Review of Developments in GMP and the Regulation of Medicines April 2022


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Vol27.2A April 2022
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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 MHRA, EU, USA and Australian regulatory authorities.


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


UK


MHRA

  • Pharmaceutical company fined for manufacturing defective medicine

  • Early Access to Medicines Scheme (EAMS) Consultation

  • Importing medicines into Northern Ireland

  • Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing

  • Nicotine containing electronic cigarettes and refill containers

  • Medicines: get scientific advice from MHRA


EU

  • PRIME enables earlier availability of life-changing medicines

  • EMA’s extended mandate

  • Q&A for marketing authorisation holders/applicants on nitrosamine impurities in human medicinal products

  • Applying for an Innovation Task Force

  • Briefing Meeting (ITF BM)

  • Advice to sponsors on managing the impact of the war in Ukraine on clinical trials

  • Q&A: Good clinical practice

  • Guidelines on good pharmacovigilance practices

  • Concept paper on the elaboration of guidance for the application of Article 34 of Regulation (EU) 2019/6

  • Online verification system for electronic certificates issued by EMA

  • Suspension of shipments

  • Ph. Eur. to launch survey for the use of total organic carbon (TOC) test as a replacement of oxidisable substances test in Water for injections

  • Update of application forms for Certificate of Suitability applications


USA

  • Pre-Launch activities importation requests (PLAIR)

  • Verification systems under the DSCSA for certain prescription drugs

  • Certain ophthalmic products: policy regarding compliance with 21 CFR Part 4


International


Australia


Therapeutic Goods Administration (TGA)

  • Regulation of products with tradition of use at the Food/Cosmetic-Medicine interfaces

  • Consultation: Repurposing of medicines

  • Unique Device Identification Webinar #7 - Global manufacturer UDI learnings


Products

  • Evusheld approved in UK to prevent COVID-19 in people whose immune response is poor

  • EMA starts rolling review of COVID-19 Vaccine HIPRA


Documents

  • Introductory guide CTIS for SMEs and Academia


Conferences

  • EDQM event "Quality requirements for nanomedicines


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK


MHRA

Pharmaceutical company fined for manufacturing defective medicine

Syri Ltd, a pharmaceutical manufacturer based in Ruislip, Hillingdon, London has been fined £51,000 and ordered to pay costs of £104,898 by Aylesbury Crown Court. Following an investigation by the MHRA and a prosecution brought by the Crown Prosecution Service (CPS), the company was convicted of supplying a medicinal product which was not of the nature or quality specified in a prescription. The investigation was prompted by a child suffering multiple seizures and their admission to hospital.  The child was prescribed magnesium glycerophosphate to help prevent seizures. However, the medicine made by the company contained just 12% of the strength specified in the prescription, which resulted in it failing to work effectively. MHRA was alerted to the issue following a report from Milton Keynes University Hospital. MHRA inspectors visited the site and found the methods used to manufacture the medicine and the checks in place to ensure appropriate standards were not met at the time the medicine was supplied. The medicine was made to a specific prescription (known as a special) for the child. The company has improved their quality assurance procedures to prevent a recurrence. 

The Crown prosecutor indicated that this was not an isolated mistake although the prosecution was only concerned with this one serious incident. Saying, “These types of prosecutions are thankfully rare, but this conviction and sentence should serve as a reminder for all pharmaceutical companies of the need for absolute care in providing essential medications to the public.” 

Early Access to Medicines Scheme (EAMS) Consultation

The UK Early Access to Medicines Scheme (EAMS) is one of the ways through which a patient with a life threatening or seriously debilitating condition can gain access to a medicine before it has gained approval from a medicines regulatory authority.

The MHRA launched a public consultation which closed on the 17th September 2021. Comments and views expressed from a variety of stakeholders from across the UK were broadly positive and there was support for amending the Human Medicines Regulations 2012 to introduce specific EAMS provisions. Therefore, based on feedback, MHRA has decided to lay a statutory instrument in early 2022. The statutory instrument will introduce the policy considered during the consultation and future guidance will be developed alongside the statutory instrument to provide the necessary interpretation and procedural support.

