News about GMP/cGMP

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 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.

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!

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

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.

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.

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.

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

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.