ATMPs (Advanced Therapy Medicinal Products). Previously, the authority's competence confirmation was limited to medicinal products.

On 1 August 2023, the UK government published a statement on the indefinite extension of CE marking recognition beyond 2024. MHRA clarifies: This extension does not apply to medical devices and in vitro diagnostic medical devices.

To a new one! The EMA Q&A on nitrosamine impurities has been updated again after only three weeks and is now available as Revision 17 corr. The update concerns Q&As 20, 21 and 22 and a correction of the table including the potency score calculation in example 4 for N-nitroso-l-nebivolol. It had been omitted in the previously revised version 17 and has now been re-introduced.

This month the US FDA issued a 28-page new guidance for immediate implementation, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs). It provides drug manufacturers and applicants with a framework for a risk-based safety assessment of NDSRIs that could be present in approved and marketed drug products, as well as products under review by the FDA. Ways to predict the mutagenic and carcinogenic risk of NDSRIs and acceptable intake (AI) limits are outlined.

The monitoring of critical parameters is largely automated and is part of the plant control system. In the event of a critical system alarm (e.g. TOC outside of tolerance limits), the control system also performs the system shutdown or the transition to a safe operation mode.

According to the new Annex 1, a Contamination Control Strategy (CCS) must be implemented for the entire cleanroom and controlled environment system of the facility.

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has again revised its GMP Guide. Changes have been made to include the new EU Annex 1 on Sterile Manufacturing of Medicinal Products, which enters into force on Friday, 25 August 2023. From this same date, the PIC/S GMP Guide will also be valid.

The UK MHRA has released guidance on the labelling and packaging of medicinal products following the Windsor Framework. It introduces a “UK Only” label and the take over of the MHRA to approve and license medicines across the UK. Furthermore, the application of the EU Falsified Medicines Directive (FMD) in Northern Ireland will no longer apply. The Windsor Framework covers the supply of medicines into Northern Ireland and will replace the current Brexit conditions.

The European Commission updated the Q&A document on the new transitional provisions for certain medical devices and in vitro medical devices with five additional questions on 18 July 2023.

The Mutual Recognition Agreement between Switzerland and the USA signed in January entered into force on 27 July 2023. As already reported, the MRA allows the FDA and the Swissmedic to share and use each other's GMP inspectional findings regarding medicinal products.

Gastrointestinal medicines, headache tablets and perhaps a gel to soothe insect bites? It's no big hassle to pack these and yet they give you a reassuring feeling of security.

The European Medicines Agency (EMA) has published four new questions and answers around Remote Batch Certification/Confirmation of a Qualified Person (QP). One Q&A deals with the residence specification for a QP. They apply to EU/EEA QP certification or QP confirmation, as described in EU GMP, and specifically in Annex 16. It applies to the manufacture and importation of human and veterinary medicinal products and investigational medicinal products.

In late June 2023, the European Medicines Agency updated two Q&A documents on centralised marketing authorization procedures. With this, EMA provides scientific and regulatory advice to pharmaceutical companies on the regulatory process for the European drug approval. Q&As relevant before, during, and after the approval of medicines for the European market have been updated or newly added.

One of the basic principles of a cleaning validation is the setting of limits for possible cross-contaminants in the subsequent product.

On 6 July 2023, the European Medicines Agency (EMA), the European Commission (EC) and the Heads of Medicines Agencies (HMA) announced that they were phasing out the extraordinary regulatory flexibilities for medicines that were effective during the COVID-19 pandemic.

The EMA has updated its Q&A document on N-nitrosamines as of 7 July 2023. Revision 16 comes with an amendment to Q&A 10 on the limits that apply for N-nitrosamines in medicinal products. Introduced are the Carcinogenic Potency Categorization Approach (CPCA) and the enhanced Ames test (EAT) for establishing acceptable intakes (AIs) for N-nitrosamines.

The US FDA’s CDER revised the Manual of Policies and Procedures (MAPP) on managing surveillance inspections based on its Site Selection Model. The CDER staff uses this model to prioritise manufacturing sites for national and international routine quality-related cGMP surveillance inspections.

On 1 July 2023, the new "Nitrosamines Specialist Group" of the Swiss regulatory agency Swissmedic started its work, as announced in May. The group is divided into a coordination office and a centre of expertise for all issues regarding nitrosamines.

The ICH published a press release on June 20, regarding a face-to-face meeting on June 12 and 13, 2023, in Vancouver, Canada. Meetings of 14 working groups, the ICH Management Committee and the MedDRA Management Committee were also held during that time.

The Australian Therapeutic Goods Administration (TGA) has opened a consultation on 16 June 2023 on the risk classification of medical devices containing certain animal, microbial or recombinant materials.

Adequate size and lighting of all areas where medicinal products, starting materials and packaging materials are stored is essential for the proper performance of operations.

Fundamentally, the use of computerised systems in GxP environments requires a consideration of regulatory requirements.

