News about GMP/cGMP

The deadline of 26 May 2020 should have been the date: The European Commission's Medical Device Regulation (MDR) was supposed to come into force. Due to the Corona crisis, the European Commission is now submitting a proposal to postpone the implementation deadline.

The European Commission published the 4-page draft version of the new Annex 21: Importation of medicinal products, on 20 March 2020. Apart from the main Chapters and Annexes of the EU GMP Guide, it has become necessary to establish specific guidelines for the activity of importing medicinal products.

The European Medicines Agency (EMA) announced that the deadline for the submission of risk assessments for all human medicines presenting a risk for the presence of nitrosamine impurities or (cross)contaminations will be extended to 1 October 2020. The announcement was made just one day ahead of the original deadline scheduled for 26 March 2020. This will give all companies affected more time to review their manufacturing processes and carry out the required risk assessments.

The reason given for this step is the challenges and impact of the restrictions in place to combat the COVID 19 pandemic.

On March 9, 2020, the European Commission published version 17 of the Q&A on safety features for medicinal products. The document is updated on a regular basis (we reported).

The Australian Therapeutic Goods Administration (TGA) has suspended all foreign GMP inspections and QMS (Quality Management System) audits until further notice.

The US FDA had already announced on 10 March 2020 that most foreign inspections would be postponed until April with immediate effect. Now domestic routine surveillance inspections will also be scaled back.

The US FDA announced that it is postponing most foreign inspections through April with immediate effect due to the Coronavirus disease. Inspections outside the US that are considered critical will be reviewed by the FDA on a case-by-case basis.

As the Indian Directorate General of Foreign Trade announced on 3 March 2020, the export of 26 active ingredients and medicinal products will be severely restricted until further notice due to the global spread of the coronavirus.

The ICH Q12 guideline on technical and regulatory considerations for pharmaceutical product lifecycle management was adopted by the CHMP (European Committee for Medicinal Products for Human Use) in January 2020. On March 4,  the EMA (European Medicines Agency) published a two page note on the implementation of ICH Q12. It addresses the fact that there are conceptual differences between ICH Q12 and the EU legal framework. Therefore, a 1:1 application in the EU is not possible without further ado.

ICH has published a training presentation on ICH Q12 Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle compiled by the Q12 Expert Working Group.

The US FDA, in cooperation with the Indian authorities, has seized 500 shipments of illegal and potentially dangerous unapproved prescription drugs and medical devices. The products were in transit to American consumers by international mail.

A first targeted consultation to the Annex 1 of the EU GMP Guide allowed about 140 companies and organizations to comment. The drafting group processed more than 6200 lines of comments. These have now been taken into account in the preparation of a second draft.

The Dublin-based National Standards Authority of Ireland (NSAI) was designated by the European Commission as the eleventh Notified Body under MDR and thus added to the NANDO database.

The International Council for Harmonisation (ICH) has made the Minutes of the ICH Assembly Meeting in Singapore, in November 2019, publicly available. In contrast to the already published press release (we reported), the meeting minutes include new details on the following interesting projects for the GMP area:

The Norwegian DNV GL Presafe AS (Notified Body 2460) is now a Notified Body for EU Medical Devices Regulation (MDR) 2017/745.

In a press release the EMA informs pharmaceutical and medical device manufacturers about the withdrawal of Great Britain from the EU on 31 January 2020. What are the current developments?

As you may have already noticed - on our website or elsewhere - we have a new company logo and also a new name.

This year's list of guidelines to be published by the CDER (Center for Drug Evaluation and Research) comprises 14 categories with a total of 89 documents. 

On 14 January 2020, the EMA published a draft Reflection Paper on the GMP-related obligations of marketing authorisation holders (MAHs). In general, these responsibilities relate to outsourcing and technical agreements. However, they are spread over the different chapters and annexes of the EU GMP Guideline and are also quite numerous. The aim of the reflection paper now is to clarify in a single document what the different responsibilities are and what they mean for MAHs at a practical level. It also addresses the legal provisions in European Directives and other Directives that relate to GMP and also affect marketing authorisation holders.

In December 2019, the International Organization for Standardization (ISO) published the revised standard ISO 14971:2019 on application of risk management to medical devices. This standard has now been added to the list of Recognized Consensus Standards by the US FDA.

End of December 2019, the EMA has updated the Q&A document for marketing authorisation holders who are currently reviewing their medicines for the possible presence of nitrosamines and testing products at risk.

In December 2019, the European Medicines Agency (EMA) revised a four-page Q&A document on the EU-US Mutual Recognition Agreement (MRA) on marketing authorisation applications and variations.

On 12 December 2019, the US Senate elected Dr. Stephen Hahn as the 24th Commissioner of the US FDA (Food and Drug Administration) by 72 to 18 votes.

During the last months, there have been repeated cases of nitrosamine contamination in sartans (we reported). As a consequence, the sartan monographs of the European Pharmacopoeia were revised: Transiently, new strict limits apply for the contamination of sartans with nitrosamines. The monographs will come into force on January 1, 2020.

On 4 December 2019, the European Commission published eight documents containing technical specifications for unique device identifiers (UDIs). 

On 25 November 2019, the European Commission published the second corrigendum to the EU Medical Devices Regulation (MDR). The corrections mainly concern Class I medical devices. 

