News about GMP/cGMP

All marketing authorisation holders for metformin-containing medicines will be asked by the EMA or the national competent authorities to test their medicines for the presence of nitrosamines before releasing them to the market. This is to be a preventive measure, as stated in the notification on the EMA website.

The European Commission announces that the EUDAMED Actor Registration Module  will go live on 1 December 2020. Meanwhile a website has been set up to explain all the necessary steps to register  for access to EUDAMED and the following modules.

The ACSS Consortium, a joint initiative of the regulatory authorities of Australia (TGA), Canada (HC), Singapore (HSA) and Switzerland (Swissmedic) announces a new membership: the British MHRA. Following as short observatory role, the MHRA will officially start to work with the consortium partners on January 1, 2021.Along with this, the group has changed its name to accommodate the new partner, and will be known as the "Access Consortium". The new name reflects the group’s key aim of providing patients with timely ‘access’ to high quality, safe and effective therapeutic products across the five countries.

The EMA (European Medicines Agency) announces that the deadline for the completion of a risk assessment for all chemically defined human medicinal products that bear the risk of nitrosamine formation or (cross)contamination will be extended until 31 March 2021. For biological medicinal products, the final date for completion of a risk assessment will be 1 July 2020.

The draft for the ICH Q3D(R2) Guideline for Elemental Impurities has reached Step 2 on September 25, 2020 and thus the consultation phase. The draft guideline includes, amongst others, corrected PDE values for gold, silver and nickel and a new appendix for impurities that are applied cutaneously or transcutaneously.  

The Brazilian health regulatory agency, ANVISA, warns of counterfeit medicinal products for which import was banned immediately.
This was announced by Swissmedic, who was informed directly by ANVISA on 23 September 2020. 

On 18 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) confirmed its recommendation to suspend all ranitidine-containing medicinal products in the EU due to the presence of low levels of the impurity N-nitrosodimethylamine (NDMA).This follows a re-examination of CHMP’s April 2020 opinion, which was requested by one of the companies marketing ranitidine medicines. The EMA has published a detailed statement on this recommendation.

The new European standard EN 17141:2020 has been issued on 12 August 2020 and will replace the DIN EN ISO 14698 (Parts 1 and 2) of the year 2003, which no longer reflects the state of the art.

The Swiss Agency for Therapeutic Products, Swissmedic, will, according to an announcement made on 1 September 2020, carry out regular GMP and GDP inspections on site again with immediate effect. Protective measures such as distance and hygiene rules must continue to be followed and infections must be traced.

How can manufacturers of pharmaceuticals and APIs detect and prevent nitrosamine impurities in pharmaceutical products and what are possible causes of the contaminations? These questions have been occupying regulatory authorities and of course the pharmaceutical industry for the last two years. Answers are now provided by the 24-page guidance on Control of Nitrosamine Impurities in Human Drugs, which was published by the US FDA on 1 September 2020.

On 1 September 2020, the British MHRA (Medicines and Healthcare products Regulatory Agency) published numerous guidelines explaining how medicinal products, active ingredients, medical devices or clinical trials are to be regulated after the brexit transition period ends on 1 January 2021.

On August 12, 2020, the European Commission published version 18 of the Q&A on safety characteristics for medicinal products. The document, which has now grown to 34 pages, was thus the second update this year (we reported).
New are the questions 4.6, 5.12, 5.13 and 6.9, which are briefly summarized below: 

On August 19, 2020, the US FDA issued a 12-page guideline for the pharmaceutical industry in the form of a Q&A, which deals specifically with questions regarding  

• Manufacturing  
• Requirements for the supply chain  
• Inspections  
• Pending applications for approval and  
• Changes in manufacturing facilities for already approved medicinal products  

during COVID-19. 

On its Inspectorate Blog, the UK MHRA (Medicines and Healthcare products Regulatory Agency) has critically reviewed the implementation of the requirements on HBELs and the prevention of cross contamination in shared facilities. What are the expectations to be met and what deficiencies have been identified in recent inspections?

According to the MHRA Inspectorate Blog, answers can be found in these two PIC/S documents:

• PI 052-1 Aide Mémoire and the corresponding
• PI 053-1 HBEL Q&A.

The World Health Organisation (WHO) has published three new draft guidelines, which are currently available for comments. In September 2020, all comments will be consolidated and reviewed. The documents will then be prepared for discussion and presented at the 55th virtual meeting of the ECSPP (WHO Expert Committee on Specifications for Pharmaceutical Preparations). It is scheduled to take place from 12 to 16 October 2020.

After the US FDA already announced the gradual resumption of on-site surveillance inspections in May (we reported), the MHRA is now also following this course. The short Guidance for industry on MHRA's expectations for return to UK on-site inspections published on 11 August 2020 sets out the procedure.   

As of July 2020 the EMA (European Medicines Agency) has amended the European "Joint Audit Programme, JAP". These adaptations enable regulatory authorities from third countries with an existing EU-MRA (Mutual Recognition Agreement) to participate as co-auditors in JAP audits of EEA GMP inspectorates.

Shortly after the publication of the EMA's final assessment report on nitrosamine impurities in medicinal products (we reported), a 15-page Q&A for marketing authorisation holders and applicants was published on 6 August 2020.

It replaces the document 'Information on nitrosamines for marketing authorisation holders' EMA/428592/2019 published in September 2019, which was withdrawn.   

On 20 July 2020, EMA published the final 10-page Guideline on the quality of water for pharmaceutical use.
The date of entry into force will be 1 February 2021.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has published a final assessment report on nitrosamine impurities.

On 1 July 2020, the Swiss Federal Council adopted the revised Ordinance on Medical Devices (MedDO) and the new Ordinance on Clinical Trials for Medical Devices (ClinO-MD).   

The French company GMED, based in Paris was designated 15th Notified Body under the new Medical Devices Regulation (MDR) on July 8, 2020.

On 25 June 2020, the Management Board of the European Medicines Agency (EMA) selected the Irish pharmacist Emer Cooke as the new EMA Executive Director from a list of candidates prepared by the European Commission.

EMA and the Korean Ministry of Food and Drug Safety (MFDS) have signed an agreement to exchange confidential information on medicines for the treatment, diagnosis or prevention of COVID-19.

The European Commission, the EMA and the European Network of Medicines Regulatory Authorities have published the third version of the Q&A on regulatory expectations for medicinal products for human use during the COVID-19 pandemic on July 1, 2020. The document has meanwhile grown from originally 7 to now 23 pages and intends to serve pharmaceutical companies as a guide on current adjustments to the regulatory framework due to COVID-19.

On 23 June 2020, the European medicines regulatory network published the outcome of a lessons learned exercise on the presence of nitrosamines in sartan medicines. This includes recommendations to help reduce the risk of impurities in medicines, and to ensure that regulators are better prepared to manage cases of unexpected impurities. The report is called "Lessons learnt from presence of N-nitrosamine impurities in sartan medicines".

As announced by TÜV Süd Product Service GmbH on 17 June 2020, the German Central Authority of the Länder for Health Protection with regard to Medicinal Products and Medical Devices (ZLG) designated the company as the fourth Notified Body according to the In Vitro Diagnostic Regulation (IVDR).

In May 2020, the WHO published the following three drafts for commentary: 

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.