The MHRA is further extending its regulatory network. A new regulatory recognition framework for medicines will be established using approvals from Australia, Canada, the European Union, Japan, Switzerland, Singapore, and the United States. It should be in place by the first quarter of 2024.

The mutual recognition of inspections of certain veterinary medicines between the European Union and the United States has reached a significant milestone: On 31 May 2023, the US FDA recognised the capability of 16 EU Member States to carry out GMP inspections for certain veterinary products at a level equal to the US. At the same time, the EU also recognised the FDA as an equivalent authority for GMP inspections of sites manufacturing veterinary medicines.

On 24 May 2023, the European Commission provided a downloadable template that notified bodies can use under Regulation (EU) 2023/607.

In the context of the revised Annex 1 (we reported), the Contamination Control Strategy (CCS) is currently an issue everyone is talking about. This concept must be implemented by 25 August 2023 – when Annex 1 comes into force.

“The new Annex 1 requires a comprehensive and overarching contamination control strategy (CCS). It records and links the different aspects and the associated accompanying measures, shows possible interactions and supports a corresponding analysis of any weaknesses or gaps in the system,“ explain Christoph Brewi and Florian Sieder in the GMP Compliance Adviser. 

The European Directorate for the Quality of Medicines & HealthCare (EDQM) published the 21st edition of the Guideline for the Preparation, Use, and Quality Assurance of Blood Components earlier this month. As a compendium of widely accepted, harmonised European technical standards the guide should provide safety, efficacy, and quality requirements for the preparation, use, and quality control of blood components in Europe and beyond.

According to a press release from the UK government Switzerland and the United Kingdom have started negotiations on a modern and free trade arrangement (FTA) this month.

As part of the recent publication of EMA's Annual Report 2022, the 3-year work plan 2021-2023 has also been updated. The 13-page work plan has been developed with a main focus on the network strategy and the scientific regulatory strategy (RSS). The security and resilience of the supply chain is of particular importance.

Pharmacopoeial standards are obtained by the chemicals officer from the issuing body and do not require further characterisation before use.

On 17 May 2023, EMA published recommendations for industry on the for marketing authorisation holders, wholesalers, distributors, and manufacturers to minimise the occurrence of medicine shortages and their impact.

The Swiss Biotech Day 2023 took place on 24 and 25 April in Basel. The conference is one of the industry's most important meeting places for developers and manufacturers of biopharmaceuticals and is growing in popularity every year.

The Swissmedic Guideline on GMP-Compliance by Foreign Manufacturers was published on 1.5.2023 as version 3.0. It is addressed to the holders of marketing authorisations for medicinal products from abroad or from Switzerland if these medicinal products contain active substances from foreign manufacturers.

On 26 April 2023, the European Commission published a 182-page proposal for the reform of the EU's pharmaceutical legislation and a 184-page proposal for the repeal of Directives 2001/83/EC and 2009/35/EC with a 103-page Annex. The proposal should pave the way for the biggest reform in more than 20 years and aims to reshape the regulation of the pharmaceutical sector.

From 1 June 2023 multi-factor authentication (MFA) will be introduced for user login to CTIS (Clinical Trials Information System) for both sponsors and Member States. This should significantly increase user account security.

A software quality plan – what is it and how do you create such a document?

This week the WHO published a draft guideline on GMP for excipients used in pharmaceutical products. With the original guideline published in 1999, a revision was overdue. Excipients play an essential role in pharmaceutical dosage forms and their impact on the quality of the finished product is considerable. The guideline is addressed to excipient manufacturers and pharmaceutical manufacturers.

Last month, the EMA published the final guideline on computerised systems and data integrity in clinical trials, which will enter into force on 10 September 2023. Clinical trials are increasingly using computerised systems for data collection, which come with progressively more complex user surfaces.

You know the sustainability goals in your company, such as achieving CO₂ neutrality by 2030 or 2050. But what does that have to do with GMP?

The European Medicines Agency EMA updated its Q&A on nitrosamines on 30 March 2023. The update amends Q&A 22 referring to the approach to control  the presence of nitrosamines exceeding the AI during CAPA implementation. It is now indicated that no variation should be submitted to implement temporary above AI (acceptable intake) limits in specifications.

The Swiss Federal Council intends to grant an extended period for the certification of medical devices in accordance with the extension of the corresponding EU regulation (we reported). This will require an amendment of the Medical Devices Ordinance (MedDO) and the Ordinance on In Vitro Diagnostic Medical Devices (IvDO). The revision of the two ordinances is planned for autumn 2023.

The ICH published a 29-page presentation on the revision of ICH Q9 on 14 March 2023. The guideline on quality risk management was published in January 2023 (we reported) and will come into force in July 2023.

The European Commission has released a 10-page Q&A document on the practical aspects of the new transitional provisions for certain medical devices and iv-medical devices. These were laid down in the Regulation (EU) 2023/607, which was published on 15 March 2023 (we reported).

