News about GMP/cGMP

On 1 June 2020, the PIC/S adopted the following two documents: 

• PI 052-1 Aide Memoire Inspection of Health Based Exposure Limit (HBEL) Assessments and Use in Quality Risk Management 
• PI 053-1 Questions and Answers on Implementation of Risk-based Prevention of Cross-Contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities’ 

On 3rd June 2020, the European Commission published a concept for the safe and affordable supply of medicinal products in Europe. 
The initiative Pharmaceutical Strategy - Timely patient access to affordable medicines is designed to facilitate innovation in the pharmaceutical industry. 

The WHO Expert Committee on Specifications for Pharmaceutical Preparations meets annually and their reports (Technical Report Series) include all adopted guidelines in form of Annexes.

With the publication of the 54th Technical Report Series No. 1025 of the WHO, several new and revised Guidelines were adopted and recommended for use.

A second revised version of the Q&A document was published on May 26, 2020. A new block of questions (sub-point 6) with six questions and answers deals with the additional temporary flexibility in the GMP/GDP area.

The Swedish company Intertek announced on 15 May 2020 that Intertek Medical Notified Body AB (IMNB) has been designated as the 14th Notified Body against the EU Medical Device Regulation 2017/745 (MDR). 

The US FDA is planning a gradual re-start of on-site surveillance inspections in cooperation with the Centers for Disease Control and Prevention (CDC).

On 15 May 2020, the European Commission has announced to extend the time frame for the consultation on Annex 21 Importation of Medicinal Products until 20 August 2020. This step is justified by the challenges arising in connection with COVID-19.

As the EMA announced on 30 April 2020, all ranitidine medicines in the EU are to be taken off the market. 

On 30 April 2020, the European Commission has announced to extend the time frame for the second consultation on Annex 1 Manufacture of Sterile Products until 20 July 2020. This step is justified by the challenges arising in connection with COVID-19.

The Co-ordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) of the EMA has published a Q&A for the practical handling of processes for mutual recognition of authorisations during the COVID 19 crisis. 

In order to address the current exceptional circumstances, the UK regulatory authority MHRA has opted for a temporary flexibility on good manufacturing practice (GMP). The authority considers these steps necessary to meet the current  supply needs of medicines in the UK. In this context, the GDP requirements for wholesalers have already been relaxed and the discretionary scope for QPs has also been extended.

On 17 April 2020, the European Parliament voted by 693 to one votes and with two abstentions to delay the entry into force of the EU Medical Device Regulation (MDR) by one year - to 26 May 2021. 

How is Switzerland adapting to the EU regarding the implementation of MDR, IVDR and ICH Q12?
 

The European Commission, the EMA and the European Medicines Regulatory Network have developed a 7-page Q&A to guide pharmaceutical companies in making flexible adjustments to the regulatory framework during the COVID 19 pandemic. The EMA has established a task force for this purpose, to take quick and coordinated regulatory action.

On 8 April 2020, the Medical Device Coordination Group (MDCG) published a five-page guideline on the conduct of audits by Notified Bodies to be applied during the COVID 19 pandemic. 

The ICH Q3C(R8) draft Guideline on Impurities: Guideline for Residual Solvents, has reached Step 2b and now enters the consulation period.

The draft document contains solemly the Permitted Daily Exposure (PDE) levels for

• 2-Methyltetrahydrofuran (proposed is a PDE of 50 mg/day and a placement in Class 3 solvents)
• Cyclopentyl Methyl Ether (proposed is a PDE of 15 mg/day and a placement in Class 2 solvents)
• Tertiary Butyl Alcohol (proposed is a PDE of 35 mg/day and a placement in Class 2 solvents).

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).

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