News about GMP/cGMP

It has been and continues to be speculated when the final version of Annex 1 on the sterile manufacture of medicinal products will finally be published. At the beginning of this month, the issue was also discussed at the ISPE Annual Conference in Dublin. Dr. Sabine Paris from the editorial office of the GMP-Verlag was on site and brought these news with her:

EMA has published a 3-page questions-and-answers document (Q&A) on the work that the EU authorities are doing to prevent medicine shortages due to the United Kingdom’s withdrawal from the EU.

On 22 March 2019, ICH published the final revision of the Guideline for Elemental Impurities Q3D (R1). The reason for the revision is an adjustment of the PDE value for cadmium by inhalation.

One week after the surprising resignation of FDA Commissioner Scott Gottlieb, Norman E. Sharpless, Director of the National Cancer Institute (NCI), was appointed Deputy Commissioner of the FDA, according to media reports.

Brexit - and no end in sight. In preparation for a "No-Deal-Scenario", the British Medicines and Health Products Regulatory Authority (MHRA) published six new guidelines on a "No-Deal-Brexit" - five on the import and export of medicines and active ingredients and one on paediatric studies.

The U.S. Food and Drug Administration (FDA) published the yearly list of new and revised draft guidances, CDER is planning to release in 2019. A total of 93 planned guidance documents have been set out which are categorised in 15 different themes.

As already reported, Marketing Authorisation Holders (MAHs) who are unable to transfer their batch testing site from the UK to the EU27 by 29 March 2019 may be permitted, for a limited period of time, to rely on quality control testing performed in the UK under certain conditions.This exempting provision has now been officially included in the EMA practical guidance as the 31st question:

Can I request a delay for transfer of batch control testing to the EU/EEA?

Furthermore, the EMA provides a 3-page template to be used for submitting such requests to the EMA.

On 27 February 2019, the EMA published a question and answer document for the practical implementation of Regulation (EU) 2017/745 for medical devices (MDR) and Regulation (EU) 2017/746 for in vitro diagnostic medical devices (IVDR).

With not even one month left until Brexit, the European Commission has sent a letter to the Director of the EMA (European Medicines Agency) and the EU27 Heads of Medicines Agencies to inform about an exemption to certain batch testing requirements for pharmaceutical manufacturers that perform their batch testing in the UK.

As reported by the European Medicines Agency EMA, the Swiss Agency Swissmedic, has started in 2019 to enter information on GMP compliance as well as on manufacturing authorisations related to Swiss manufacturers into the European Union’s EudraGMDP database. This applies for all new or renewed manufacturing authorisations and the related GMP-certificates issued using new templates (similar to those of EMA). This will allow replacing the current practice of issuing paper documents, i.e. GMP and should lead to easier information-sharing and efficiency gains for all stakeholders.

The British MHRA (Medicines and Healthcare Products Regulatory Agency) has launched a new website  containing all guidances and documents released for a no-Brexit-deal.

On 7 February 2019, the FDA has confirmed the capability, capacity and procedures in place of Poland and Slovenia to carry out GMP inspections at a level equivalent to the US. This concludes the FDA's assessment of a total of 22 EU member states, whose inspection results will be trusted in the future. This process is to be completed for all EU states by 15 July 2019. According to the EMA the plans for the agreement to come into operation in all EU Member States by 15 July 2019 are well on track. As Germany is still not officially recognised, the US FDA will continue to carry out its inspections there.

The European Medicines Agency and the European Commission have updated the following three documents related to Brexit that are intended to complement each other:

• Q&As related to Brexit within the framework of the centralised procedure

• Practical guidance for procedures related to Brexit within the framework of the centralised procedure

• Notice to stakeholders on the withdrawal of the United Kingdom.

The Executive Working Group, EWG has published an interim report on the current status of its work. The focus is on the development of short- and medium-term practicable solutions in regulatory matters. In the area of pharmaceuticals and medical devices, the following approaches are being pursued or further pursued:

The relocation of the European Medicines Agency EMA to the Spark building in Amsterdam is proceeding according to plan. The move from London to Amsterdam should be completed by 1 March 2019. From 4 March, the EMA will then officially operate under a new address and the EMA staff will move into the new domicile in the week from 11 to 15 March.