The 6-page amending Regulations (EU) 2023/607 with new transitional provisions for certain medical devices and in vitro diagnostic medical devices was published in the Official Journal of the European Union on 20 March 2023. It entered into force upon publication. This is intended to alleviate supply shortages of important medical devices (we reported). The regulation is binding in its entirety and directly applicable in all member states.

On 16 March 2023, the FDA issued its final guidance on detailed definitions around "suspect products" and "illegitimate products".

Assessment of GxP relevance

Every upcoming change must be checked for GxP-relevance by the responsible person for GDP.

On 8 March 2023, the European Commission published Delegated Regulations (EU) 2023/502 and 2023/503 to extend the reassessment period for notified bodies under MDR/IVDR to five years. The new time frame has already come into force.

The Northern Ireland question was one of the trickiest open issues in the Brexit negotiations. A general political agreement has now been reached with the so-called "Windsor Framework": The European Commission and the government of the United Kingdom have put together a comprehensive package of solutions to reconcile the movement of goods to Northern Ireland while ensuring effective protective measures for the EU's internal market. The Windsor Framework is to replace the previous Northern Ireland Protocol in the future. The legally binding adoption is pending.

Pharmaceutical water systems are used for a number of different applications by pharmaceutical manufacturers. These include, for example, the cleaning of various pieces of equipment, the generation of pure steam and the use of water as an ingredient for solid, semi-solid and liquid medicinal products.

On 1 March 2023, the final ICH Guideline Q13 on continuous manufacturing (CM) of active pharmaceutical ingredients and drug products was published by the FDA. In addition to the guidance, the agency also issued a discussion paper on AI for stakeholders' comments. With these publications, the FDA aims to facilitate the adoption of advanced manufacturing technologies for the pharmaceutical industry.

On 16 February 2023, the European Parliament voted positively to extend the deadline for the certification of medical devices under the EU Medical Devices Regulation (MDR). In January, the deadline extension was proposed by the European Commission to prevent massive supply shortages. Not enough Notified Bodies are available for the recertification of many medical devices, as a requirement of the MDR.

The EMA has published a question and answer document on the regulatory requirements for the authorisation of Cannabis-derived medicinal products in the EU and the work of the Committee for Herbal Medicinal Products (HMPC) in relation to medicinal plant monographs. This was considered useful as those involved in the production of Cannabis products often have little experience of the EU regulatory system for medicinal products.

On February 6^th, 2023, the European Medicines Agency (EMA) published the first revision of the guideline "ICH Guideline Q9 (R1) on Quality Risk Management (QRM) Step 5".

The 27-page document includes "principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality.“

Swissmedic announced on 23 January that companies with a valid manufacturing licence for the manufacture of medicinal products can apply for a GMP certificate. The certificates do not contain a validity date, but the date of the GMP inspection.

In this feature we take look at the ‘black sheep’ of pharmaceutical production. As cute and charming as they may be in the animal world, in the world of GMP they can be rather disturbing.

PIC/S has published the following two guidance documents for GDP inspectors: an "Aide-Memoire on the Inspection of Good Distribution Practice for Medicinal Products in the Supply Chain" (PI 044-1) and a "Questions & Answers (Q&A) document regarding the PIC/S GDP Guide" (PS/INF 22/2017).

As we already reported in December 2022, the use of the Clinical Trials Information System (CTIS) is now obligatory in the EU.

The International Council for Harmonisation (ICH) published a revised version of its Q9 guideline on 20 January, updating the original guideline, which is now 18 years old.

The US government's Office of Information and Regulatory Affairs has issued a timeline for harmonizing, or converting, the 21 CFR 820 with the European ISO 13485 for medical devices.

On 12 January 2023, the FDA signed a Mutual Recognition Agreement between the United States and Switzerland, allowing the FDA and Swissmedic to share each other's GMP inspectional findings, which will reduce unnecessary costs and duplicative efforts.

The EMA added two good distribution practice (GDP) questions to its Q&A section on GMP/GDP topics in early January 2023. They should clarify how the GDP rules apply to brokers operating outside the European Economic Area (EEA).

The European Medicines Agency (EMA) has adopted the ICH guidance on the continuous manufacturing of drug substances and drug products which marks the Step 5 process of document adoption by the Regulatory Members of the ICH Assembly. The document was released on 6 January 2023 and will come into effect on 10 July 2023.

The life cycle of an equipment begins with initial qualification and ends with decommissioning. Once a qualification status has been achieved, it must be guaranteed over the entire life cycle until the equipment is decommissioned.

As of 31 January 2023, using the new Clinical Trials Information System (CTIS) will become mandatory. CTIS serves as a single entry point of contact for the submission and assessment of clinical trial data in all EU and EEA countries. This facilitates the daily business of sponsors in the EU immensely. In the past sponsors had to submit clinical trial applications separately to competent national authorities (NCAs) and ethics committees in each European country to gain regulatory approval. Publication of the trial information is built into the system, as well.

