GMP:Blog

ICH published the revised version (Step 4) of the ICH Q3C(R8) Guideline on Impurities: Guideline for Residual Solvents on 22 April 2021.

As announced by PIC/S on 23 April, 2021, the PIC/S GMP Guide has been revised. The changes will take effect on 1 May 2021. 

On 14 April 2021 the US FDA has published a new guidance “Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency”. This in fact was long overdue.  It outlines 

• how remote interactive evaluations will be requested by the FDA and 

• how they will be conducted for the duration of the COVID-19 pandemic.

On 16 April 2021, Swissmedic announced that it is seeking harmonization with EU regulations regarding the handling of nitrosamine impurities.

On 12 April 2021, Dr Janet Woodcock, acting head of the US FDA, announced Dr Patrizia Cavazzoni's new role as director of CDER.

The European Union has published the Delegated Regulation (EU) 2021/457 in its Official Journal on 17 March 2021. It amends the Delegated Regulation (VO) 2016/161 on safety features necessary for the packaging of medicinal products for human use. The amendment is to exempt the obligation for wholesalers to deactivate the unique identifier of medicinal products exported to the United Kingdom, being considered a third country now.

EMA published Revision 3 of the Q&A on the Protocol on Ireland and Northern Ireland on 5 March 2021. The 11-page document contains 28 pairs of questions and answers. It is updated regularly and will be of interest to all GMP professionals who have business relationships with companies in Northern Ireland.

The CMDh (EMA's Coordination Group for Mutual Recognition and Decentralized Procedures) has approached one of the EMA's Safety Working Parties (SWPs) with the following two questions regarding chlorobutanol:

1. Can the Safety Working Party confirm that the levels of chlorobutanol commonly used in medicinal products are safe from a toxicological point of view?
2. Is it possible to determine acceptable intake levels of chlorobutanol?

The EMA published the 15-page SWP response document to these questions on March 17, 2021.

The MHRA announces its return  to on-site risk based GxP inspections starting from 29 March 2021. However, it is planned to use a combined approach of both, remote and on-site inspections.

The Medical Device Coordination Group (MDCG) published an eight-page Q&A document titled Questions and Answers on Custom-Made Devices & considerations on Adaptable medical devices and Patient-matched medical devices (MDCG 2021-3) on 15 March 2021.

The European Commission published a Notice this January dealing with the legal framework for medicinal products marketed in Northern Ireland. On 9 March 2021, the UK MHRA, for its part, followed up and also addressed the issue. 

On 4 March 2021, Swissmedic announced the numbers on medicinal products illegally imported into Switzerland. In 2020, 6733 illegal imports were recorded. Compared to the previous year, the number has decreased only slightly.  Among the countries of origin, Singapore has replaced India, which has long been in the lead. It was followed by Western European countries such as the UK and Germany in particular.

Singapore is increasingly being used as a hub by suppliers of illegal medicinal products.

WHO published a 31-page draft guideline, "GMP for investigational radiopharmaceutical products", in March 2021. It offers recommendations for minimum standards in the manufacture of new radiopharmaceuticals for Phase I-III clinical trials that do not have a marketing authorization (MAA).

As reported earlier, the European Pharmacopoeia Commission implemented five new sartan monographs in a rapid procedure at the end of February. They are scheduled to become effective already on 1 April 2021. For holders of a Certification of Suitability (CEP), this may, but does not necessarily, mean adjusting their control strategies for nitrosamine impurities. EDQM has now published supplemental information on this topic:

On 23 February 2021, the European Directorate for the Quality of Medicines & HealthCare (EDQM) announced that five monographs on sartans have been revised. They will be effective immediately as of 1 April 2021. 

On 22 February 2021, the European Medicines Agency (EMA) published a 14-page implementation plan dealing with the prevention of nitrosamine impurities. It is based on the results of the CHMP's scientific review of the subject.   

On 15 February 2021, the European Commission published a 13-page document on the management of legacy devices. It clarifies questions on how these will be identified in EUDAMED or how the different Unique Device Identifiers (UDI) will be generated or assigned.  

On 24 February 2021, the U.S. Food and Drug Administration announced a revision to its September 3, 2020, Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs. The revision extends the recommended timeframe for manufacturers to assess the risk of nitrosamines in active pharmaceutical ingredients (APIs) and drug products from 6 to 7 months.

On 17 February 2021, Swissmedic announced that it will now permanently support the "Orbis" project. Orbis enables manufacturers to submit their marketing authorization applications submitted to the US FDA simultaneously to other international regulatory authorities, provided they participate in the project.

The WHO published a 29-page draft guideline on Good Manufacturing Practices for Medical Gases in February 2021. The reason given for this step is a sharp increase in the demand for medical gases, particularly oxygen used to provide respiratory care to covid patients.

As announced by the European Commission on 18 February 2021, the Italian Istituto Superiore di Sanità (ISS) has been designated as the 19. Notified Body under the EU Medical Devices Regulation (MDR) 2017/745.

EMA published the document "GMP requirements applicable to the early manufacturing steps for comminuted plants and herbal extracts used as active substances" in February 2021.

Following the detection of 1-nitroso-4-methyl-piperazine (MeNP) impurities in some batches of rifampicin in February 2021, the EMA is requesting manufacturers to test the drug for the presence of MeNP. 

As announced on 26 January 2021, the Jordan Food & Drug Administration (JFDA) has submitted a complete application for membership to the PIC/S.

The European Medicines Agency (EMA) has launched an initiative to collaborate with non-EU authorities and WHO to drive the evaluation processes for COVID-19 vaccines and therapeutics.

In January 2021, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) published the English translation of the document on remote inspections, Procedure for Remote Inspection as a Part of Compliance Inspection on Drugs and Regenerative Medical Products.

This year's Center for Drug Evaluation and Research (CDER) list of guidance documents scheduled for publication includes 18 categories with a total of 105 documents.

PIC/S has updated the following four Aide-Mémoires, which became effective on 1 January, 2021:

Dr. Janet Woodcock has been appointed as acting commissioner of the FDA. The previous commissioner, Dr. Stephen M. Hahn, stepped down from his role at the start of President Biden's term of office.