At the beginning of the year, PIC/S published its annual work plan for 2019. In addition to organisational matters, a new group of experts on veterinary medicines will be set up and the training of inspectors will be further expanded. In the area of harmonisation, PIC/S is actively involved in the revision of the EU GMP guidelines.

In January 2019, the European Commission published a new version 13 of the Questions and Answers document on Safety Features for Medicinal Products for Human Use. Nine new questions were added and one question was revised.

The International Council for Harmonisation (ICH) met in Charlotte, USA, from 10 to 15 November 2018. The steadily increasing number of members (16) and observers (28) is an indication of the continuous development of the ICH into a global initiative. During the General Assembly, the Iranian authority NRA was welcomed as a new regulatory member.

The International Council for Harmonisation (ICH) has published the final concept paper for ICH Q14 (Analytical Procedure Development) on its website. In the course of the preparation of this new guideline, ICH Q2 (Validation of Analytical Procedures) will also be revised. It will be adapted to the state of the art to include modern analytical methods in the future. Both guidelines are intended to supplement the existing documents ICH Q8 - ICH Q12.

The Management Committee of the ICH has endorsed the final concept paper and business plan on the new quality guideline ICH Q13 on continuous manufacturing for drug substances and drug products. Both documents are published on the ICH website.

On 13 December 2018, the US FDA has announced the availability of the final guidance for industry “Data Integrity and Compliance with Drug CGMP: Questions and Answers.” The guidance updates a draft version released in 2016. It has been revised to include additional information on the agency’s current thinking on best practices and covers the design, operation and monitoring of systems and controls to maintain data integrity.

As stated in a European Council press release on 26 November, the Council of the EU adopted the "Veterinary Medicinal Products Package" with two new Regulations in the following areas:

• veterinary medicinal products
• the manufacture, placing on the market and use of medicated feed

and changes to the existing rules laying down procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.

On 30 November 2018, the PIC/S has published Draft No 3 of the “Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments” (PI 041-1) for a focused stakeholder consultation.

The 28-page document setting out frequently asked Q&As regarding the implementation of the rules on the safety features for medicinal products for human use has been revised. As of November 2018, it is available in Version 12.

The changes compared to the superseded version regard questions 1.20 and 2.21:

On 16/28 November 2018, the US Food and Drug Administration (FDA) confirmed the capability of the following five additional EU Member States to carry out GMP inspections at a level equivalent to the United States:

On 19 November 2018, the EMA informed on their website that Valsartan from the Indian manufacturer Mylan Labortories is currently not allowed to be used for the production of medicinal products containing Valsartan for the EU. The CEP (Certificate of Suitability) of Mylan has been suspended by EDQM (European Directorate for the Quality of Medicines and Healthcare) because N-nitrodiethylamine (NDEA) has been found in some batches of valsartan.

The Comprehensive Economic and Trade Agreement (CETA) between the EU and Canada also includes the CETA GMP Protocol. In continuation of the MRA of 2003 between the EC and Health Canada this protocol also confirmed the  continued  mutual  recognition  of  GMP  inspections  and  batch  certification  between  EU  and  Canada  for  medicinal  products  for  human  use  and  veterinary medicines.

On 15 November 2018, the EMA has published a draft of the “Guideline on the Quality of Water for Pharmaceutical Use” for public consultation until 15 May 2019.

This 10-page document, once final, will replace the current “Note for guidance on quality of water for pharmaceutical use” from 2002 and the “CPMP Position Statement on the Quality of Water used in the production of vaccines for parenteral use".

The parallel preparing of the UK’s exit from the EU, the physical move to Amsterdam and operating “business as usual” as long as possible is the declared aim of the EMA. As of October 2018, EMA has launched Phase 3 of the “Brexit Prepardness Plan”, which results in additional temporary suspensions and scaling back of activities.

As of November 1, 2018 the Therapeutic Goods Administration (TGA) of Australia and Health Canada expanded their mutual recognition agreement (MRA) to cover active pharmaceutical ingredients (APIs).

The PIC/S Committee met on 24-25 September 2018, in Chicago. The meeting was attended by 38 Participating Authorities as well as by a number of Applicants, Pre-Applicants and Associated Partner Organisations. The event was hosted by the US FDA which symbolised the effort to strengthen inspectional approaches and assessments worldwide and to further share and discuss respective regulatory decisions and information. The keyword “harmonisation” and the impact of PIC/S on this matter had been especially highlighted by the FDA.

