Review of Developments in GMP and the Regulation of Medicines May 2021


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Vol 26-2B May 2021
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INTRODUCTION


During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the EU, USA & PIC/s regulatory authorities.

A significant number of product related issues are noted in relation to Covid-19.These relate largely to risk based decision making and include items from the EU, Australian TGA and the UK MHRA.


The topics covered in this edition of the “Update” include:



EU

  • GMP Guidance Q&A

  • Increase in vaccine manufacturing capacity and supply for COVID-19 vaccines from AstraZeneca, BioNTech/Pfizer and Moderna

  • Paediatric investigation plans (PIP) - rapid procedure for COVID-19 treatments and vaccines

  • Authenticity verification for electronic certificates

  • Certification of medicinal products

  • Nitrosamine Implementation Oversight Group (NIOG) - meeting with pharmaceutical industry

  • Nitrosamines update – Rifampicin medicines

  • Overview of comments received on 'Public guidance: Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation

  • Clinical Trials Information System reaches major milestone towards go-live and application of the Clinical Trial Regulation

  • Concept paper for the revision of the guideline on the summary of product characteristics for anthelmintics

  • Pharmeuropa 33.2

  • Update on the Ph. Eur. policy on elemental impurities – Monographs on substances for veterinary use only

  • Adoption of the revised Raman spectroscopy chapter


USA

  • Development of abbreviated new drug applications (ANDAs) during the COVID-19 pandemic – Q&A.

  • Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency


International


PIC/S

  • Revision of PIC/S GMP Guide (PE 009-15)


Products

  • AstraZeneca’s COVID-19 vaccine:

  • EMA finds possible link to very rare cases of unusual blood clots with low blood platelets

  • AstraZeneca’s COVID-19 vaccine: benefits and risks in context

  • Data gathering Astra Zeneca COVID 19 vaccine

  • UK MHRA issues new advice, concluding a possible link between COVID-19 Vaccine AstraZeneca and extremely rare, unlikely to occur blood clots

  • Australian Technical Advisory Group on Immunisation (ATAGI) advice on the AstraZeneca COVID-19 vaccine in response to new vaccine safety concerns

  • Increase in vaccine manufacturing capacity and supply for COVID-19 vaccines from BioNTech/Pfizer and Moderna

  • EMA and ECDC join forces for enhanced post-marketing monitoring of COVID-19 vaccines in Europe

  • COVID-19 Vaccine Janssen: assessment of very rare cases of unusual blood clots with low platelets continues

  • EMA starts review of VIR-7831 for treating patients with COVID-19

  • EMA starts evaluating use of Olumiant in hospitalised COVID-19 patients requiring supplemental oxygen


Documents

  • SME Office Newsletter

  • Human Medicines highlights


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe


EMA

GMP Guidance Q&A

The Q&A has been updated to include a new section on GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs.

A GMP certificate is not required for manufacturing and testing sites of starting materials for ATMPs. For certain starting materials of biological origin, (such as e.g. linear DNA used as template for ex vivo transcription into mRNA, plasmids to generate viral vectors and/or mRNA, and vectors) used to transfer genetic material for the manufacturing of ATMPs it is, however, mandatory that the principles of GMP are complied with.

This new Q&A document doesn’t set new GMP requirements but it gives guidance on what principles of GMP mean and how to implement them. To this end, a methodology is described to identify minimal requirements in the fields of quality management system, risk management product development, production and quality control to define the principles of GMP applicable to the relevant starting materials. The Q&As cover:-

  • How are starting materials for ATMPs defined?

  • What does ‘principles of GMP’ mean?

  • When does principles of GMP apply to starting materials used for the manufacturing of ATMPs?

Increase in vaccine manufacturing capacity and supply for COVID-19 vaccines from AstraZeneca, BioNTech/Pfizer and Moderna

EMA’s human medicines committee CHMP has adopted several important recommendations that will increase manufacturing capacity and supply of COVID-19 vaccines in the EU.

  • A new manufacturing site has been approved for the production of AstraZeneca’s COVID-19 vaccine active substance. The Halix site is located in Leiden, the Netherlands, and will bring the total number of manufacturing sites licensed for the production of the active substance of the vaccine to four.