Questions about the EU-UK Trade and Cooperation Agreement, which will apply from January 1, 2021, were clarified by the European Commission in a 39-page Q&A on the EU-UK Trade and Cooperation Agreement on December 24, 2020. In total, it consists of 133 pairs of questions and answers.

The competent authorities of the Russian Federation submitted a complete membership application to PIC/S in Geneva on 13 January 2021. The rapporteur(s) will be appointed in written procedure or at the next meeting of the PIC/S Committee.

In the second week of January, the European Commission (EC) published a list of members appointed to the MDR and IVDR expert panels. On 10 September 2019, the 12 expert panels were designated by the Commission Implementing Decision (EU) 2019/1396.

On 11 January 2021, the European Commission (EC) announced what needs to be considered when Notified Bodies conduct remote audits of medical device and in vitro diagnostic manufacturers due to the COVID-19 situation.

On 5 January 2021, the UK MHRA published a joint statement by the UK and Canada, which applies on an interim basis and is intended to avoid trade disruptions as a result of the Brexit. 

The transition period until Brexit came into effect ended on 31 December 2020. The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published another batch of documents for the processes that are now starting. They cover all aspects of the regulation of medicinal products and medical devices in the UK.

Shortly before the end of the year, WHO published a 38-page draft with twelve chapters and two appedices on technology transfer in pharmaceutical manufacturing.

In December 2020, the Medical Device Coordination Group (MDCG) of the European Commission published a six-page Q&A document on Notified Body audits of medical device manufacturers during the COVID 19 pandemic. 

As announced by the UN Commission on 2 December 2020, cannabis was removed from Schedule IV of the 1961 Single Convention on Narcotic Drugs following WHO's recommendation.

What should a crisis-proof drug supply in Europe resemble? In this regard, the European Commission presented a 25-page pharmaceutical strategy on November 25, 2020. It was awaited with great interest. One thing is for certain: the implementation of the strategy will not leave the EU pharmaceutical legislation unaffected.

As the PIC/S announced on 30 November 2020, the Brazilian National Health Authority 'Agência Nacional de Vigilância Sanitária' (ANVISA) has become the 54th member of PIC/S. 

The European Commission (EC) designated the German company TÜV Rheinland as a Notified Body under the In Vitro Diagnostics (IVDR) Regulation on 1 December 2020.

Swissmedic clarified on 20 November 2020 that GMP certificates issued after routine inspections in 2017 or 2018 are valid until 2021 or until the conduct of the next routine inspection.  

In November 2020, the WHO published a first draft on GMP for research and development facilities.

The WHO published a draft on GMP for investigational products in November 2020. The 28-page working document comprises 18 chapters and can be commented on until 6 January 2021. The guideline currently in force and consisting of 12 pages was published in 1996.  

Emer Cooke from Ireland began her mandate as Executive Director of the EMA on November 16, 2020. On June 25, 2020 she was the first woman nominated for this position (we reported).

In a statement dated 13 November 2020, EMA announces that its CHMP (Committee for Medicinal Products for Human Use) has aligned recommendations for limiting nitrosamine impurities in sartan medicines with recent recommendations it issued for other classes of medicines.

On 9 November 2020, Swissmedic announced to further extend the deadline for the completion of a risk evaluation for medicinal products for human use with a risk of nitrosamine formation or (cross)contamination to 31 March 2021. For biological medicinal products, the final date for the completion of an evaluation is 1 July 2020. Switzerland is thus following the EU, which announced an extension of the deadline in early October.
 

Given the changed situation regarding COVID-19 and the differing measures introduced by the various cantons in Switzerland, Swissmedic has decided to adapt the way inspections in the healthcare field are carried out. As of 3 November 2020, inspections will only be performed after prior clarification of possible COVID-19-related capacity problems.

On 27 October 2020, the European Medicines Agency (EMA) published an implementation plan to reduce nitrosamine impurities in medicinal products.

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.  

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 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. 

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.

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.

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.

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.

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).

On 26 June 2019, the US FDA granted Germany the ability to carry out GMP inspections at a level equivalent to that of the USA. With this, the MRA between the US and the EU has almost reached its goal: By 15 July 2019, the recognition of all 28 EU Member States should be completed.

The European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT), together with the GMDP Inspectors Working Group and the Blood Products Working Party, released a Q&A document on how companies should handle OOS batches of authorized cell or tissue-based advanced therapy medicinal products (ATMPs). For manufacturers, importers and Marketing Authorisation Holders of ATMPs this 2-page document will be of good value.

Across the EU, an increasing number of discussions are highlighting concern about the challenges facing each stakeholder in the sector (manufacturers, notified bodies, authorised representatives, distributors, competent authorities, European Commission) in implementing the new MDR/IVDR Regulations on time and effectively.

The ICH (International Council for Harmonisation) met from 1 to 6 June 2019 in Amsterdam, Netherlands. 

Once again, two counterfeit batches of the drug Xarelto® 20 mg from the original manufacturer Bayer AG in Polish-Slovak packaging were discovered at a parallel distributor in Great Britain. Xarelto®, with the active ingredient Rivaroxaban, is used to prevent strokes and systemic embolisms as well as to treat pulmonary embolisms and venous thromboses.

On 10 June 2019, the FDA has confirmed the capability, capacity and procedures in place of Luxembourg and the Netherlands to carry out GMP inspections at a level equivalent to the US. This concludes the FDA's assessment of a total of 26 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.

On 6 June 2019, the European Commission published a Q&A document to clarify new obligations under the medical device and in vitro diagnostic regulations (MDR/IVDR) regarding notified bodies (NBs).

The 8-page document has been endorsed by the Medical Device Coordination Group (MDCG). The MDCG is composed of representatives of all Member States and it is chaired by a representative of the European Commission.

It answers four sets of questions on a range of MDR/IVDR requirements relating to NBs. The clarifications cover organizational and general requirements, as well as resources requirements and process requirements.

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

With the publication of the 53nd Technical Report Series No. 1019 of the WHO, several new and revised Guidelines were adopted and recommended for use.

TÜV SÜD Product Service was designated by the German Central Authority of the Länder for Health Protection with regard to Medicinal Products and Medical Devices (ZLG) as the second Notified Body for the EU Medical Devices Regulation (MDR).