Importing medicines into Northern Ireland

This guidance is part of Brexit Business Guidance. Industry must notify the MHRA if they will not be using these flexibilities.

Marketing Authorisation Holders' submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing

This guidance was first published 18 December 2019 and was last updated 15 March 2022.

Marketing Authorisation Holders should review their manufacturing processes to identify and, if found, to mitigate the risk of nitrosamine impurities being present.

Nicotine containing electronic cigarettes and refill containers

MHRA has issues 3 guidances, (advice for consumers / GB presentation guidance / advice for retailers and producers) relating to these products.

Medicines:- get scientific advice from MHRA

Due to the pandemic, all scientific advice meetings will be teleconferences until further notice.

There is currently high demand for scientific advice and a need for MHRA to prioritise COVID-19 vaccines and therapeutic products. Lead times for non-COVID-19 related scientific advice may therefore be longer than usual. If you have any questions about this, please contact the scientific advice team [on this updated email address - scientific_advice@mhra.gov.uk] stating the proposed indications for your product, whether it is a chemical or biological medicine and your stage of development (i.e. Phase I, II, III or post marketing) and MHRA will advise you of the current lead time.



Europe


EMA

PRIME enables earlier availability of life-changing medicines

EMA’s Priority Medicines scheme (PRIME) has had a positive impact on the authorisation of new medicines that address patients’ unmet medical needs. The time to marketing authorisation was reduced for medicines that benefitted from PRIME support, giving patients earlier access to transformative treatments that can make a real difference to their health.

From March 2016 to June 2021, a total of 18 medicines that had PRIME support were approved in the European Union (EU). Among these, 10 received a conditional marketing authorisation (CMA) enabling them to access the market earlier and reach patients more quickly; seven are ATMPs, which have the potential to reshape the treatment of a wide range of conditions; and 16 concern rare diseases.

PRIME medicines represent significant progress in their therapeutic areas. They include innovative technologies such as CAR T-cells therapies, one-time curative gene therapies, treatments for rare cancers and a vaccine to protect against the Ebola virus.

Enhanced interaction with EU regulators through PRIME is particularly useful for developers of more complex products and for applications that rely on smaller datasets. This includes for example ATMPs and orphan diseases, which often present new scientific and regulatory challenges.

At the time of publication of the report, 98 medicines have been accepted into the scheme. This also includes the first academia-led development, an ATMP intended to treat relapsed or refractory acute lymphoblastic leukaemia in adults over 25 years old

EMA’s extended mandate

The regulation reinforcing EMA’s role in crisis preparedness and management of medicinal products and medical devices becomes applicable as of 1 March 2022. It puts some of the structures and processes established by EMA during the COVID 19 pandemic on a more permanent footing, while entrusting several new tasks to the Agency.

EMA is now responsible for monitoring medicine shortages that might lead to a crisis situation, as well as reporting shortages of critical medicines during a crisis. The Agency will also coordinate responses of EU / EEA countries to shortages of critical medical devices and in-vitro diagnostics in crisis situations, after an initial transition period up to 2 February 2023.

Over the next few weeks and months, EMA will set up a number of new bodies and formalise existing ones to manage the new tasks.

EMA is organising a workshop on 1 April 2022 to inform stakeholders of its extended mandate and explain the plans and timelines for its implementation, and to listen to stakeholders’ views and any concerns. The workshop will be broadcast live on EMA’s website.

Q&A for marketing authorisation holders/applicants on nitrosamine impurities in human medicinal products

EMA has updated this Q&A

Applying for an Innovation Task Force Briefing Meeting (ITF BM)

The innovation task force secretariat has issued this very useful guide and Q&A.

[This very clear guide / Q&A should prove extremely useful to prospective applicants.]