The European Commission's Medical Device Coordination Group (MDCG) published a definition on ‘hybrid audits’ in early December.

The document gives notified bodies some flexibility regarding the duration of physical presence during audits under the Medical Device Regulation (MDR) and the In Vitro Diagnostic Device Regulation (IVDR).

With the publication of Delegated Regulation 2022/2239, the European Commission has released the revised and amended labeling requirements for unauthorized investigational and auxiliary medicinal products under the EU Clinical Trial Regulation (CTR). This eliminates the need to retroactively label the expiration date on the primary packaging of unapproved investigational products for which new stability and shelf-life data become available over time.

In Mid-November, the ICH Q13 Guideline on Continuous Manufacturing of Drug Substances and Drug Products (Step 4)" was finally adopted during the General Assembly of the International Council for Harmonisation (ICH). With the adoption within the ICH organization, the guidelines are considered harmonized and thus represent the current state of science and technology. A concept paper for the Guideline was first submitted in November 2018.

Standards such as those in the DIN EN ISO series are not laws, so they differ quite fundamentally from legally binding regulations. Good Manufacturing Practice (GMP), on the other hand, is laid down in laws, regulations and guidelines.

The Access Consortium is a collaborative initiative of like-minded, medium-sized regulators from Australia, Canada, Singapore, Switzerland, and the United Kingdom.

On 16 November 2022, the European Medicines Agency EMA published a concept paper on the planned revision of Annex 11 "Computerised Systems". The reason: The existing document of the EU GMP Guideline dates back to 2011 and no longer corresponds to the state of the art in various areas or does not consider increasingly important new technologies for the GMP field, according to the EMA.

On 8 November 2022, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) published a blog post announcing the resumption of international on-site inspections.
Important to know: Notwithstanding, the ‘expiry’ of GMP certificates issued by the MHRA will again be extended until the end of 2023.

A definition of the term “qualification master plan (QMP)“ is not to be found in the GMP guidelines, only the term “validation master plan (VMP)”, which serves as a parent document.

On 25 October 2022, the UK Regulatory Agency MHRA, announced that the introduction of the future UK Medical Device Regulation will be delayed by twelve months. The intended date for introduction of the new and standalone regulation is now set for July 2024.

The European Medicines Agency (EMA) has published a revised version 12 of its Q&A on nitrosamines for marketing authorisation holders dated 10 October 2022. The revision includes an update of Q&A 10 on the limits for nitrosamines in medicinal products and introduces a new Q&A 21 on the approach to control presence of nitrosamine while the AI is being established.

The European Medicines Agency (EMA) answers frequently asked GMP/GDP questions discussed in the GMP/GDP Inspectors Working Group in its Guidance on good manufacturing practice and good distribution practice: Questions and answers. The document is continuously revised, as last in October 2022. The answers are intended to provide additional clarification to the current EU GMP and GDP regulation.

On 08. October 2022, the Australian Therapeutic Goods Administration (TGA), published the draft guidance "Boundary and combination products - medicines, medical devices, and biologicals". The current guidance originally dates back to 2005. Since then, there have been significant changes in the regulation of therapeutic goods.

On 11 October 2022, the ICH published the revised Guideline Q5A(R2) on viral safety evaluation of biotechnology products derived from cell lines of human or animal origin as Step 2 document. This guideline addresses the testing and evaluation of the viral safety of biotechnology products and explains what data should be provided in the application dossier for the marketing and registration of these products.

On 10 October 2022, the EMA published a 24-pages document on data quality (DQ) framework, which is open for consultation until 18 November 2022. As the topic of data quality and data overall becomes more and more critical to regulating medicinal products, a Data Quality Framework for EU medicines regulation is a logical consequence to provide a unitary approach. Thus, the amount of data that digitalisation brings along not only opens up new possibilities, but also increasingly complex data landscapes.

GMP or GDP – Which applies for importation? Although the import of medicinal products is an act related to distribution and logistics, this activity is considered GMP relevant in the EU and is therefore subject to GMP requirements.

DEKRA Certification UK Ltd has become the first organisation after Brexit to complete the new designation process that any potential organisation must go through to become approved to certify medical devices in the UK. With this step taken it is now designated as a UK approved body to undertake assessments for general medical devices (known as Part II designation) and has joined the three current UK Approved Bodies BSI Assurance UK Ltd, SGS United Kingdom Ltd, and UL International (UK) Ltd. These three bodies had been approved before Brexit.

On 30 September 2022 the MHRA informed that the use of the European Commission Decision Reliance Procedure (ECDRP) for Great Britain has been extended for another 12 months until 31 December 2023. The procedure allows a company to submit a product that has received approval from the EMA directly to the MHRA. The MHRA can then grant a license with a shorter review than normally conducted, relying on the EMA’s decision.