In April 2019, the PIC/S Committee and the PIC/S Executive Bureau met in Geneva, Switzerland. The meeting was attended by 45 out of 52 PIC/S Participating Authorities as well as by a number of Applicants, Pre-Applicants, Associated Partners and Guests. Here are the topics addressed in the area of GMP:

On 14 May 2019, the European Commission confirmed that the quality of APIs produced in the Republic of Korea is in line with EU standards. APIs manufactured in third countries like the Republic of Korea, and intended for the EU market, have to be produced in an EU equivalent regulatory system. This includes the rules for GMP.

In March 2019, the European Medicines Agency (EMA) published the 25-page final version of the guideline "Sterilisation of the Medicinal Products, Active Substance, Excipient and Primary Container". The document will enter into force on 1 October 2019.

The European Commission published Version 14 of the Q&A document on Safety Features for Medicinal Products for Human Use at the beginning of this month. The document complements the Counterfeiting Directive 2011/62/EU and the Delegated Regulation (EU) 2016/161.

On 29 April 2019, the FDA has confirmed the capability, capacity and procedures in place of Bulgaria and Cyprus to carry out GMP inspections at a level equivalent to the US. This concludes the FDA's assessment of a total of 24 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.

In terms of the InstA (Institutional Agreement) between Switzerland and the EU, there is legal uncertainty. This directly impacts the entire medical technology industry in Switzerland, as it does not ensure an update of the MRA (Mutual Recognition Agreement) Switzerland/EU. Will the third country requirements of the MDR perhaps soon apply to Switzerland? And what has to be done to be prepared?

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:

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.

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.

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:

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 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.

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.

On 17 July 2018, the Members of the British Parliament voted 305-301 to continue a close collaboration with the EMA after Brexit. This amendment to the Brexit Trade Bill on ‘UK participation in the European medicines regulatory network’ means that British Government is now 'in charge' to negotiate an active and full participation in the EMA following the United Kingdom’s exit from the EU.

The European Union and Japan have extended their Mutual Recognition Agreement (MRA) on 18 July 2018. The MRA now also includes sterile products, APIs and biologicals including vaccines.

The European Medicines Agency EMA expresses “serious concerns” over the preparedness of some marketing authorisation holders for centrally authorised products with an important step in their regulatory processes in the United Kingdom (UK) regarding the necessary actions to smoothly transition once the UK will exit the EU in March 2019. This conclusion was drawn after evaluating the results of an industry survey which was initiated by the Agency in January 2018 (we reported).

The ICH (International Council for Harmonisation) met in Kobe, Japan, from June 2 – 7, 2018. The corresponding press release provides insight on the topics discussed.

The US FDA initiated two new programs on a voluntary basis to gather industry feedback regarding the use of quality metrics. Namely these are a

• Quality Metrics Feedback Program and a
• Quality Metrics Site Visit Program

Highly Purified Water (HPW) wird aus dem europäischen Arzneibuch gestrichen, so berichtet die Europäische Arzneibuch-Kommission nach ihrer 160. Sitzung, die vom 20.-21. März 2018 in Straßburg stattfand. Die Monographie 1927 wird aufgrund der Redundanz von HPW und Wasser für Injektionszwecke (WFI) im April 2019 entfallen. Die revidierte Monographie für WFI (Wasser für Injektionszwecke, 0169) ist seit April 2017 in Kraft (wir berichteten).

On 26 and 27 June 2018, the PDA Europe Annual Meeting took place in Berlin. Thomas Peither, Excecutive Editor and President of Maas & Peiter AG, participated in the conference and brought back interesting insights.

The European Commission has now published the final version of Annex 2 "Manufacture of Biological active substances and Medicinal Products for Human Use". It is in operation since 26 June 2018.

Almost two years after publishing a draft document of Annex 17: Real Time Release Testing the European Commission has now published the final version newly entitled Annex 17: Real Time Release Testing and Parametric Release. The eight-page document will come into operation on 26 December 2018 and will finally replace the preceding version of the year 2002.

The following new PIC/S Guidance documents have now been published on the PIC/S website:

• PIC/S Aide-Memoire on “Cross-Contamination in Shared Facilities” (PI 043-1).
• PIC/S Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use (PI 045-1);
• PIC/S Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (PI 046-1);
• PIC/S Guidelines on the principles of Good Distribution Practice for active substances for medicinal products for human use (PI 047-1)

On 19 June 2018 the European Medicines Agency (EMA) published

• Revision 2 of its practical guidances for procedures related to Brexit for medicinal products for marketing authorisation holders (MAH) and
• Revision 3 of the related Q&A document.

Both documents shall assist pharmaceutical manufacurers in preparing for Brexit.

The US FDA is currently alerting patients, health care professionals and those involved in the drug supply chain of more than 16,000 packages of the injectable fertility medications Gonal-f RFF Redi-ject and Gonal-f Multi-Dosethat have been stolen in Italy.

With the publication of the 52nd Technical Report Series No. 1010 of the WHO, eleven Guidelines were adopted and recommended for use:

The US Food and Drug Administration (FDA) confirmed the capability of Lithuania and Ireland to carry out GMP inspections at a level equivalent to the US.

The ICH Q3D(R1) Revision of the ICH Q3D Guideline for Elemental Impurities reached Step 2b of the ICH Process in May 2018 and now enters the consultation period. The revision is focused on an error correction in the calculation of the Cadmium inhalation Permitted Daily Exposure (PDE) level.

On 23 May 2018, the European Medicines Agency (EMA) released a guideline laying out the principles for managing investigational medicinal products for use in a clinical trial and in accordance with Good Clinical Practices (GCPs) and Good Manufacturing Practice (GMPs) for public consultation.

In May the US FDA has issued five Warning Letters that address cGMP-violations on a large scale. The drug facilities involved are:

• Jilin Shulan Synthetic Pharmaceutical und Nox Bellcow Cosmetics Co, China
• Jalco Cosmetics, Australia
• Europharma Concepts, Ireland
• Reine Lifescience, India.

The UK government must secure a post-Brexit deal for the pharmaceutical industry that ensures the closest possible regulatory alignment with the EU and the minimum border friction possible or risk harming patients and seeing the pharma sector losing its status as a world leader, say the Business, Energy and Industrial Strategy Committee of the UK parliament.

From 16 to 18 April 2018 the PIC/S Committee and PIC/S Executive Bureau meetings took place in Geneva, Switzerland.

