News about GMP/cGMP

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.

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 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.

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. 

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.

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.

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

What's new?

• Question 1.29: Do the unique identifiers of reference and retention samples taken from stock in compliance with Annex 19 of the EU GMP Guidelines5 and uploaded to the EMVS have to be decommissioned? If yes, to what status?
  Answer: Yes, if a sample of a batch is taken as reference or retention sample after uploading in EMVS, it should be decommissioned as "sample". If a sample is taken voluntarily by a wholesaler that fall outside the scope of Annex 19, they should be decommissioned as "destroyed".

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).

On 26 November 2021, the European Commission issued the Implementing Regulation (EU) 2021/2078 on the European Database for Medical Devices, Eudamed. The document provides a legally binding framework for all users.

As of 2 December 2021, the new general chapter <1469> on nitrosamine impurities has been added to the United States Pharmacopeia (USP). With this, it is intended to support both pharmaceutical manufacturers and authorities in assessing the presence of nitrosamines and implementing appropriate control strategies and analytical procedures. The chapter is aligned with the current FDA guidances.

The European Medicines Agency has revised its 142-page document European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure. The publication of 22 November 2021 includes the adjustments already made in October, as well as an update to paragraph 2.9 on the procedural structure of application from November. All changes to the document are marked with a corresponding date reference and concern section 2 "Steps prior to submitting the application".

The European Medicines Agency (EMA) has published a 13-page Q&A including 87 questions and answers from a webinar held on the topic of integrating EudraGMDP and OMS (Organisation Management Services) into the new regulatory framework for veterinary medicines.

Finally, the long-awaited nomination for the next FDA commissioner is here. President Biden has nominated Dr. Robert Califf, a clinical trial expert and founding director of the Duke Clinical Research Institute.

The European Medicines Agency has published two new concept papers for Annex 4 and Annex 5 for veterinary medicinal products on 11 November 2021:

• Concept paper on the revision of annex 4 of the guidelines on good manufacturing practice – manufacture of veterinary medicinal products other than immunologicals
• Concept paper on the revision of annex 5 of the guidelines on good manufacturing practice for medicinal products – manufacture of immunological veterinary medicinal products

The European Commission has tasked its ad-hoc working group (WG) on pharmaceuticals in the environment with drafting a concept paper on the regulatory framework. The WG formed in 2020, is joined by the following Member States: Austria, The Czech Republic, Finland, France, Germany, Ireland, The Netherlands, Slovenia, Spain, Sweden, Poland, Romania, Italy and the European Medicines Agency (EMA).

The Australian Therapeutic Goods Administration, TGA,  updated its GMP approach to overseas manufacturers of medicines and biologicals on 1 November 2021. With the COVID-pandemic still being an issue, TGA named remote inspections the only currently available option for certification applications.

The European Commission has revised and restructured the Compilation of Community Procedures on Inspections and Exchange of Information. In addition to new content and editorial adjustments, the 295-page document has been divided into a Part I including procedural topics and a Part II containing interpretation documents and templates. The documents were last updated in 2014.

The FDA’s Center for Devices and Radiological Health (CDRH) has published its lists with guidance documents intended to be published next year. At this stage CDRH is interested in receiving external feedback on whether the listed documents should be revised or withdrawn.

The US FDA, Health Canada, and the British regulatory agency MHRA have jointly released 10 guiding principles to support the development of Good Machine Learning Practice (GMLP). As a basic framework it should help to promote safe, effective, and high-quality medical devices, while using AI (artificial intelligence) and ML (machine learning).

The FDA’s Office of Regulatory Affairs (ORA), responsible for inspections and other field activities, has released its summary on inspectional observations listed on FDA Forms 483 from October 2020 to September 2021.

The United States Pharmacopeia has released a new Chapter 1220 on “Analytical Procedure Life Cycle” prior to its official publication and entering into force on 1 May 2022. The chapter considers the validation activities that take place across the entire life cycle of an analytical procedure and provides a framework for the implementation of the life cycle approach.