  • A new site has also been approved for the production of Comirnaty, the COVID-19 vaccine developed by BioNTech and Pfizer. The facility, which is in the German city of Marburg, will produce both active substance and the finished product. There are currently three active substance manufacturing sites supplying the EU included in the marketing authorisation. In addition to the new manufacturing facility for this vaccine, the CHMP has also given a positive opinion to allow transportation and storage of vials of this vaccine at temperatures between -25 to -15˚C (i.e. the temperature of standard pharmaceutical freezers) for a one-off period of two weeks. This is an alternative to the long-term storage of the vials at a temperature between -90 to -60˚C in special freezers. It is expected to facilitate the rapid roll-out and distribution of the vaccine in the EU by reducing the need for ultra-low temperature cold storage conditions throughout the supply chain.

  • The CHMP has also recommended approving the addition of a new manufacturing site for the production of active substance and finished product intermediates for Moderna’s COVID-19 vaccine. The addition of the new manufacturing lines at the Lonza facility, located in Visp, Switzerland, together with other changes to the manufacturing processes

As for any medicine in the EU, COVID-19 vaccines can only be manufactured in approved sites that are included in the marketing authorisation following regulatory assessment.

This requires that a manufacturer has a manufacturing licence from the national competent authority of the Member State in which the pharmaceutical manufacturing site is located to ensure that the production process complies with the standards of good manufacturing practice (GMP). National competent authorities carry out GMP inspections in coordination with EMA to check that manufacturers comply with EU standards, the conditions of their licence and the marketing authorisation if obtained.

In addition, the marketing authorisation needs to submit strong evidence to demonstrate that the site is capable of consistently producing high-quality vaccines according to agreed specifications.

Once the appropriate data are available, the company applies to add the new manufacturing site to the marketing authorisation. This is done via a variation application. EMA is ready to assess such requests rapidly.

Paediatric investigation plans (PIP) - rapid procedure for COVID-19 treatments and vaccines

EMA has updated its guidance to encourage applicants to use a specific template to submit a letter of intent ahead of their PIP application, providing EMA with key information about the product, its intended use in preventing or treating COVID-19 and timelines. This helps ensure that EMA is duly prepared to assess the application when it arrives:

Authenticity verification for electronic certificates

Health authorities outside the European Union (EU) and any interested party can verify the authenticity of an electronic certificate issued by the European Medicines Agency (EMA) using the authenticity verification system on this page. This confirms the marketing authorisation marketing authorisation status of a medicine and compliance of manufacturing sites with GMP.

Certification of medicinal products

EMA’s electronic system for issuing certificates permanently replaces the previous paper-based system, as part of EMA’s drive to digitalise procedures.

Nitrosamine Implementation Oversight Group (NIOG) - meeting with pharmaceutical industry

The Nitrosamine Implementation Oversight Group (NIOG) was set up by the European medicines regulatory network to oversee the harmonised implementation of the Article 5(3) CHMP opinion on nitrosamines in human medicinal products.

The NIOG will be the main interface between regulators and industry to agree on topics requiring further scientific discussion.

This is the first meeting of the NIOG with industry stakeholders. The aim is to explain the NIOG's mandate and operating methods, and to future interactions with industry on specific nitrosamine-related topics.

The agenda for the first meeting, presentations on the Means of operation & interaction plus the related workplan and topics for the QWP and SWP IP meeting can all be viewed on-line.

Nitrosamines update –

  • Rifampicin medicines The national competent authorities are asking marketing authorisation holders for rifampicin-containing medicines to test their medicines for the presence of nitrosamines before releasing them onto the market. This is a precautionary step to ensure patient safety while the investigation is ongoing. It is in line with the measures introduced by EMA's Article 5(3) review to limit the presence of nitrosamines in human medicines. The national competent authorities will carefully monitor responses to this request and take action if necessary. Rifampicin is a first-line treatment for tuberculosis. It is also used for treating several other serious infections, including blood infections and leprosy.

  • Risk evaluations The deadline has passed for submitting step 1 risk evaluations for medicines containing chemically synthesised active substances. Any marketing authorisation holder for such products that has not yet submitted a step 1 risk evaluation should do so as a matter of priority Marketing authorisation holders for medicines containing biological active substances should respect the step 1 submission deadline of 1 July 2021. The European medicines regulatory network is not currently considering any regulatory actions with regards to marketing authorisations or product distribution, but reminds marketing authorisation holders of their responsibility to ensure the quality, safety and efficacy of their medicines.