The Danish Medicines Agency recently met with representatives from the Japanese Ministry of Health, Labour and Welfare (MHLW), and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) in Copenhagen.

The European Medicines Agency (EMA) and the Netherlands have finalised the text of a Seat Agreement which describes how the Agency, its bodies and its employees will be treated by the Dutch once they start operating in the Netherlands.

On Tuesday, 27/4/2018, MHRA (Medicines and Healthcare products Regulatory Agency) published is five-year Corporate Plan for 2018 - 2023.

On 30 April 2018, the EMA published the final, revised version of the Q&A document with its focus on setting health-based exposure limits for risk identification and the risk-based prevention of cross-contamination. The Q&A covers 13 questions and answers relating to the “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”, which has been in force since June 2015.

In January 2017, the EMA released a draft for public consultation (we reported). But this paper constituted a roll backwards!

In July 2016, the Pharmaceuticals and Medical Devices Agency (PMDA) established the Innovative Manufacturing Technology Working Group (IMT-WG) as part of the “Projects Across Multi-Offices” in PMDA. The IMT-WG launched activities to examine desirable regulations that streamline the introduction of new manufacturing technologies, and selected continuous manufacturing as their primary target.

Almost one year ago, the ICH published its Guideline for Residual Solvents in the version ICH Q3C (R6) introducing new PDE-Levels for Triethylamine and Methylisobutylketone.

The FDA (US Food and Drug Administration) finalised the ICH Q7 Q&A Guidance on GMPs for APIs on Thursday April 19, 2018.

With an increasing globalisation of medicine manufacturing and supply chains, regulatory authorities across the world consider themselves responsible to cooperate in the overall interest of public health. Pharmaceutical companies that are outsourcing their production of APIs to contract manufacturers located in other countries have led to an increased need for inspections, to ensure adequate oversight of these facilities

The WHO has released three interesting documents on its website for public comments:

• A 4-page inquiry regarding production of “Water for Injection” (March 2018)
• A 20-page draft on GMP for HVAC systems for non-sterile pharmaceutical dosage forms: Part 2; Interpretation of Part 1 – GMP for HVAC systems (February 2018)
• An 11-page draft on Validation Appendix 6, Guidelines on Qualification 

On 3 April 2018, the EMA has published a 4-page public consultation document concerning the European Union template for GMP non-compliant statement. The GMP/GDP Inspectors Working Group is currently discussing possible actions required if inspections conclude with serious GMP non-compliance when at the same time this conclusion would block the availability of life-saving medicines. “What happens when?” is the question that EMA is now putting up for public discussion.

At the International Conference on Medical Device Standards and Regulations in Arlington VA, hosted by the AAMI (Association for Advancement of Medical Instrumentation), experts discussed the upcoming regulatory changes occurring with the new European regulations on medical devices (MDs) and in vitro diagnostics (IVDs). They urged the companies to prepare for these changes because it is likely that the medical device industry needs to invest a lot of time and resources to prepare for and comply with the upcoming requirements when it comes to trading goods with the European industry or manufacturing in the EU.

The German BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte) published a statement about counterfeit CellCept® 500 mg film-coated tablets on March 14, 2018. The medicinal product which is manufactured by Roche Reg. Ltd., is used to avoid rejection reactions after transplantations.

The European Medicines Agency (EMA) discussed the following points at its 15 March meeting in London:

Two years after the release of a draft data integrity document, the British MHRA published the final version of its GxP data integrity guide on March 9, 2018. Data integrity (DI) is important throughout the pharmaceutical lifecycle.

The US Food and Drug Administration (FDA) released two warning letters sent to over-the-counter (OTC) drugmakers in China and Hong Kong and a third one to a drug manufacturer in the USA. In addition, two Form 483s for India-based Sun Pharmaceutical Industries and Aurobindo Pharma were released.

While Theresa May promoted the benefits of the UK becoming an associate member of the EMA, the EU took quite an opposite position. In a draft guideline published on 7 March 2018 the EU sets out how the EU council sees its future with the UK. A comment by the British newspaper “The Guardian” states that while the British government does Brexit by speeches the EU prefers releasing documents.

On 1 March 2018, the FDA listed four additional recognised authorities under Article 7 of the Sectoral Annex for Pharmaceutical Good Manufacturing Practices (GMPs). This confirms the capability of the following four European Member States to carry out GMP inspections at a level equivalent to the US:

The MHRA has updated its interesting guidance on how to handle OOS results. The issue faced when dealing with “Out of Specification” results is always a challenge. Many customer requests we receive address this issue.

The European Medicines Agency EMA has published the adopted 2018 Work Plan for the GMP/GDP Inspectors Working Group. The 8-page document lists, inter alia, new guidance documents and also guidance documents to be revised within the EU GMP Guide. According to the EMA, the plan has been agreed in view of preparing for the relocation of the agency to Amsterdam and is, therefore, subject to further review and reprioritisation.

Following the Commission Report on Member State penalties for falsification (we reported) the European Commission has released a Questions and Answers document alongside this topic (Version 9) on 13 February 2018. The document addresses an overall of 90 frequently asked questions regarding the implementation of the rules on the safety features for medicinal products for human use. These rules are enshrined in Articles 47a, 54(o) and 54a of Directive 2001/83/EC, and in the Commission Delegated Regulation (EU) No 2016/161. They will become mandatory in February 2019.

The British MHRA (Medicines and Healthcare products Regulatory Agency) and the China Food and Drug Administration (CFDA) signed a Memorandum of Understanding (MoU) on 1 February 2018

The European Commission (EC) has published a report that takes a closer look at the implementation of the Falsified Medicines Directive 2011/62/EU in the European member states which

• introduces mandatory safety features on prescription medicines from February 2019 on
• strengthens good distribution practices and requirements for wholesale distributors
• reinforces rules on importation, controls and inspections of active substances and their manufacturers, and
• established an EU-wide logo to allow the identification of legal online retailers of medicines (as of 1 July 2015).

The European Medicines Agency released two updated documents for ATMPs (Advanced Therapy Medicinal Products) on 1 February 2018:

• Procedural Advice on the Evaluation of ATMPs
• Draft Guideline on Safety and Efficacy follow-up and Risk Management of Advanced Therapy Medicinal Products.