The United States Pharmacopeia (USP) has opened a 90-day review period for their proposed Cannabis Species Inflorescence Monograph in the Herbal Medicines Compendium (HMC), a laboratory quality standards testing reference used internationally. 

The European Medicines Agency (EMA) plans to establish clear quality guidelines for drug companies manufacturing synthetic peptides and oligonucleotides. This week, EMA published new concept papers, explaining current requirements on impurities testing, specifications and the control of DNA-reactive chemicals either partly or fully exclude synthetic peptides and oligonucleotides.

The European Borderline and Classification Working Group (BCWG), a sub-group of the Medical Device Coordination Group, has created a manual for determining whether a product is classed as a medical device under the new regulations MDR and IVDR. BCWG developed the document as part of an attempt to prevent member states from having different interpretations of the legislation.

The PMDA (Japanese Pharmaceuticals and Medical Devices Agency) published the English translation of the revised document on remote inspections, Procedure for Remote Inspection as a Part of Compliance Inspection on Drugs and Regenerative Medical Products. The document describes the specific procedure for a remote inspection and how to organize, prepare and share the necessary paperwork for remote assessment by PMDA (we reported).

On 24 August 2022 the EMA (European Medicines Agency) published a 72-pages strong overview on the comments received as feedback on the draft of ICH Q2 Validation of analytical procedures along with a 54-pages PDF on comments made regarding the draft of ICH Q14 Analytical procedure development. The volume of the documents indicates the large number of comments that were submitted.

The long-awaited final version of the new EU Annex 1 "Manufacture of Sterile Medicinal Products" was published on 25 August 2022. The deadline for entry into force is 25 August 2023. Regarding section 8.123 on freeze-drying and product transfer, the deadline for entry into force is two years from now and will thus become mandatory on 25 August 2024.

The first draft of version 9 of Annex 1 of the EU GMP Guide on 20 December 2017 attracted a lot of interest globally – firstly because it was the first publication on the topic in almost a decade, and secondly because PIC/S and WHO co-authored the document.

One thing is certain: The FDA’s utilizing remote regulatory assessment is here to stay and remain a regular tool to support onsite inspections. This was addressed by FDA Commissioner Robert Califf and his associate Commissioner for Regulatory Affairs, Judith McMeekin, in a statement released end of July.

The Committee for Medicinal Products for Human Use (CHMP) and the CMDh (Coordination Group on Mutual Recognition Procedures and Decentralised Procedures) of the EMA extended the deadline for submission of variation applications under Step 3: "Variation of marketing authorisation for chemical medicinal products" from 26 September 2022 to 1 October 2023.

The quality of a medicinal product cannot be left to chance, but must be the result of carefully planned actions. The sequence "planning, acting, evaluating, improving" is referred to as "management".

On 26 July 2022, the EMA published a concept paper to start the process for the revision of the Guideline on the chemistry of active substances. The document dates from 2016 and does not consider the nitrosamine issue that has developed in recent years.

From 23 to 30 June 2022, Interpol conducted its 15^th globally coordinated operation PANGEA against the illegal online trade of medicines. From fake COVID-19 tests to doping substances or narcotics, the range of illegal shipments was broad.

The EDQM informs that the 11th Edition of the European Pharmacopoeia (Ph. Eur.) is now available. Holders of Certificates of suitability to the monographs of the Ph. Eur. (CEPs) are invited to update their applications according to the revised monographs that will be implemented on 1 January 2023, and to follow the instructions that the EDQM provides.

In June 2022, the European Commission published the Question & Answers document on safety features for medicinal products for human use in version 20, coming along with one new Q&A on UI verification of authenticity.

For the third time in a row, the European Commission has updated its Q&A on nitrosamine impurities (we reported). Version 10 was published on 23 June 2022. Questions 5, 10 and 14 have been revised. What is new?

On 4 July 2022 the European Commission published the Implementing Regulation (EU) 2022/1107 to establish common specifications for certain class D in vitro diagnostic medical devices considered to be high-risk. These relevant harmonised standards had already been partially introduced in the repealed Directive 98/97/EC. Now the specifications have been updated and adapted to the state of the art.

“While there are clearly defined GMP requirements for particulate and microbial air cleanliness for the sterile manufacturing area, there are no concrete requirements for air cleanliness for the non-sterile manufacturing area. In pharmaceutical practice, terms such as "cleanroom Grade E or F", "grey or black area" and, more recently, the terms "CNC" (classified not controlled) and "NC" (not classified) have become common for non-sterile manufacturing“, explains GMP Senior Expert Christine Oechslein.

The International Coalition of Medicines Regulatory Authorities (ICMRA) is announcing the initiation of two regulatory collaboration pilots addressing facility inspections and Chemistry and Manufacturing Controls (CMC) and Post-Approval Change (PAC) submission assessments and related regulatory actions.