Overview of comments received on 'Public guidance: Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation

Article 58 of Regulation (EC) No 726/2004 provides that the European Medicines Agency (EMA) may give a scientific opinion for medicines intended to be used outside the European Union, primarily for low- and middle-income countries (LMICs). This work is done in cooperation with the World Health Organization, and with regulators and experts from third countries where the medicines are intended to be used. It is now called EU Medicines for All or EU-M4all. In addition to the EU-M4all procedure exclusively intended for third-country markets, the EMA is now offering the possibility to run the evaluation of centralised and EU-M4all applications in parallel, to obtain an EU-M4all Scientific Opinion and a Centralised Marketing Authorisation at about the same time. This initiative offers opportunities for work-saving and reduced duplication of efforts since most elements of the CHMP scientific advice and assessment for the centralised procedure and EU-M4all are the same. Seven Interested parties (organisations or individuals) commented on the draft document.

The Public Guidance document which was formally adopted on 13 April 2021.

Clinical Trials Information System reaches major milestone towards go-live and application of the Clinical Trial Regulation

EMA has confirmed that the clinical trial EU Portal and Database, one of the main deliverables of the Clinical Trial Regulation and the key component of the Clinical Trial Information System (CTIS), is now fully functional and on track to go live by 31 January 2022. The EMA Management Board confirmed that it has verified that the system meets the agreed requirements following an independent audit of this new IT system.

Concept paper for the revision of the guideline on the summary of product characteristics for anthelmintics

A concept paper proposing the revision of the existing guideline on the SPC for anthelmintics was already released by the CVMP for public consultation in 2017; however, due to the Agency’s relocation to Amsterdam, CVMP working parties had to discontinue their work. With the restart of work by CVMP working parties in 2020, and the new Regulation (EU) 2019/6 on veterinary medicinal products in force, more emphasis is now put on the need to limit the development of antiparasitic resistance. It is therefore proposed to extend the scope of the revision of the current guideline on the SPC for anthelmintics further, to also include other antiparasitic veterinary medicinal products.

The closing date for comments is 31 May 2021.


EDQM

Pharmeuropa 33.2

All new European Pharmacopoeia (Ph. Eur.) texts and texts that have undergone technical revisions are published in Pharmeuropa for public consultation. The deadline for comments on Pharmeuropa 33.2 is 30 June 2021.

Users and interested parties are welcome to comment on these drafts. It should be noted that:

  • although draft monographs must not be regarded as official standards, they will, once adopted by the Ph. Eur. Commission at a later date, become applicable and legally binding standards for the products concerned in all Ph. Eur. member states;

  • if general texts are not legally binding per se, they become mandatory when referred to in a monograph. Changes to general texts may therefore impact monographs.

Update on the Ph. Eur. policy on elemental impurities – Monographs on substances for veterinary use only

The European Pharmacopoeia (Ph.Eur.) has launched a public consultation on its proposal to delete the test for “heavy metals” (HMs), general chapter 2.4.8) in monographs on substances “for veterinary use only”. The 16 monographs concerned have been published in Pharmeuropa 33.2 together with other new texts and technical revisions of the Ph.Eur. The deadline for comments is 30 June 2021.

Adoption of the revised Raman spectroscopy chapter

The European Pharmacopoeia (Ph. Eur.) Commission adopted revised chapter 2.2.48 on Raman Spectroscopy.

Raman spectrometers are increasingly deployed in the pharmaceutical environment.

Technological developments in the field have prompted revision of the current chapter, focusing on aspects that enhance the reliability of the results, in particular if Raman spectroscopy is intended to be used as an alternative to IR spectroscopy for release.

The following modifications were made to the current chapter, as well as editorial improvements:

  • the section on the response-intensity scale has been updated;

  • a section on spectral resolution, using calcium carbonate, has been introduced.

  • procedures for the comparison of spectra have been described.

The attention of users has been drawn to the importance of aspects such as access to data, spectra in particular, and to any verifications, instrument settings and measurement parameters.

The revised chapter will be published in Ph. Eur. Supplement 10.7, available in October.



United States of America


The US Food and Drug Administration (USFDA)

Development of abbreviated new drug applications (ANDAs) during the COVID-19 pandemic – Q&A.