The MHRA (Medicines and Healthcare products Regulatory Agency, UK) has published an update on the negotiations between the EU and the UK which have now entered the second phase.

The European Medicines Agency (EMA) has launched a survey to gather information from companies on their Brexit preparedness plans and identify any particular concerns with regard to medicines supply that may impact public or animal health.

The U.S. Food and Drug Administration (FDA) published the yearly list of new and revised draft guidances, CDER is planning to release in 2018. A total of 98 planned guidance documents have been set out which are categorised in 18 different themes.

This week the US FDA (Food and Drug Administration) has already released five warning letters, all dealing with significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals and APIs. Following is a short summary of the various findings:

Swissmedic has announced that as of now, the foreign comparator product with a biosimilar for the main studies can also originate from the USA, while that for supplementary studies can now also originate from Canada.

The Economic Times of India has published an article saying that the Indian government has issued showcause notices to eight Chinese pharmaceutical companies. Those companies were inspected by a special Indian inspection team and were found to supply poor quality APIs to drug manufacturers in India.

On 20 December 2017 the European Commission has published the long awaited draft of Annex 1 “Manufacture of Sterile Medicinal Products”. The public consultation period is open from 20 December until 20 March 2018.

Three years after the publication of a concept paper Q12 “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management”, the ICH has now published the Step 2 draft document including an Annex with illustrative examples. The document was endorsed on 16 November 2017.

The EMA (European Medicines Agency) and the European Commission have published an updated version of the Q&A document which is intended to help the pharmaceutical industry to organise the UK’s withdrawal from the EU for their company.

On 24 November 2017, the European Medicines Agency has published a practical guidance document on post-Brexit Changes. The Practical Guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure comes in the form of nine questions and answers and outlines the practical and simplified requirements that companies should follow when they apply for changes to their marketing authorisation.

According to the Swiss Federal Office of Public Health FOPH, Switzerland is revising its medical devices legislation, closely modelled on the various new EU requirements aiming at an improvement on the safety and quality of medical devices.

On 24 November 2017, the European Commission has published the final version of the Guidelines on GMP specific to Advanced Therapy Medicinal Products. The term “Advanced Therapy Medicinal Products” (ATMPs)  is used to designate gene therapies, somatic cell therapies and tissue engineered products.

The city to host the new headquarter of the European Medicines Agency EMA is chosen. Amsterdam emerged as the winner ahead of Milan and Copenhagen, the two other cities that reached the second and final round.

A draft of the monography to Purified Water was published in the European Pharmacopoeia, which includes a new section on Elemental Impurities.

The German Federal Ministry of Health “Bundesministerium für Gesundheit, BMG” has published the official German translation of Annex 16: Certification by a Qualified Person and Batch Release, which is part of the EU GMP Eudralex Volume 4 GMP guidelines.

As of 1 November 2017, the Mutual Recognition Agreement (MRA) between the European Union and the United States enters the operational phase. The MRA, which will allow to recognise inspections of manufacturing sites for human medicines conducted in each partners’ respective territories shall update the agreement dating back to 1998.

On 16 October 2017, the EMA (European Medicines Agency) has published its 17-page Business Preparedness Plan to ensure continuity of the Agency’s operations once the United Kingdom is no longer a member country of the European Union.

The plan identifies three main priorities:

• Not to jeopardise EMA’s positioning in the pharmaceutical arena in the post-Brexit era.
• In parallel, to demonstrate its preparedness for addressing any emerging consequences by taking decisive and timely action when needed.
• To provide a balanced communication and full transparency, both internally and externally.

According to Swissmedic, the new Article 64a of the revised Therapeutic Products Act (revTPA) will already enter into force on 1 January 2018. This Article governs cross-border inspections and includes inspections carried out in Switzerland by foreign authorities, as well as inspections by Swiss authorities abroad.

Between 12 and 19 September 2017, authorities around the world targeted the illicit online sale of medicines and medical devices. More than 123 countries took part in Operation PANGEA X which led to a record number of 25 million illicit and counterfeit medicines seized worldwide.

The European Medicines Agency EMA has clarified its process for lifting a GMP non-compliance statement. The new process is outlined in an update to the question and answer document on GMP of the EMA.

On September 11, 2017, Michael Kopcha, Ph.D., R.Ph. and FDA’s director of the Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), announced the opening of a public docket to seek input from experts in areas of science, technology and best practices concerning “Continuous Manufacturing”. To establish common guiding principles to this new technology shall help to push this production method forward.

PIC/S: Three New Participating Authorities
Swissmedic: Combat Against Illegal Pharmaceuticals

The US Food and Drug Administration's (FDA) Center for Devices and Radiological Health (CDRH) published a whole new round of warning letters. They are addressed to three manufacturers from the US and five in Brazil, the Netherlands, Germany, China and Bulgaria.

According to the ICH (International Council for Harmonisation), the ICH Q11 Q&A reached Step 4 of the ICH process in August 2017. The document is now entering Step 5 – the implementation period.

The British Medicines and Healthcare products Regulatory Agency (MHRA) is dealing with the outcome of the EU referendum to move things into the right direction for the post-Brexit period.

The European Medicines Agency EMA, the European Commission and the US FDA have signed a new confidentiality commitment. It enables US and EU regulators to share non-public and commercially confidential information, including trade secret information relating to medicine inspections.

The European Medicines Agency (EMA) is responsible for the scientific evaluation, supervision and safety monitoring of medicines in the EU. The agency will need to be relocated in the context of the UK's withdrawal from the EU. There have been 19 offers to host the European Medicines Agency (EMA).

The government of India has published a draft document on the „Essential Principles for Safety and Performance of Medical Devices“, e.g. fundamental design and manufacturing requirements. It provides an overview on meeting these principles leaving flexibility to the manufacturers rather than dictating how a manufacturer should prove that the essentials laid down are being met.

According to the published 15-page document that summarises the negotiating results of the Economic Partnership Agreement between the EU and Japan, the MRA (Mutual Recognition Agreement) in the area of GMP will be expanded to new pharmaceutical products.