The FDA issued a draft guidance outlining a framework of methods, designs and controls for preventing cross-contamination of non-penicillin beta-lactam antibacterial drugs and compounds, which serves as an update for a 2013 guidance with the same title. (Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination; Draft Guidance for Industry; Availability).

The Pharmaceutical Inspection Cooperation Scheme (PIC/S) has published its 2022 work plan with the organization’s planned actions for this year. Not only does PIC/S plan to resume its assessments for membership application but also to revise or draft new GMP guidelines.

The question "How does process validation differentiate itself from other elements of quality management?" is not easy to answer, because there is still no uniform and generally applicable definition for validation. On the contrary, the term is becoming increasingly blurred with the related technical terms qualification and verification.

 The European Medicines Agency (EMA) has published a revised version 9 of its Q&A on nitrosamines for marketing authorisation holders dated 20 May 2022.

Concurrent with the application of the IVDR in the EU, the new Swiss regulation on in vitro diagnostic medical devices, IvDO, came into force on 26 May 2022. This is the first time since 2001 that the "third country rules" apply to IVDs in Switzerland, as they already do for all other medical devices for a year now (we reported). As of the same date, clinical trials with in vitro diagnostic medical devices are regulated in the Ordinance on Clinical Trials with Medical Devices (CTO-MedD) and no longer in the Ordinance on Clinical Trials (ClinO).

After a one-year postponement period, the European In Vitro Diagnostic Medical Devices Regulation (IVDR) finally came into force on 26 May 2022 and follows the Medical Device Regulation (MDR), which has been in force for one year.

On 12 May 2022, the EMA published the final guideline on quality of herbal medicinal products/traditional herbal medicinal products. The Committee on Herbal Medicinal Products (HMPC) at the European Medicines Agency (EMA) originally started working on the revision of the guideline in 2015. Revision 3 which now represents the final guidance was adopted in January 2022.

The new Annex 21: Importation of medicinal products to the EU GMP Guide has been published on February 21, 2022 and will enter into force on August 21, 2022. The 6-page annex summarises the GMP requirements for Manufacturer/Importer Authorisation (MIA) holders to import medicinal products (human, investigational and veterinary) from outside the EU/EEA (we reported).

ICH Q3D (R2) has reached Step 4 of the ICH-Process and will now be distributed to the Member States for implementation. The revision (R2) focused on the establishment of limits for elemental impurities by the dermal route of exposure, summarized in a new Appendix 5 and error corrections of the PDEs for Silver (oral), Gold (oral, parenteral and inhalation) and Nickel (inhalation).

The US FDA has revised its 16-year-old guidance on how to investigate out-of-specification (OOS) test results in laboratories. The document includes all necessary steps to be taken when investigating OOS test results. It also considers the responsibilities of the analyst and the laboratory supervisor in case of OOS results being identified, along with additional testing steps and a final evaluation of all results.

The EMA has published a four-page consultation document in the form of Q&As concerning the physical attendance and the place of a personal residence of a Qualified Person on 11 May 2022. The guidance states that the work of a QP must be adapted to current standards to enable remote certifications without a QP being present at the site. A public consultation is possible until 13 June 2022.

On 26 May 2022, the European IVD Regulation (EU) 2017/746 (In vitro Device Regulation) will enter into force. This will be accompanied by various transitional periods and requirements, which have been summarised and explained by the MDCG (Medical Device Coordination Group) in a new guidance document. The 17-page Guidance on significant changes regarding the transitional provision under Article 110(3) of the IVDR is aimed at manufacturers who have so far complied with the requirements of Directive 98/79/EC and may continue to market their in vitro diagnostic devices in accordance with this Directive during the transitional periods.

The European Medicines Agency (EMA) has updated the annexes for the conduct of GCP inspections. First published in 2007, the annexes compile a number of seven documents.

Centrally authorised medicinal products placed on the market in one European Member State may be marketed under the same name in any other Member State by a distributor independent of the marketing authorisation holder. This process of parallel distribution is supervised by the EMA.

Japan's PMDA (Pharmaceuticals and Medical Devices Agency) published changes to its principles for global clinical trials late last year. This revised document was published in English at the end of April 2022.

The EMA has released the comments of the ICH guideline Q9 (R1) draft from december 2021 in late april. The document contributes principles and examples of tools for quality risk management. The document consists of 56 pages of comments from organizations such as the PDA, EFPIA and many others. In the following some excerpts:

A CAPA system should be understood as an important element of the pharmaceutical quality system and implemented uniformly throughout the company or group. In principle, it can be implemented in two different ways: as an autonomous or as an integrated system.

On 19 April 2022, the EMA published the annual report of the GMP/GDP Inspectors Working Group for the year 2021. Both, Brexit and the COVID pandemic had resulted in no reports being issued for the last three years. Instead the EMA had published a Business Continuity Plan (BCP), which was primarily based on a prioritisation of tasks.

