News about GMP/cGMP

On 27 July 2021, ICH published the anticipated draft of its Q13 Guideline on Continuous Manufacturing of Drug Substances & Drug Products. In Stage 2 of the ICH process the 44-page document has thus been released for public commentation.

The guideline is intended to provide "scientific and legal considerations for the design, implementation, operation and lifecycle management of continuous manufacturing (CM)".

As part of the annual budget planning acting FDA Commissioner Janet Woodcock has addressed the problem of weaknesses in the medical devices supply chain and its overall dependence on foreign medical devices.

PIC/S published a new guidance COVID-19 Risk Assessment for Routine On-Site Inspections” (PI 055-1) which entered into force on 15 July 2021.

The guidance is addressed to inspectors and covers the actions to be taken during the planning phase of an inspection, in consultation with the site to be inspected.

On 15 July 2021 the PIC/S recommendation document How to Evaluate and Demonstrate the Effectiveness of the Pharmaceutical Quality System with regard to Risk-Based Change Management (PI 054-1) came into force. The document provides practical guidance and covers all relevant steps in change management process – change proposal, change assessment, change planning and implementation, change review and effectiveness checks.

The European Commission announced on 14 July 2021, that the Italian company Kiwa Cermet Italia S.P.A. has been appointed as the 21st Notified Body under the EU Medical Devices Regulation (MDR) 2017/745. It has been assigned the number 0476 in the EC's Nando database.

After five years of drafting, PIC/S has now published the final version of a new guideline on data integrity, the PIC/S Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1). The document has already been applied in practice on a trial basis during this time and has been modified twice.

EMA has updated its Q&A document on drug-device combination products by end of June 2021. It includes the current requirements under the Medical Devices Regulation (MDR), which entered into force on 26 May 2021. Marketing authorisation holders of combination products are provided with detailed information on all current adjustments.

On 2 July 2021 the European Medicines Agency has released a revised version of the 17-pages Q&A to aid marketing authorisation holders to assess their risk for nitrosamine impurities. The revision affects questions 3 and 10:

• For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities? (Q&A 3)

• Which limits apply for nitrosamines in medicinal products? (Q&A 10).

The aborted negotiations between Switzerland and the EU on the institutional framework agreement (we reported) are casting their shadow: new regulations are needed to ensure the safe supply of medical devices within Switzerland. However, not only Swiss manufacturers are affected. Medical device manufacturers who are not domiciled in Switzerland but who place products on the market there must also mandate an authorized representative in Switzerland.

The Netherlands’ DEKRA Certification B.V. was named the fifth notified body under the Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) in June 2021. Dekra Certification B.V. is also a designated notified body under the MDR.

The European Commission published version 18B of the Q&A on safety features for medicinal products in late May 2021. In the 34-page document, question 1.14 "Are there mandatory specifications for tamper evidence?" was updated.

PIC/S has started the consultation process for the adoption of Annex 16 of the EU GMP Guide. It is a very important step towards international harmonisation of GMP requirements.

As every year, the EMA now publishes its report for 2020, in which it outlines achievements, decisions and objectives of the year.

In early June, the FDA unveiled the Generic Drug Cluster, the first forum for leading regulatory authorities to address the global development of generic drugs.

Once a year, operation PANGEA takes place, a globally organized action by Interpol against the online distribution of illegally imported medicines. Within this week of action, participating countries check (and close) suspicious websites and seize counterfeit medicines. In addition, this action aims to create public awareness of the issue.

The European Medicines Agency, EMA, has updated its regulatory and procedural guidance documents on parallel distribution as of 9 June 2021. 

The two facilities of the Italian company Steril Milano S.r.L. in Monza and Reggiolo have closed their doors since March 2021. The company, which offers a sterilization service for medical devices, is facing serious allegations of manipulation. In the meantime, Steril Milano S.r.L's certificate has been withdrawn by the responsible accreditation body.

The FDA has finalized two guidance documents to help ensure that prescription drugs are identified and traced properly while moving through the supply chain. The documents address how to comply with the DSCSA (Drug Supply Chain Security Act) requirements.

Finally the date has come: as of 26 May 2021 the EU rules on medical devices (EU MDR) entered into force. Following a one year postponement due to COVID-19, this regulation is considered a big step forward to improve the safety and quality of medical devices. There are, however, still plenty of uncertainties for their manufacturers, but there is also a saying that every journey begins with single steps.

The new European medical device regulation came into force on 26 May 2021. Parallel, a complete revision of the Medical Devices Regulation MepV was carried out in Switzerland, under the responsibility of the Swiss BAG (Federal Office of Public Health). In context of the alignment of the MepV and the KlinV-Mep with the new EU regulations MDR and IVDR on medical devices, it was also necessary to update the existing MRA (Mutual Recognition Agreement) between Switzerland and the EU. This agreement ensures barrier-free market access and joint implementation. The MRA is, in turn, part of an "overall package" of an institutional framework agreement (Insta), which has not yet been conclusively agreed on. On the contrary: Switzerland has meanwhile broken off negotiations with the EU and described them as "having failed".

On 18 May 2021, Swissmedic and the Federal Office of Consumer Protection and Food Safety (BVL) signed a first Memorandum of Understanding on cooperation in the area of veterinary medicinal products.

On 17 May 2021 the USFDA has released a revised version of its Q&A guidance on remote inspections. The 14-page document was originally published in August 2020 (we reported). As the pandemic still restricts most onsite inspections the FDA further clarifies general questions that came up since then.

The British MHRA has set up a standalone MHRA-GMDP database as a new service (alpha release). This step obviously separates the UK from the EudraGMDP where the competent EU authorities publish manufacturing and wholesale approvals, GMP certificates and non-compliance reports.

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. 

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.

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

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.