Advice to sponsors on managing the impact of the war in Ukraine on clinical trials

In view of the disruptions caused by the Russian invasion of Ukraine, the European Commission (EC), (EMA) and the Heads of Medicines Agencies (HMA) are issuing initial advice for sponsors on how to manage the conduct of clinical trials in this situation. The ongoing war in Ukraine may require sponsors to adjust the way clinical trials are run in this region, and sponsors may need advice on how to deal with the impact of protocol deviations and other consequences of the disruptions. Where applicable, sponsors are advised to use the experience gained during the COVID-19 pandemic and apply the approaches and flexibilities agreed in this context.

In the EU, clinical trials are authorised and supervised at national level. Sponsors are, therefore, advised to also check any available guidance at national level and to contact the relevant authorities in case of specific questions. Scientific advice on methodological aspects and the impact of using affected study results for regulatory purposes can be provided by EMA or the national competent authorities.

Q&A: Good clinical practice

EMA has updated the guidance it provides in forms of questions and answers (Q&As) on good clinical practice (GCP), as discussed and agreed by the GCP Inspectors Working Group.

Guidelines on good pharmacovigilance practices

A public consultation is launched for Addendum III of Module XVI on pregnancy prevention programmes and other pregnancy-specific risk minimisation measures. This new guidance defines the elements of a pregnancy prevention programme and provides for deciding when such programme is needed or other risk minimisation measures are considered appropriate to avoid adverse pregnancy outcomes due to use of medicines and to preserve health of both the mother and the child. See:-Concept paper on the elaboration of guidance for the application of Article 34 of Regulation (EU) 2019/6

Article 33(1)(b) of Regulation (EU) 2019/6 specifies that in case of a favourable assessment, the outcome of a competent authority’s assessment on an initial marketing authorisation application shall include the classification of a veterinary medicinal product in accordance with Article 34.14

Article 34 of Regulation (EU) 2019/6 sets out criteria according to which veterinary medicinal products shall be subject to a veterinary prescription. The article is structured in three paragraphs:-

  • In paragraph 1, the eight categories (a-h) of veterinary medicinal products that shall be classified as subject to veterinary prescription by the competent authority or the Commission, as applicable, are listed.

  • Paragraph 2 provides discretion to competent authorities to, notwithstanding paragraph 1, classify a veterinary medicinal product as subject to veterinary prescription if it is classified as a narcotic drug in accordance with national law or where special precautions are contained in the summary of product characteristics referred to in Article 35 of Regulation (EU) 2019/6.

  • Finally, paragraph 3, by way of derogation from paragraph 1, lists the seven, cumulative conditions (also known as ‘exemption criteria’) (a-g) to be fulfilled for a veterinary medicinal product falling within the scope of paragraph 1 before it may be classified as not subject to veterinary prescription, noting the exception for veterinary medicinal products referred to in points (a), (c), (e) and (h) of paragraph 1 which may never be classified as not subject to veterinary prescription.

Consideration of whether a product is subject to veterinary prescription or not is an important component of product assessment that merits detailed consideration. Any application of Article 34 to veterinary medicinal products authorised in accordance with Directive 2001/82/EC or Regulation (EC) No 726/2004 may have the potential to result in the reclassification of their prescription status in some cases

Online verification system for electronic certificates issued by EMA

Since March 2020, EMA only issues fully electronic PDF certificates for medicinal products.

Health authorities and interested parties, both within and outside of the European Union (EU), can verify the authenticity of an electronic certificate for a human or veterinary medicinal product issued by the EMA using the authenticity verification system.

The system verifies the authenticity of electronic certificates issued by EMA on behalf of the European Commission, under the World Health Organization certification scheme. It does not include site-specific GMP certificates


EDQM

Suspension of shipments

Due to the recent events in Ukraine, all carriers have suspended their activities in Belarus, Moldova, Russia and Ukraine until further notice.

Therefore, the EDQM can no longer proceed with any shipments for Reference Standards, Publications or Proficiency testing studies (PTS) to these countries.