The US Food and Drug Administration (FDA) presented a "scaled-down" plan for collecting quality metrics from drug manufacturers end of March. The docket is an attempt to reactivate previously paused efforts to collect manufacturing quality metrics data. The primary aim of the program is to mitigate potential drug shortages and promote improved quality management in the pharmaceutical industry.

The Japanese MHLW (Japanese Minister of Health, Labour and Welfare) has released the 18^th Edition of the Japanese Pharmacopoeia (JP) as an English translation for download free of charge.

From the start of the project to the release of the technical design: Risk analysis is a constant companion.
Risk analyses can or must be carried out at different points in time within the process of procurement and qualification. Here is a brief outline of the phases of risk analyses in project implementation.

The Australian regulatory authority for therapeutic goods TGA has updated its19-pages quality requirements for medical cannabis products. These are now in line with TGO 93 and refer to

• any medicinal cannabis product imported into or supplied in Australia
• cannabis plant used in the manufacture of medicinal cannabis products e.g., as an ingredient or as a starting material for an extract used as an ingredient
• any other ingredients used in the manufacture of medicinal cannabis products, such as excipients
• steps and procedures carried out in the manufacture of medicinal cannabis product.

The Medical Device Coordination Group MDCG, a group of Member States experts, endorsed a joint implementation plan on the implementation of the IVDR, more precisely Regulation (EU) 2017/746 on invitro diagnostic medical devices. The plan should serve to set priority actions and monitor their implementation.  The IVDR will enter into force on 26 May 2022 with an extended transitional period of five years.

The draft ICH Q14 guideline on analytical procedure development reached stage 2 of the ICH process on 24 March 2022. This also applies to the revised ICH Q2 (R2) guideline on the validation of analytical procedures. Both documents are now in the public consultation phase. They jointly describe the development and validation activities that should be applied during the life cycle of an analytical procedure to assess the quality of medicinal substances and products.

Based on the risk assessment documented in the excipient dossier and the risk profile of the excipient, the risk team defines the necessary GMP requirements in the next step.

On 14/15 March 2022, the ISPE Aseptic Conference took place in North Bethesda, USA. The hybrid conference opened with a keynote presentations on regulatory news.

Paul A. Gustafson, who is chairing the PIC/S this year, gave an overview on the PIC/S activities and in this context referred to the future Annex 1 of the EU GMP Guide: The document is in its final adoption process. A publication is to be expected between the beginning of July and the end of September this year. The European Commission is currently awaiting the review of the PIC/S and the WHO. Both organisations had contributed to the two draft documents of Annex 1. The European Commission has not revealed a release date, yet.

Deviation management plays an increasingly important role in the collection and review of KPIs (Key Performance Indicators) for pharmaceutical production and quality processes. Tracking the cause of deviations in particular provides information on how stable the respective processes are, where there are gaps and where countermeasures need to be taken with corrective and preventive actions (CAPAs).

The HPMC (Committee on Herbal Medicinal Products, HPMC) of the EMA has published a concept paper on Good agricultural and collection practice for starting materials of herbal origin on 1 March 2022. Of interest to GMP professionales is, that the revision of the original guideline dating back to 2006, will address open questions about the applicability of GACP versus GMP, or a requirement of a combination of both. With a growing market for herbal medicinal product, e.g., Cannabis products, enhanced guidelines on the subject intent to clarify open issues.

Swissmedic announces the following regarding the validity of GMP certificates:

"The GMP certificates issued by Swissmedic list the date of the underlying inspection. They do not contain a validity date. However, following the practice for GMP certificates in the EU database EudraGMDP, it is often assumed by companies or other authorities that GMP certificates based on an inspection more than 3 years ago lose their informative value about the compliance status and therefore lose their validity."

The IPEC (International Pharmaceutical Excipients Council Federation) has published a summarizing position paper on „The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products. The 7-page paper describes the IPEC Federation’s position on the role of excipients when conducting N-nitrosamine risk assessments for medicinal products.

The US FDA is proposing to amend the cGMP requirements of the Quality System Regulation for medical devices, namely the 21 CFR Parts 4 and 820. Finally, the ISO 13485:2016 should be incorporated in the US Quality System, by reference. This proposal comes four years after the US FDA announced its willingness to align the two systems.

The EU GMP Annex 21: Importation of medicinal products has finally been published on February 21, 2022, and will enter into force on August 21, 2022. The 6-page new Annex summarises the GMP requirements for Manufacturing Import Authorization (MIA) holders of human, investigational, and veterinary medicinal products from outside the EU/EEA. Medicinal products entering the EU/EEA for export only and are neither processed in any way nor released for placing on the EU/EEA market, are not covered by this Annex.

CDER released its Guidance Agenda for the year 2022. The list includes all guidances planned to be developed or finalised this year. The agenda should be seen as an indicator for the topics CDER is advancing to tackle but is not binding for the Center.