On 14 October 2021, the European Commission has proposed a “progressive roll-out” of the upcoming In Vitro Diagnostic Medical Devices Regulation, IVDR. The reason given for that is to prevent disruption in the supply of those essential healthcare products that fall under it, as well as a serious shortage of notified body capacity. The IVDR was planned to apply as of 26 May 2022.

The European Medicines Agency EMA has further updated its Q&A on nitrosamine impurities. The document is intended to support marketing authorization holders of human medicinal products and considers the latest regulatory requirements (we reported).

The Chinese NMPA applied for PIC/S pre-accession on 24 September 2021. Although this stage is a voluntary assessment process, gaps are identified between PIC/S membership requirements and the system used by the regulatory agency that is interested.

The European Directorate for the Quality of Medicines, EDQM, has identified another azido impurity which was tested positive in a mutagenic evaluation. So far, it has only been found in "Losartan potassium".

The European medicines regulatory network has announced the automatically applied extension of the validity of GMP and GDP certificates for sites in the EEA (European Economic Area) until the end of 2022, unless there are restrictions on the validity period stated in the clarifying remarks of the certificate. This extension also applies to time-limited manufacturing and import and wholesale authorisations.

As communicated by the EMA, the EUDRAGMDP database will be „merged“ with EMA’s Organisation Management Service (OMS). This is an important change to be aware of for all manufacturers, importers and distributors of human and veterinary medicines whose information is recorded in EUDRAGMDP.

On 17 September 2021, the US FDA released the revised Q&A Guidance on Biosimilar Development and the BPCI Act. The 28-page document provides rapid, development-related guidance to biosimilar and interchangeable biosimilar sponsors and other stakeholders on discrete issues.

On 21 September 2021, an amendment to Delegated Regulation (EU) 2016/161 was published in the Official Journal of the European Union. Article 47 "Evaluation of notifications" was adapted and in Annex I, containing the list of medicinal products exempted from the obligation to bear the safety features, a new entry has been added.

On September 15, the U.S. Pharmacopeia USP published the final draft of the chapter <1083> Supplier Qualification.

As of July 2021, the European Pharmacopoeia (Ph. Eur.) now contains chapter 2.1.7 "Balances for analytical purposes". It was included as an addition to section 2.1 Apparatus and defines the requirements placed on the "balance" tool in an analytical procedure.

In July 2021, EDQM published a revised version of the document "Guidance for electronic submissions for Certificates of Suitability (CEP) applications" (PA/PHCEP (09) 108). This guidance includes the current requirements for how an application for Certificates of Suitability must be conducted in eCTD format.

This month, the Medical Devices Coordinating Group of the European Commission, MDCG, published a 7-page guideline for notified bodies, distributors, and importers of medical devices. It should provide a basis for the certification of quality management systems (QMS) related to repackaging and relabeling processes of medical devices according to MDR and IVDR.

The WHO has published three GMP-relevant draft documents in recent weeks:

• WHO good manufacturing practices for investigational products
• WHO good manufacturing practices for medicinal gases, Rev.1
• WHO good practices for research and development facilities of pharmaceutical products

The European Medicines Agency (EMA) has issued a 31-page draft guideline describing the information to be included in the Summary of Product Characteristics (SmPC), labelling and package leaflet for Advanced Therapy Medicinal Products (ATMPs) that contain genetically modified cells.

Following a two-years drafting process the CHMP of the EMA has adopted the final guideline on quality documentation for medicinal products when used with a medical device on July 22, 2021.

On 23 July 2021, EMA has finalized its reflection paper on GMP-related responsibilities and marketing authorisation holder companies (MAHs). As various tasks are spread over different chapters and annexes of the EU GMP Guide and various directives, the paper now summarizes them in a single 29-page document. This is to provide clarity on which responsibilities are to be considered and what they signify for MAHs at a practical level.