The WHO Expert Committee on Specifications for Pharmaceutical Preparations has recently published its 51st report (Technical Report Series No. 1003). The WHO Technical Report Series covers the findings of various international groups of experts that provide WHO with the latest scientific and technical advice on medical and public health subjects. TRS No. 1003 summarises the outcome of the Expert Committee Meeting of October 2016 in Geneva. In addition, the 252-page report contains all adopted guidances or draft guidances in the form of Appendices.

According to pharmabiz.com, India is planning to set up a joint pharmaceutical venture in the region of Chelyabinsk in Russia and is now seeking views and suggestions from its pharmaceutical industry. On July 17, a interactive meeting with government senior officials and industry leaders will take place.

As a result of the revised Swiss Therapeutic Products Act of March 2016, the relevant ordinances also need to be comprehensively adjusted. This affects ordinances issued both by the Federal Council and the Agency Council of Swissmedic and will last until October 2017.

The European Council has published a timetable for the relocation of the Euorpean Medicines Agency (EMA) that is currently based in London.

On June 28, 2017 the US FDA (Food and Drug Administration) published a revision of its draft guidance on medical gases entitled „Current Good Manufacturing Practice for Medical Gases Guidance for Industry“. This document is intended to supersede the guidance already issued in 2003.

The FDA has released a Q&A document on the 21 CFR Part 11 “Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers”.

According to ICH, the China Food and Drug Administration (CFDA) has been approved as a new Regulatory Member.

According to a press release by the BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte, the German Federal Institute for Drugs and Medical Devices), a counterfeit pack of Gilead Sciences’ hepatitis C drug Harvoni® has entered the legal supply chain in Germany. The “falsified medicinal product” was identified by a patient who noticed a change in colour which was orange instead of white.

Following a Notice to MAHs (Marketing Authorisation Holders) based in the UK the European Medicines Agency EMA and the European Commission have now released a Q&A document regarding the withdrawal of the UK from the European Union. It should help the pharmaceutical industry to prepare for the upcoming changes.

The China Food and Drug Administration (CFDA) released a detailed report on inspections conducted throughout the last year. A total of 431 inspections including pre-approval inspections, GMP certification inspections, GMP follow-up inspections, unannounced inspections, overseas inspections, GSP unannounced inspection and inspection observations are analysed therein.

According to the Swiss Therapeutic Products Agency Swissmedic, the agency achieved its objectives last year. Regulatory approval was granted for more than 40 innovative medicinal products partially due to a fast-track procedure.

In collaboration with APEC (Asia Pacific Economic Cooperation), the US FDA has created a Supply Chain Security Toolkit for Medicinal Products. The intention behind this new tool is to maximize available global resources and to deliver quality trainings and best practices in order to secure the global supply chain. It covers the entire supply chain and lifecycle from raw materials to use by patients.

On May 11, 2017 the US FDA issued a warning letter to Jintan Qianyao Pharmaceutical Raw Material Factory in Changzhou, China, for significant deviations from cGMP for APIs. The findings can be summarized as a complete lack of written procedures, quality-related procedures or an overall quality system.

In January 2017, the FDA issued the long-awaited Biosimilar Interchangeability Guidance for public consultation. In this guidance, the Agency details its expectations for demonstrating biosimilar interchangeability.

The deadline for commenting the draft guidance ended on 19 May, with a number of 45 comments being received. Comments came from big pharmaceutical manufacturers like Pfizer, Boehringer Ingelheim, Sandoz, Johnson and Johnson or Genentech or from organisations, e.g the American Society of Clinical Oncology, the Academy of Managed Care Pharmacy, the Combination Products Coalitions or the Biosimilars Forum.

The GMDP Inspectorate of the British MHRA (Medicines & Healthcare products Regulatory Agency) has published its yearly report on inspection deficiency findings. This time the method of gathering the data has been improved, thus introducing new data trending.

The European Medicines Agency plans to clarify its role regarding drugs manufactured in the EU solely for the export market.

EMA officials met with delegates from European and African nations to discuss the issue in a recent workshop in Malta.

Following PIC/S strong criticism on the proposed stand-alone ATMP (Advanced Therapy Medicinal Product) GMP Guidelines of the European Commission (we reported), PIC/S has now published a second letter to the EC on its website.

Following the introduction of ICH Q8, Q9 and Q10, the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) launched a joint pilot program for the parallel assessment of applications containing Quality by Design (QbD) in 2011. To facilitate the exchange of information between the two agencies the program was laid down under US-EU Confidentiality Arrangements. Both agencies have now issued a report that addresses the outcome of the 5-year-program so far.

This month the FDA has updated its yearly list of the new and revised draft guidances CDER is planning to publish in 2017.

In July 2015, US FDA released a draft guidance on quality metrics. The intention behind the introduction of quality metrics was described as a measure to improve drug quality and to encourage the implementation of a modern, risk-based pharmaceutical quality assessment system. The document aroused a storm of criticism by the pharmaceutical industry and its organisations as soon as it appeared.

In 2017, the US FDA has already listed the impressing number of 73 Warning Letters on its website. One topic that emerges again and again is the violation of data integrity, with rising tendency. Remarkably often, those violations are found in China and India. This time, the following pharmaceutical manufacturers are involved:

Last week the EMA (European Medicines Agency) published a concept paper on the need for revision of note for guidance on quality of water for pharmaceutical use (H+V) which addresses the need to update and revise the guidance which originally went into effect on 1st June 2002.

During its February Meeting in Switzerland, which was attended by representatives of 37 of its regulatory authorities, the Pharmaceutical Inspection Co-operation Scheme (PIC/S) unveiled a new road map for the next two years.

Following a three-year-process, the United States (represented by the US FDA) and the European Union (represented by the European Commission) have now finally announced their agreement to mutually recognise each other's GMP inspections of pharmaceutical facilities.

This news summarizes the latest regulatory changes for medical devices in China and the newly issued five year-plan of the CFDA (China Food and Drug Administration).

The ICH (International Council for Harmonisation) has developed a training presentation on the ICH Q11 Q&A document Selection & Justification of Starting Materials. Therein the Expert Working Group gives answers to the following questions:

The European Medicines Agency (EMA) has just released a “Concept paper on developing a guideline on quality requirements of medicinal products containing a device component for delivery or use of the medicinal product”.