Ph. Eur. to launch survey for the use of total organic carbon (TOC) test as a replacement of oxidisable substances test in Water for injections

The experts of the European Pharmacopoeia (Ph.Eur.) are considering replacing the test for oxidisable substances by the test for total organic carbon (TOC) in the Tests section of the “Sterilised water for injections” part of the monograph on Water for injections (0169).

The experts of the Ph.Eur. would like to gather information from manufacturers, before the official consultation phase, to make sure that the method and acceptance criteria envisaged in the discussions with partner pharmacopoeias would be appropriate and feasible for European manufacturers of sterilised water in containers. EDQM is asking industry stakeholders for support in gathering information on this subject.

Update of application forms for Certificate of Suitability applications

The forms for the submission of Certificate of Suitability to the European Pharmacopoeia monographs (CEP) applications (new applications, revisions and sister files) have been updated in order to facilitate their handling and the transfer of the collected data in the new IT tools implemented at the EDQM. The implementation date for the updated forms is 1 April 2022.



United States of America


The US Food and Drug Administration (USFDA)

Pre-Launch Activities Importation Requests (PLAIR)

This final guidance describes the FDA’s policy regarding requests for the importation of unapproved finished dosage form drug products by an applicant preparing the product for U.S. market launch based on anticipated approval of a pending new drug application (NDA) or abbreviated new drug application (ANDA).This guidance also applies to unapproved biologics licensing applications (BLAs) regulated by the Center for Drug Evaluation and Research (CDER), and unapproved combination products assigned to CDER (21 CFR part 3) for which NDA, ANDA, or BLA approval is anticipated. Moreover, this guidance describes the procedures for making requests for importation of unapproved finished dosage form drug products before final approval of the application and the factors that FDA will consider in granting such requests.

Verification systems under the DSCSA for certain prescription drugs

This revised draft guidance addresses the verification systems that manufacturers, repackagers, wholesale distributors, and dispensers must have in place to comply with the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the Drug Supply Chain Security Act (DSCSA). Specifically, this draft guidance covers the statutory verification system requirements that include the quarantine and investigation of a product determined to be suspect and the quarantine and disposition of a product determined to be illegitimate. It also addresses the requirement for notification to the FDA of a product that has been cleared by a manufacturer, repackager, wholesale distributor, or dispenser after a suspect product investigation because it is determined that the product is not an illegitimate product. Finally, this draft guidance addresses the requirement for responding to requests for verification and processing saleable returns.

Certain ophthalmic products: policy regarding compliance with 21 CFR Part 4

FDA is implementing this guidance without prior public comment because it has determined that prior public participation is not feasible or appropriate

FDA has determined that the language in § 200.50(c) indicating that eye cups, eye droppers, and ophthalmic dispensers are regulated as drugs when packaged with ophthalmic drugs is now obsolete, because these articles meet the “device” definition. Accordingly, an ophthalmic dispenser that meets the definition of device in section 201(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and that is packaged together with an ophthalmic drug is now regulated as a device constituent part and, as such, is subject to the requirements in part 4. Because the drug constituent part provides the primary mode of action of these combination products, generally FDA's Center for Drug Evaluation and Research (CDER) will have primary jurisdiction over these products.

This change impacts products subject to pending applications, approved products, and products marketed pursuant to section 505G of the FD&C Act without an approved application under section 505 of the FD&C Act (commonly referred to as over-the-counter monograph drugs).




International


Australia


Therapeutic Goods Administration (TGA)

Regulation of products with tradition of use at the Food/Cosmetic-Medicine interfaces

This presentation by Alex Stevenson of TGA gives a regulatory perspective on the Food-Medicine and Cosmetic-Medicine interfaces, including a description of the criteria and tools used to categorise products at the interface.

[This could prove useful to manufacturers of such products intending to supply the Australian market. MBH]

Consultation: Repurposing of medicines

The TGA has released a follow up consultation on 10 March 2022 that seeks input on how it might

  • Address commercial and intellectual property issues

  • Identify the best candidates for repurposing

  • Shortlist candidates; and

  • Approach and incentivise the market for repurposing a medicine.

