Review of Developments in GMP and the Regulation of Medicines July 2020
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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 Australian EU, China, ICMRA UK, PIC/s, and USA regulatory authorities.
The topics covered in this edition of the “Update” include:
European Commission, EMA and FDA agree new priorities to strengthen their collaboration on medicines
Exchange of non public information on Health / Medical Products with Health Canada
Adoption of a new European Pharmacopoeia (PhEur) general chapter on Multivariate Statistical Process Control
The new approach to extraneous agent testing in immunological veterinary medicinal products (IVMPs) in the European Pharmacopoeia
COVID-19: What's new
EU actions to support availability of medicines during COVID-19 pandemic – update #7
Mandate of the European Innovation Network
European regulators make recommendations drawing on lessons learnt from presence of nitrosamines in sartan medicines
Academia developing medicines for rare diseases to receive free EMA scientific advice
MHRA and FDA Joint Paper 'Data Integrity in Global Clinical Trials'
GMP considerations for responding to COVID-19 infection in employees in drug and biological products manufacturing
Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency
Risk Evaluation and Mitigation Strategies: Modifications and Revisions
COVID-19 delays to adoption of TGO 91 labels
COVID-19 and eligibility to request consent to supply therapeutic goods that do not comply with the new labelling requirements of TGO 92
Notice - the implications of adopting the PIC/S Guide to GMP PE009-14
Country of origin and medicine quality
Newly Revised Provisions for the Supervision and Administration of Drug Production
Supporting the development of COVID-19 vaccines and treatments
Entry into Force of New PIC/S Guidance Documents (PI 052-1 and PI 053-1)
PIC/S virtual meetings
The value of safe and effective vaccines
Levothyroxine product - specific bioequivalence guidance (EU)
From laboratory to patient: the journey of a medicine assessed by EMA
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EC
European Commission, EMA and FDA agree new priorities to strengthen their collaboration on medicines
EC – (DG SANTE), EMA and the US FDA held their 2020 bilateral regulatory dialogue meeting on 18 and 19 June. During this virtual two-day meeting, the authorities reviewed their ongoing joint initiatives, discussed strategic priorities for the coming years and identified areas where their already close collaboration can be further strengthened.
In the context of the COVID-19 pandemic, the EC, EMA and FDA have further intensified their collaboration through regular interactions, notably under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA).
Other topics discussed included:
Facilitating the development, review and availability of COVID-19 vaccines.
Opportunities for cooperation on individualised / bespoke therapies for ultrarare diseases
Real world evidence use to support regulatory decisions: through ICMRA, EMA and FDA have agreed to collaborate on observational research in COVID-19 as a model, specifically on vaccines surveillance, building international cohorts, and the use of medicines in pregnant women with COVID-19. The parties agreed to collaborate on the development of a roadmap for international collaboration on real world evidence.
Following the July 2019 milestone of the full implementation of the Mutual Recognition Agreement (MRA) for certain human medicines, the partners discussed the next milestones. These include the expansion of the current MRA to veterinary medicines and the consideration to include vaccines and plasma-derived products by July 2022.
Orphan and paediatric medicines: information sharing on initiatives and discussion on possible cooperation in the area of data analysis for the characterisation of rare diseases.
Exchange of non public information on Health / Medical Products with Health Canada
This Working Arrangement between DG SANTE / EMA and Health Canada replaces the previously signed Confidentiality Agreement which was concluded 22 February 2013. Changes introduced in 2020 include references to personal data legislation and the permanent validity of the arrangement.
EDQM
Adoption of a new European Pharmacopoeia (Ph,Eur) general chapter on Multivariate Statistical Process Control
The European Pharmacopoeia (Ph. Eur.) Commission adopted a new chapter on Multivariate Statistical Process Control (5.28). The Ph. Eur. is the first pharmacopoeia to tackle this topic.
The Commission also adopted a revised version of chapter 5.25 on Process analytical technology, which has been updated to refer to the newly elaborated chapter 5.28.
Multivariate Statistical Process Control (MSPC) can be defined as the application of multivariate statistical techniques in order to analyse complex process data with potentially correlated variables. MSPC in combination with automated data collection and analysis may be used to generate control charts based on a multivariate (chemometric) model. These charts can then be used to control and improve manufacturing processes. In combination with a high degree of automation, MSPC may facilitate continuous manufacturing (CM), as well as real-time release testing (RTRT). It can be combined with process analytical technology (PAT), quality by design (QbD) and design of experiments (DoE), in line with relevant ICH guidelines.
This general chapter provides an introduction to the use of MSPC. The objective is to give guidance on good practices: it is intended to be for information only and will not become legally binding.
The new approach to extraneous agent testing in immunological veterinary medicinal products (IVMPs) in the European Pharmacopoeia
In June 2019, the European Pharmacopoeia Commission adopted the following texts:
The revision of the general monographs Vaccines for veterinary use (0062) and Immunosera for veterinary use (0030), the general chapters (5.2.5 Management of extraneous agents in IVMPs and 5.2.4 Cell cultures for the production of vaccines for veterinary use) and around 40 vaccine specific monographs
The addition of a new chapter 2.6.37 Principles for the detection of extraneous viruses in IVMPs using culture methods
and the deletions of chapters 2.6.24 Avian viral vaccines: tests for extraneous agents in seed lots and 2.6.25 Avian live virus vaccines: tests for extraneous agents in batches of finished product.