The ICH has now published the Meeting Minutes of the ICH Assembly meeting which was held in Osaka, Japan in November 2016. Following you will find the key points on guidance progress in the area of GMP and on new members and observers in brief:

The US Food and Drug Administration (FDA) already issued 7 Warning Letters in 2017, one of which went to Porton Biopharma Limited in Salisbury, United Kingdom. The UK-government owned manufacturer of biopharmaceutical products was inspected from March 7 to 18, 2016 and previously on January 12 to 23, 2015. Both inspections resulted in similar violations and a Form 483.

The following chapters of the PIC/S GMP Guide have been revised based on the equivalent chapters of the EU GMP Guide:

The US Food and Drug Administration released a 59-page final guidance on the CGMP requirements for combination products. The guidance describes and explains specific provisions from 21 CFR Part 4 (final rule on CGMP for combination products) that was released in 2013. A draft version of this document was issued in January 2015.

The U.S. Food and Drug Administration (FDA) published the yearly list of new and revised draft guidances, CDER is planning to publish in 2017. A total of 102 planned guidance documents have been set out.

The EMA has released a Q&A draft document with its focus on setting health-based exposure limits for risk identification and the risk-based prevention of cross-contamination. The draft covers 14 questions and answers relating to the “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”, which was published in November 2014 and has been in force since June 2015.

The US FDA (Food and Drug Administration) released a warning letter sent to Interquim S.A., Barcelona, Spain. The drug manufacturing facility was inspected in May 2016. It summarizes significant deviations from current GMP for active pharmaceutical ingredients (APIs).

The ICH Q11 Questions and Answers (Q&As) on the Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) regarding the selection and justification of starting materials, reached Step 2b of the ICH process and enters the consultation period.

The ICH Q3C(R6) Guideline “Impurities: Guideline for Residual Solvents” reached Step 4 of the ICH Process in November 2016 and now enters into the implementation period (Step 5).

On 22 November, 2016, the US Food and Drug Administration (FDA) finalized its long awaited Guidance on Contract Manufacturer Quality Agreements.

On 23 November 2016, the US Food and Drug Administration (FDA) released a Revision 1 of the draft guidance to Quality Metrics which was initially published in July 2015. The revision with the new title “Submission of Quality Metrics Data” came on short notice and is open for comments and suggestions until 24 January 2017.

On 5-10 November 2016, the International Council for Harmonisation (ICH) met in Osaka, Japan, for its assembly meeting and has now published a press release.

In October, the 15th round of negotiations for TTIP (Transatlantic Trade and Investment Partnership) took place in New York. The European Commission has now published a report, which covers inter alia the mutual recognition of US/EU-GMP-inspections.

According to RAPS, the CFDA (Chinese Food and Drug Administration) has released a draft guidance on drug data management practices. The paper is addressed to manufacturers, developers and distributors of pharmaceutical products and aims at an accurate, timely and traceable recording of data.

On 4 October 2016, EMA published an interesting Concept Paper on Good Manufacturing Practice and Marketing Authorisation Holders (MAH). The document aims at giving clarity and a better understanding as to what the responsibilities of MAHs actually are in their  totality, and what they mean at a practical level.

The European Directorate for the Quality of Medicines and Healthcare (EDQM) announced a new agreement with Japanese authorities. The intention is to share more information on the outcome of GMP inspections of manufacturing sites of active pharmaceutical ingredients (APIs) that are of interest to both Europe and Japan.

FDA’s Center for Drug Evaluation and Research (CDER) published a comprehensive Report on the Drug Safety Priorities 2015-2016: Initiatives and Innovation. It highlights the key safety priorities and details FDA’s mission for ensuring drug safety and the protection of public health.

The European Commission has published a revised Version 7 of its Question and Answers Document that sets out frequently asked questions on importation of active substances for medicinal products for human use. This document is continuously updated and further supplemented.

Almost one year ago, on 15 September 2015, the European Commission published a comprehensive draft version of Annex 17: Real Time Release Testing (we reported). The seven-page document was open for public consultation until December 2015. All in all 12 responses were received which have now been published on the Commission's website.

As previously announced, the International Council on Harmonization (ICH) has now published the additional two training modules to ICH Q3D Elemental Impurities on its website. The modules 8 (case studies) and 9 (FAQs) are part of a comprehensive training programme prepared by the ICH Implementation Working Group (our news of March 2016).

According to pharmabiz.com, the Indian Central Drug Standards Control Organization (CDSCO) is planning to recruit 500 more drug inspectors by the end of 2017. Up to now 147 inspectors have already been trained to enhance inspections of manufacturing units in line with current Good Manufacturing Practices (cGMP).

According to pharmabiz.com, the Indian Central Drug Standards Control Organization (CDSCO) is planning to recruit 500 more drug inspectors by the end of 2017. Up to now 147 inspectors have already been trained to enhance inspections of manufacturing units in line with current Good Manufacturing Practices (cGMP).

On 8 August 2016, the U.S. Food and Drug Administration (FDA) updated the list of new and revised draft guidances CDER is planning to publish until the end of this year.

EMA has added the topic of Data Integrity to its list of Q&As regarding the overall area of EU-GMP.

The EMA has just published a draft for a questions and answers paper on production of water for injections (WFI) by non-distillation methods. The Ph.Eur. monograph for WFI was revised to include, in addition to distillation, reverse osmosis (RO) coupled with suitable techniques, for the production of WFI.

From 4 to 8 July 2016, the MHRA hosted the following events in Manchester (UK): PIC/S Committee meeting, PIC/S Executive Bureau meeting, and PIC/S Annual Seminar.

The international hot topic of data integrity continues to develop. Eighteen months after releasing its GMP data integrity guidance, the MHRA (Medicines and Healthcare Products Regulatory Agency, UK) has now published a revision thereof. The draft document entitled GxP data integrity definitions and guidance for industrycomprises 14 pages and can be seen as the next phase of MHRA guidance.

WHO has recently issued a 21-page draft document “Guidelines on Validation” which covers the main principles of validation and qualification. The guidelines are not intended to be prescriptive in specific validation requirements but focus on the overall concept of validation. The principles may be considered useful in its application in the manufacture and control of starting materials and finished pharmaceutical products (FPPs) as well as other areas. Validation of specific processes and systems, e. g. sterile product manufacture, are beyond the scope of the guideline.