The intention of this consultation is to inform the development of options for Government consideration, noting that that some options may have legislative, regulatory change or financial implications.

This consultation is for three weeks and closes on 1 April 2022.

Feedback received from this consultation will be used to shape options for Government consideration. It is likely that further consultation will be required to determine the final approach.

Unique Device Identification (UDI) Webinar #7 - Global manufacturer UDI learnings

This presentation on the current status of the work to establish the Australian UDI system, plus Q&As was made as a webinar on 22 March 2022 by Michelle Van Wijk, UDI Project Manager, TGA and Debbie Connors, Senior Director Regulatory Affairs, Smith+Nephew



Products


Evusheld approved in UK to prevent COVID-19 in people whose immune response is poor

A new medicine, Evusheld (tixagevimab / cilgavimab), has been authorised for COVID-19 prevention by the UK MHRA. Developed by AstraZeneca, Evusheld is a combination of two long-acting antibodies that works by binding to the spike protein on the outside of the SARS-CoV-2 virus, the virus that causes COVID-19. This in turn prevents the virus from attaching to and entering human cells.

For most people, the best way to prevent infection is vaccination. Evusheld has been approved for use in adults who are unlikely to mount an immune response from COVID-19 vaccination or for whom vaccination is not recommended.

There is not yet enough data to know how effective Evusheld is against Omicron or the duration of its effect against this variant, and the MHRA will work with the company to establish this.

EMA’s CHMP has also recommended granting a marketing authorisation for Evusheld

EMA starts rolling review of COVID-19 Vaccine HIPRA (PHH-1V)

EMA’s CHMP has started a rolling review of COVID-19 Vaccine HIPRA (also known as PHH-1V). This protein-based vaccine is being developed by HIPRA Human Health S.L.U. as a booster vaccine for adults who have already been fully vaccinated with a different COVID-19 vaccine. COVID-19 Vaccine HIPRA works by preparing the body to defend itself against COVID-19. It contains two versions of part of the spike protein (the receptor binding domain) which have been produced in the laboratory: one version corresponds to part of the spike protein of the alpha variant and the other corresponds to that of the beta variant. The vaccine also contains an adjuvant, a substance to help strengthen the immune responses to the vaccine.

When a person is given the vaccine, their immune system will identify the two proteins in the vaccine as foreign and produce natural defences — antibodies and T cells — against them.



Documents


Introductory guide CTIS for SMEs and Academia

The European Medicines Agency developed this training material to enhance public access to information on the Clinical Trial Information System (CTIS) Regulation (EU) No 536/2014 (the Clinical Trials Regulation or CT Regulation) was published in the EU Official Journal on 27 May 2014. From its application, it replaces the existing Clinical Trials Directive (CT Directive) and it becomes applicable across the EU/EECTIS is the single-entry portal for submitting clinical trials information in the EU. The system supports the day-to-day business processes of authorities and sponsors throughout the life- cycle of a Clinical Trial (CT). CTIS is intended for interventional clinical trials with human medicinal products including low-intervention clinical trials with adapted requirements. The main objective of Module 19 is to explain in a simple and summarised way all the relevant information for the sponsor workspace, focusing on SMEs, Academia and CROs.



Conferences


EDQM event "Quality requirements for nanomedicines

The COVID-19 pandemic and the emergence of mRNA vaccines highlighted the importance of nanoparticle formulations – especially lipid-based systems – used for nucleic acid-based APIs.

Seen as part of a broader trend, modern formulations using nanoparticle systems (e.g. liposomes) have long been the focus of pharmaceutical research. Consequently, attention is turning increasingly to issues surrounding the creation and implementation of standards for medicinal products using liposomes or other nanoparticle-based preparations.

The aim of this event is to identify any gaps and opportunities for standards concerning modern nanoparticle-based formulations, which can be filled by the European Pharmacopoeia (Ph.Eur.). The event is planned as an in-person event to be held at the EDQM premises in Strasbourg, France 7-8June 2022.




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.