News about GMP/cGMP

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

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

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

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

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

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

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

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

A particularly noteworthy milestone is:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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:

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

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

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