FDA has published an 11-page draft guidance on elemental impurities that provides recommendations regarding their control in human drug products marketed in the United States. The draft document is set up in consistence with ICH Q3D, published in August 2015 by the ICH (International Council for Harmonisation). The FDA draft guidance intends to help manufacturers to comply with ICH and United Pharmacopeial Convention (USP) standards.

The International Council for Harmonisation (ICH) met in Lisbon, Portugal in June 2016. Two new members were accepted and 14 new observers welcomed.

The FDA has issued a 10-page technical specifications document providing recommendations on the submission of data to support quality metrics as part of the process validation lifecycle and pharmaceutical quality system assessment. The guide serves as the technical reference for implementation of the draft FDA guidance “Request for Quality Metrics” that was published in July 2015 and can be seen as a supplement.

Almost one year after publishing the draft, the WHO has now issued the final version of the Guideline to “Good Data and Record Management Practices”. The document is part of the Technical Report Series No. 996, 2016 and is therein listed as Annex 5.

With the U.K. voting to leave the EU, the speculation about a new headquarter for the European Medicines Agency EMA have started. The London-based EMA approves medicines for all EU countries. With a full-time staff of around 750, it is the largest EU body in Britain.

According to the US FDA, two Indian manufacturing facilities have been added to the Red List of foreign firms that are now banned from shipping product to the US. Cheryl Laboratories, Mumbai, producing active pharmaceutical ingredients (APIs) and Phalanx Laboratories, Visakhapatnam, producing APIs and intermediates both refused FDA inspections without giving any comment.

On 7 June 2016, Maas & Peither-GMP Publishing received a SIPAward in Washington, DC, USA, at the 40th SIPA Annual Conference. The GMP MANUAL was nominated out of 228 applications in the special category "Best New Success Story" and was awarded 3rd place. The GMP MANUAL is the world’s largest GMP knowledge database for the pharmaceutical industry and impressed the jury with “Save Drugs through Better GMP Understanding”. Prizes in a total of 25 categories were awarded.

From May 30 to June 7, 2016, the Ninth Annual International Internet Week of Action took place. This global cooperative effort, led by INTERPOL, aims at fighting the unlawful sale and distribution of illegal and potentially counterfeit medical products on the internet. The operation involved regulatory authorities, custom agencies and law enforcement form more than 100 countries.

In April 2016, the Transatlantic Trade and Investment Partnership „TTIP” , negotiated between the EU and the US, was taken one step further. The 13th round of negotiations took place in New York. The European Commission has now published a detailed report on the three negotiated areas market access, regulatory cooperation and rules. Furthermore the EU has released a 7-page EU-proposal for an annex on medicinal products containing details for the pharmaceutical sector.

The WHO has revised its Technical Report Series, No. 961, 2011, Annex 5: Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. A draft has been published for public consultation.

The European Commission is about to adopt an amendment to the Mutual Recognition Agreement (MRA) with Switzerland. The amendment would cover the mutual recognition of GMP inspections in third countries as well as products manufactured outside Switzerland.

The European Medicines Agency (EMA) has finalized a guidance that covers process validation including process characterization and process verification in the manufacture of biotechnology-derived active substances. This document provides guidance on the data to be included in a regulatory submission to demonstrate that the manufacturing process is in a validated state.

Another Indian drug maker received a warning letter issued by the US FDA. Once more the hot topic is data integrity – a common feature nowadays.

Data manipulation and data integrity issues are topics that constantly appear in the press. In recent years, cGMP violations involving data integrity have been increasingly observed, especially in China and India. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy and quality of drugs. Following the MHRA and the WHO, that have both released draft documents on this subject in 2015, the US Food and Drug Administration (FDA) has now published a Draft Guidance on Data Integrity and Compliance with cGMP, as well.

The US Food and Drug Administration (FDA) approved a second biosimilar, Inflectra (infliximab-dyyb), biosimilar to Janssen Biotech’s arthritis treatment Remicade (infliximab). Inflectra, coming from Celltrion and Pfizer, is a monocional antibody biosimilar. The European Medicines Agency already approved Celltrion’s Remicade biosimilar in 2013. Other countries that already gave their approval are Canada, Japan and Korea.

Following the three final guidances on quality considerations, scientific considerations and Q&As about biosimilars, the FDA has now released a 15-page draft guidance for industry on Labeling for Biosimilar Products. The guidance provides an overview of FDA’s recommendations for biosimilar product labeling and is intended to assist industry in developing draft labeling for submission in proposed biosimilar product applications.

21 March 2016 marked the date on which Manufacturing Authorisation Holders (MAHs, also known as pharmaceutical product manufacturers) needed to be compliant with the “Guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use”. IPEC Europe has developed and published a 36-pages "How-to" documentto help explain how a company might perform a risk assessment to determine the appropriate GMPs necessary for each excipient they use in drug products.

On 9 March 2016, a meeting of the EU-China Working Group on Pharmaceuticals was held in Beijing. A delegation of the CFDA met with Andrzej Rys, Director of DG Sante of the European Commission and Guido Rasi, Executive Director of the EMA (European Medicines Agency).

The Central Drug Standard Control Organization CDSCO of India has published a new Guideline on Similar Biologic. The 58-pages document will replace the previous guidance issued in 2012. The new version is now open for discussion until April 30, 2016.

The European Commission has published a revised Version 6 of its Question and Answers Document that sets out frequently asked questions on importation of active substances for medicinal products for human use.

During its 154th Session, the Ph. Eur. Commission adopted a revision of its monograph for Water for Injections (0169). Up to now, the production of Water for Injections (WFI) had been limited to distillation only.

The revised Annex 1 on sterile and aseptic production of the EU GMP Guide is expected to appear this autumn. The draft will be discussed soon in the EMA IWG and the PIC/S. Afterwards it will proceed as an approved draft to public consultation. The document will be completely revised without being restricted to isolated improvements.

According to Andrew Hopkins, MHRA, the new ISO 14644:2015 will be given a 12-month period for implementation. This was explained during the introduction of the contents of the new Annex 1 at a conference in in Frankfurt.

The European Pharmacopoeia envisages the production of water for injections (WFI) in Europe as well with the aid of reverse osmosis. Susanne Keitel, EDQM, reported in Frankfurt that the decision is expected to be made this week.