Robert M. Califf, M.D., was sworn in as new Commissioner of the Food and Drugs Administration on February 17, 2022. He has previously served as Commissioner from February 2016 to January 2017, during President Obama’s final year in office. 

"Contaminants in medicinal products – focus on nitrosamines" was the title of an online training course organised by the German FORUM Institute on 12 November 2021. Four renowned experts from the authorities, industry and consulting shed light on all aspects of nitrosamines that play a role in the life cycle of a medicinal product.

The European Medicines Agency (EMA) issued a revised Version 7 of its Q&A guidance on nitrosamines dated January 22, 2022. The revision includes a new nitrosamine for testing and an updated section on testing and control of multiple impurities in one product. For such a case, a step-by-step decision tree is presented in Annex 1.

The Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) entered into force on 28 January 2022.  It modernises the existing rules on the authorisation and use of veterinary medicines in the European Union (EU). 

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has revised its PIC/S GMP Guide to Good Manufacturing Practice (GMP) for Medicinal Products to include

• the revised Annex 13 on the Manufacture of Investigational Medicinal Products and
• the new Annex 16 on the Certification by the Authorised Person and Batch Release.

As of 31 January 2022, the new Clinical Trials Regulation (EU) No. 536/2014 (CTR) entered into force, repealing the Clinical Trial Directive (EC) No. 2001/20/EC. This step is meant to facilitate the daily business of sponsors in the EU immensely, when it comes to filing clinical trial applications. The new Clinical Trials Information System (CTIS) serves as a single-entry point for submission and assessment of clinical trial data for all EU and EEA countries and has gone live.

Receipt of medicinal products: When materials or products are delivered, their quality is assessed. Therefore, this work step should be carried out by experienced and particularly reliable employees.

The EMA released Version 2 of its Reflection paper on GMP and Marketing Authorisation Holders on 10 January 2022. A minor text addition to the document was performed: The section on „Serialisation Data - Uploading Responsibilities" was amended with the following paragraph regarding Contract Manufacturing Organisations:

The US FDA announces that the spread of the Omicron variant will lead to further delays in resuming inspection activities. Originally, this step was planned for February 2022. The date is now being pushed further back. With the current developments of the Covid 19 pandemic, no new resumption date has been communicated.  

Already in March last year, an adaption of the Delegated Regulation (EU) 2016/161 on safety features allowed a temporary derogation of the obligation for wholesalers to deactivate the individual identifier (IE) of medicinal products exported to the UK - as a third country we reported). This exemption was granted for the year 2021.

From a regulatory perspective, the year 2021 had plenty in store. Parallel to the omnipresent COVID-19 pandemic, the authorities around the world managed to finalize draft documents that became “sideshows” while the pandemic took centre stage. What topics kept the GMP professionals on their toes?

The European Commission published Version 19 of the Q&A on safety features for medicinal products in late December 2021.

On 16 December 2021, EMA published the ICH Q9 draft document on Quality Risk Management (QRM) in step 2b. The draft provides important additional guidance on four specific areas:

• the levels of subjectivity in risk assessments and in QRM outputs,
• the product availability risks,
• the lack of understanding as to what constitutes formality in QRM work, and
• the lack of clarity on risk-based decision-making.

The International Coalition of Medicines Regulatory Authorities, ICMRA, has published a comprehensive reflection paper on experiences with different inspection models to maintain GCP and GMP inspections during the covid pandemic. The working group responsible for the paper was composed of representatives from various regulatory agencies around the world. To anticipate the group's conclusion: Remote inspections enable minimal regulatory oversight during the pandemic but will not be able to replace on-site inspections in the future.

The Australian authority TGA has published a revision of the guideline on licenses and certification "Guidance on Australian manufacturing licenses and overseas good manufacturing practice (GMP) certification" on 1 December 2021. The revision relates to an expansion of possible inspection types as well as the scheduling of the inspection for licensing procedures.

On 6 December 2021, the EMA published all stakeholder comments received on the Guideline on quality documentation for medicinal products when used with a medical device (we reported). It will enter into force on 1 January 2022. Comments were received from 36 different stakeholders from all over Europe, including e.g., MedTech Europe, Medicines for Europe or the Parenteral Drug Association, PDA.

To ensure market surveillance of medical devices, manufacturers, authorized representatives and importers based in Switzerland must register with Swissmedic within three months of first placing a product on the market. This was revealed in a Swissmedic announcement in late November.
After the applicants have undergone the process, they will be assigned an individual Swiss identification number, the Swiss Single Registration Number (CHRN).

For almost all purposes in the GMP sector, it is mandatory to use original data and documents or only true copies thereof. This requirement also forms part of the ALCOA principle. Since it is only possible in a few cases in operational practice to work with the sole original document, the question arises as to what requirements are to be placed on the requisite true copies (see definition in Figure 15.B-6). Figure 15.B-7 compares different types of copies with the concept of original data.