The ICH (International Council for Harmonisation) met in Singapore from 16-20 November 2019. More than 450 participants attended the meeting and fourteen Working Groups met to progress their work.

A particularly noteworthy milestone is:

• ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management was finalised in Singapore and has reached Step 4 of the ICH process.

On 18 November 2019, the European Commission published the "Aide-Mémoire for GDP inspection of wholesalers compliance with commission delegated regulation (EU) 2016/161 for safety features". As a checklist, the six-page document is intended to assist wholesalers in complying with the relevant GDP regulations on safety features.

In late October 2019, the WHO published a 28-page draft guideline on data integrity. It clarifies basic aspects to ensure reliable data and information in the manufacture and control of medicinal products. A 7-page annex provides additional examples for the practical implementation of the requirements.
 

The Swiss Agency for Therapeutic Products (Swissmedic) is working on adapting the requirements for combination products to the new EU Medical Devices Regulation (MDR). A notification was published on the Swissmedic website on 5 November 2019.

On 4 November 2019, the ICH has published the survey results on the level of implementation and adherence to ICH Guidelines within its Regulatory Member and Observer countries. The results have been compiled in a 26 page report. Especially interesting is the resulting tabular overview of the data including a search function:

On its website, the European Commission has officially announced that the launch of the European Database on Medical Devices, EUDAMED, has been postponed:

On 22 October 2019, the European Medicines Agency (EMA) released an revised and updated Q&A on the implementation of the EU Medical Devices Regulation (MDR) and EU In Vitro Diagnostic Regulation (IVDR).

According to the ICH, the PDE value for ethylene glycol was reinstated to its previous PDE value of 6,2 mg/day and a concentration limit of 620 ppm. This value was changed in October 2018 with the ICH Q3C(R7) version  to a PDE of 3.1 mg/day and a concentration limit of 310 ppm. The process was then preceded by an error correction procedure (we reported).

On 10 October 2019, the European Commission announced the first Notified Body designated under the EU Vitro Diagnostics Regulation (IVDR).

The updates on this document are overturning: On 25 September 2019, the European Commission published Version 16 of the document on safety features for medicinal products for human use. 

On 19 September, the notified body TÜV SÜD announced the certification of the first Class III medical device in accordance with the new EU Medical Devices Regulation (MDR).

On 3 September 2019, the UK notfied body BSI announced the Novartis Concept1 inhaler as first medical device certified under the new EU Medical Devices Regulation (MDR).

The United States FDA works on the harmonisation of the Quality System Regulation, 21 CFR 820 with ISO 13485, the international standard for quality management of medical devices (we reported), saying that

In summer 2018, production-related contamination of the antihypertensive valsartan with the nitrosamines NDMA and NDEA caused a stir in the pharmaceutical world (we reported). A risk assessment conducted by the European Medicines Agency (EMA) followed this. The results can be found in the detailed EMA report from February 2019.

A Q&A published by the European Medicines Agency (EMA) on 28 August 2019 clarifies when exemptions from batch re-testing of imported advanced therapy medicinal products (ATMPs) are permitted.

On August 20, 2019, the US FDA published a warning letter to Ningbo Huize Commodity Co., a Chinese manufacturer of OTC drugs. The case concerns serious violations of good manufacturing practice and, in this context, the serious manipulation of data. In addition to this the FDA has gone public with detailed information.

As announced by the European Commission on 20 August 2019, the IMQ Istituto located in Milan, Italy, has been notified as the fourth Notified Body under the new European MDR to come in 2020. This is still too little, according to the opinion within the medical device industry.

In addition to BSI UK and TÜV Süd, the German DEKRA Certification GmbH is now recognised as a third Notified Body for the EU Regulation 2017/745 (MDR).

According to RAPS, a US-statement to the Committee for Technical Barriers to Trade of the World Trade Organization (WTO) from 24 July 2019, raises concerns regarding the implementation of the new European Medical Devices Regulation (MDR) and the Regulation on In Vitro Diagnostics (IVDR). The MDR is already due to enter into force on 26 May 2020, the IVDR in 2022.

From today’s perspective, the UK will be a third country as of 1 November 2019. As a result, all  batch  testing  facilities will have to be fully transferred to the EU27/EEA by  1  January  2020.  The European Commission has now published a reminder announcement regarding the requirement of batch release sites to be established in the EU. This applies also to MAHs which were granted an exemption to continue relying on quality control testing performed in the UK earlier this year (we reported).

The TGA (Australian Therapeutic Goods Administration) has expressed concern about a looming shortage of Notified Bodies under the new Medical Device and In Vitro Diagnostics Regulations (MDR/IVDR) in Europe. Not without reason, though.

As the EMA announced on 12 July 2019, Slovakia is the last EU member state to be recognized by the USA under the Mutual Recognition Agreement (MRA).

In England, imported medicines have appeared which have apparently been removed or "stolen" from the legal supply chain in order to be reintroduced later into regular sales. With this, both correct transport and appropriate storage conditions are no longer guaranteed.

On 1 July 2019, the Medical Device Coordination Group (MDCG) published two guidance documents on the Medical Device Regulation (MDR) and the In-Vitro Diagnostics Regulation (IVDR).