FDA is issuing this guidance to provide general recommendations to prospective applicants and applicants of abbreviated new drug applications (ANDAs) related to generic drug product development and regulatory submissions in the form of questions and answers that have been received and addressed by FDA during the COVID-19 public health emergency.

Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency

This guidance is being implemented without prior public comment because the Food and Drug Administration (FDA or Agency) has determined that prior public participation is not feasible or appropriate but it remains subject to comment in accordance with the Agency’s good guidance practices. FDA is issuing this guidance to describe how it will request and conduct voluntary remote interactive evaluations at facilities where drugs are manufactured, processed, packed, or held; facilities covered under FDA’s bioresearch monitoring (BIMO) program; and outsourcing facilities registered under section 503B of the FD&C Act for the duration of the COVID-19 public health emergency. This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19.


International


PIC/S


Revision of PIC/S GMP Guide (PE 009-15)

The PIC/S GMP for Medicinal Products has been revised to include a new Annex 2A and 2B:

  • Annex 2A: Manufacture of Advanced Therapy Medicinal Products for Human Use (ATMP); and

  • Annex 2B: Manufacture of Biological Medicinal Substances and Products for Human Use

Annex 2A provides PIC/S GMP requirements for ATMP - it is not a standalone document but it enables reasonable harmonisation with the standalone ATMP Guidelines published by the European Commission. Annex 2B had very minor revisions and continues to harmonise with the EU Annex 2 for human use biological medicinal substances and products.

The revised GMP Guide (PE 009-15), with the new Annex 2A and 2B, entered into force on 1 May 2021.


Products


AstraZeneca’s COVID-19 vaccine

  • EMA finds possible link to very rare cases of unusual blood clots with low blood platelets EMA confirms overall benefit-risk remains positive EMA’s safety committee (PRAC) has concluded today that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca). In reaching its conclusion, the committee took into consideration all currently available evidence, including the advice from an ad hoc expert group. EMA is reminding healthcare professionals and people receiving the vaccine to remain aware of the possibility of very rare cases of blood clots combined with low levels of blood platelets occurring within 2 weeks of vaccination. So far, most of the cases reported have occurred in women under 60 years of age within 2 weeks of vaccination. Based on the currently available evidence, specific risk factors have not been confirmed.

  • AstraZeneca’s COVID-19 vaccine: benefits and risks in context The EMA has published this report which states that the benefits of Vaxzevria outweigh its risks in adults of all age groups; however, very rare cases of blood clots with low blood platelets1 have occurred following vaccination. To support national authorities making decisions on how to best use the vaccine in their territories, EMA’s human medicines committee (CHMP) has further analysed available data to put the risk of these very rare blood clots in the context of the vaccine’s benefits for different age groups and different rates of infection. The analysis will inform national decisions on the roll out of the vaccine, taking into account the pandemic situation as it evolves and other factors, such as vaccine availability. The analysis could change as new data become available. The Committee also considered available data on the use of the second dose.

  • Data gathering Astra Zeneca COVID 19 vaccine The European Commission (EC) has formally written a letter to EMA requesting that a possible link between the AstraZeneca vaccine and very rare cases of unusual blood clots with low blood platelets. The Commission noted that while confirming that the overall benefit-risk of the vaccine remains positive, additional safety information has been included in the product information to inform about possible adverse effects. The EC noted that whilst most of the cases reported so far have occurred in women under 60 years of age within 2 weeks of vaccination, the evidence available at the time of the Agency recommendation did not allow to conclude on specific risk factors, such as age and gender at this stage. Stratified data on the rollout of the vaccines per age group and gender would be also needed from all Member States to complete the assessment. Against this background and with the aim to provide more specific recommendations to the Member States to guide their vaccinations programs, the EC requests the Agency on behalf of the Commission to carry out as a matter of great urgency a further analysis and stratification of data under Article 5(3) of Regulation (EC) 726/2004. This analysis should include vaccination data, and data on disease epidemiology including infection rates, hospitalisations, morbidity and mortality to better characterise the benefit and risk of the vaccine Vaxzevria in different age groups and/or gender as well as possible other risk factors that could be identified.

UK MHRA issues new advice, concluding a possible link between COVID-19 Vaccine AstraZeneca and extremely rare, unlikely to occur blood clots

The benefits of vaccination continue to outweigh any risks but the MHRA advises careful consideration be given to people who are at higher risk of specific types of blood clots because of their medical condition.