This year’s Operation PANGEA – an international effort to disrupt the online sale of fake and unlicensed health products around the world – took place from October 9 to 16, 2018. Starting with just eight countries in 2008, the operation has grown to 116 countries that participated this year.

As announced on the ICH website on October 25, the ICH Q3C(R7) Guideline along with Q3C Support Documents 1, 2, and 3 have now been published. The new R7-version of ICH Q3C is the result of an error correction of the Permitted Daily Exposure (PDE) for ethylenglycol as per the correct value calculated in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997 S36.

According to pharmabiz.com, the Indian regulatory authority CDSCO has published a draft version of the revised Schedule M. However, the document is currently only available in Indian language.

On October 4, the British MHRA (Medicines and Healthcare products Regulatory Agency) has launched a public consultation seeking views on how the agency’s legislation and regulatory processes would have to be modified in the event of the UK not securing a deal with the EU after the UK’s exit, with no implementation period. This consultation covers no-deal proposals on medicines, clinical trials and medical devices.

On September 17, the US FDA announced a new online application, cGMP declarations. FDA's CDER will send ‘cGMP declarations’ to regulatory authorities in other countries where US firms want to market drug products.

On 3 October 2018, the US FDA’s Center for Devices and Radiological Health (CDRH) has published three lists of guidance documents that may be published in 2019:

We have already reported about the intention of the US FDA/CDRH to changing its quality system requirements for medical device manufacturers and utilise the International Organisation for Standardization (ISO) updated quality management standard, 13485:2016. Obviously the intention has already been put into action.

On 14 September 2018 the FDA has confirmed the capability, capacity and procedures in place of Portugal to carry out GMP inspections at a level equivalent to the US. There are now a total of 15 European Member States whose inspection results the FDA relies on to replace their own inspections.

Health Canada has identified a second impurity, N‑nitrosodiethylamine (NDEA) in valsartan manufactured by Zhejiang Huahai Pharmaceuticals in China. All drugs containing valsartan manufactured from that source have already been recalled in Canada after the first impurity, N-nitrosodimethylamine (NDMA), was identified earlier this summer. Both, NDEA and NDMA are classified as probable human carcinogens, which means that long-term exposure could cause cancer.

The EMA has published a tracking tool on its website, showing how things stand for the relocation to Amsterdam. It covers all aspects on EMA's temporary premises, its permanent premises, staff relocation, financial and legal aspects, removal and logistics and external communication.

On 5 September 2018, the US FDA has published a 7-page Manual of Policies and Procedures, MAPP, on how manufacturing facilities are prioritized and scheduled for surveillance inspections. This step should add greater transparency around the “Site Selection Model (SSM)”, used by CDER staff.

The US Food and Drug Administration, FDA, has added six Asian drug manufacturers to its import alert list this month, that refused a planned inspection of the FDA.

The European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) have set up a task force with representatives from the European Commission, interested national competent authorities and other regulatory working groups. Their aim is to develop and coordinate actions for better prevention, identification, management of and communication on issues that can affect the availability of medicines.

Even though it is unlikely to happen, the UK government has got its plan B if, in any case, a no deal scenario for leaving the EU might materialise. Guidance thereto was published by the Department for Exiting the European Union on August 23, 2018.

Following the suspension of the CEP – a certificate verifying that the quality of its valsartan meets European requirements – for Zhejiang Huahai in July 2018, a second Chinese company Zhejiang Tianyu has now lost its authorisation to manufacture the valsartan active substance for EU medicines.

The Compounding Expert Committee intends a revision of the General Chapter USP <797> Pharmaceutical Compounding – Sterile Compounding. The draft version has been published for public commentation until November 30, 2018.

EMA reported, that it will lauch the next phase of its business continuity plan on 1 October 2018 at the latest. This will allow the Agency to safeguard core activities related to the evaluation and supervision of medicines, while it has to intensify its preparations for the physical move to Amsterdam in March 2019 and cope with significant staff loss.

The MedTech Europe industry group calls on the European institutions to offer solutions to meet the deadlines for the new MDR and IVDR. Both regulations will apply from May 2020 and May 2022 respectively.

The World Health Organization (WHO) has prepared a new questions and answers document to clarify earlier biosimilar guidelines. It will provide answers to questions asked by regulators over the last eight years.