Australian Technical Advisory Group on Immunisation (ATAGI) advice on the AstraZeneca COVID-19 vaccine in response to new vaccine safety concerns

  • ATAGI notes further evidence of a rare but serious side effect involving thrombosis (clotting) with thrombocytopenia (low blood platelet count) following receipt of COVID-19 Vaccine AstraZeneca.

  • ATAGI recommends that the COVID-19 vaccine by Pfizer (Comirnaty) is preferred over COVID-19 Vaccine AstraZeneca in adults aged under 50 years. This recommendation is based on the increasing risk of severe outcomes from COVID-19 in older adults (and hence a higher benefit from vaccination) and a potentially increased risk of thrombosis with thrombocytopenia following AstraZeneca vaccine in those under 50 years.

  • COVID-19 Vaccine AstraZeneca can be used in adults aged under 50 years where the benefits clearly outweigh the risk for that individual and the person has made an informed decision based on an understanding of the risks and benefits.

  • People who have had the first dose of COVID-19 Vaccine AstraZeneca without any serious adverse effects can be given the second dose, including adults under 50 years.

Increase in vaccine manufacturing capacity and supply for COVID-19 vaccines from BioNTech/Pfizer and Moderna

EMA’s human medicines committee (CHMP) has adopted two important recommendations that will increase manufacturing capacity and supply of COVID-19 vaccines in the EU.

  • Scaled-up processes for BioNTech/Pfizer’s COVID-19 vaccine EMA has approved an increase in batch size and associated process scale up at Pfizer’s vaccine manufacturing site in Puurs, Belgium. The recommendation by the Agency’s Committee for Human Medicines (CHMP) is expected to have a significant impact on the supply of Comirnaty, the COVID-19 vaccine developed by BioNTech and Pfizer, in the European Union.

  • New filling manufacturing line for COVID-19 vaccine Moderna The CHMP also recommended the approval of a new filling line at Moderna’s finished product manufacturing site for the EU in Rovi, Spain. The new line will enable an increase in finished product fill activities, to synchronize with the active substance scale-up process approved last month at the Lonza Visp site. EMA is in continuous dialogue with all marketing authorisation holders of COVID-19 vaccines as they seek to expand their production capacity for the supply of vaccines in the EU. The Agency provides guidance and advice on the evidence required to support and expedite applications to add new sites or increase the capacity

COVID-19 Vaccine Janssen: assessment of very rare cases of unusual blood clots with low platelets continues

The US FDA and CDC recommended that the use of the vaccine should be paused while they review six reported cases in the United States. More than 6.8 million doses of the vaccine have been administered.

Janssen has announced their decision to proactively delay the rollout of the vaccine in the EU while investigations continue.

Following a thorough safety review, including two meetings of the CDC’s Advisory Committee on Immunization Practices, the U.S. Food and Drug Administration and the U.S. Centers for Disease Control and Prevention have determined that the recommended pause regarding the use of the Johnson & Johnson (Janssen) COVID-19 Vaccine in the U.S. should be lifted and use of the vaccine should resume.

EMA starts review of VIR-7831 for treating patients with COVID-19

EMA is reviewing currently available data on the use of the monoclonal antibody VIR-7831 (also known as GSK4182136) in the treatment of patients with COVID-19. EMA is starting this review to support national authorities who may decide on the use of this medicine for COVID-19 prior to marketing authorisation.

EMA starts evaluating use of Olumiant in hospitalised COVID-19 patients requiring supplemental oxygen

Olumiant is an immunosuppressant. It is currently authorised for use in adults with moderate to severe rheumatoid arthritis or atopic dermatitis (eczema). Its active substance, baricitinib, blocks the action of enzymes called Janus kinases that play an important role in immune processes that lead to inflammation. It is thought that this could also help reduce the inflammation and tissue damage associated with severe COVID-19 infection. EMA will communicate on the outcome of its evaluation, which is expected to reach an opinion by July unless supplementary information is needed.


Documents


SME Office Newsletter

EMA has published issue 52 of this newsletter, The newsletter provides information for small and medium sized enterprises. It is published four times a year and contains information on the EU regulatory environment for medicines.

Human Medicines highlights

This newsletter is addressed primarily to organisations representing patients, consumers and healthcare professionals. It provides a summary of key information relating to medicines for human use published during the previous month by the EMA


And finally…

Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.

We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.