These changes came into force on the 1 July 2020.
EMA
COVID-19: What's new
The EMA including maintains an on-line informative listing of all relevant news and press releases (some of the latest of these are covered in greater detail elsewhere within this month’s Review).
EU actions to support availability of medicines during COVID-19 pandemic – update #7
In order to prepare for a potential second wave of coronavirus infections and to ensure that patients in Europe will have access to crucial medicines, the extended steering group continued to discuss how to improve the forecasting of future demand of medicines used in intensive care units (ICUs) and of other medicines and how to better match the estimated demand with the available supply.
The steering group agreed to further improve the collection of demand data, taking into account best practices at national level, and to subsequently share these data within the European Medicines Regulatory Network. For this purpose, it was decided that EMA will establish an ad hoc working group that will be tasked with the development of a common framework for collecting and sharing demand data in the EU/EEA, in view of a possible next wave of the current COVID-19 pandemic in the autumn. The ad hoc group on forecasting demand data in the EU/EEA will also determine which medicines will be included in this exercise, which might go beyond ICU medicines, and will define adequate metrics for data collection at EU level. The new group will comprise experts nominated by the NCAs and have a limited time duration.
Mandate of the European Innovation Network
Innovative medicines development projects emerge throughout Europe, especially from Small and Medium-Sized Enterprises (SMEs), hospitals and academia. The Innovation Task Force (ITF) of the European Medicines Agency (EMA) and innovation offices of National Competent Authorities (NCAs) play an important role in supporting innovation in an early phase of development by promoting awareness, dialogue and understanding of regulatory requirement. The objective of the EU Innovation Network is to facilitate the development of innovative medicines and technologies for drug development by addressing gaps in early regulatory support to innovation by:
Making the regulatory support available at national and EU level more visible and attractive to innovators since early stage;
Reinforcing dialogue with innovators with a wider EU exposure of identified issues;
Providing a platform for regulators to share good practices and multidisciplinary expertise and improve the flow of knowledge from early stage innovators (with their agreement) to NCAs and to EMA scientific committees;
Identifying and encouraging sponsors of promising drug development projects, including combination products, digital devices and therapeutics and advanced therapy medicinal products, to move into the next appropriate regulatory level for national and EU advice and evaluation;
Actively contributing to and integrating into relevant EU initiatives enabling innovative medicines development and access to patients.
European regulators make recommendations drawing on lessons learnt from presence of nitrosamines in sartan medicines
The European medicines regulatory network has issued recommendations on impurities in medicines following the conclusion of an exercise to draw on lessons learnt from the presence of nitrosamines in a class of blood pressure medicines known as sartans.
The recommendations aim to clarify the roles and responsibilities of companies involved in the manufacture of medicines and to amend guidance on controlling impurities and GMP. The recommendations also cover the management of impurities once detected, communication with patients and healthcare professionals, and international cooperation.
A copy of the report has been issued from the Heads of Medicines Agencies (HMA).
[The above report is likely to have far reaching GMP implications for MAHs and on future / revised GMP guidance MBH]
An overview of comments on the recommendations by seven stakeholder organisations has been published by EMA.
Academia developing medicines for rare diseases to receive free EMA scientific advice
To further encourage the development of treatments for rare diseases, EMA will waive all fees for scientific advice for academia developing orphan medicines. Early interaction with EU regulators is important for academia to understand the regulatory requirements and allow the generation of robust evidence needed to establish the medicines’ benefits and risks. This helps them to navigate the regulatory process and ultimately to translate their discoveries into authorised, patient-focused medicines.
UK
MHRA
MHRA and FDA joint paper 'data integrity in global clinical trials'
This blog indicates that following on from an event in Washington DC in October 2018 MHRA GCP Inspectors and US FDA have produced a joint paper ‘Data Integrity in global Clinical Trials’ authored by those who presented at the event.
Although UK and US legislation around clinical trials is different, the main principles of good clinical practice (GCP) which are the protection of the rights, safety and well-being of trial subjects and the production of credible data, are the same for both Regulators. If either Regulator had concerns with data reliability this could lead to rejection of data used in submission of a marketing application, but it can also pose significant subject safety risks. The paper, which is published in the Journal of Clinical Pharmacology and Therapeutics discusses both Agencies’ perspectives on how to ensure Data Integrity in clinical trials. Each section includes case studies where MHRA and FDA have raised concerns during GCP inspections.
United States of America
The US Food and Drug Administration (USFDA)
GMP considerations for responding to COVID-19 infection in employees in drug and biological products manufacturing
FDA is issuing this guidance to provide recommendations to drug and biological product manufacturers regarding:
Manufacturing controls to prevent contamination of drugs
Risk assessment of SARS-CoV-2 as it relates to drug safety or quality
Continuity of manufacturing operations
This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19 However, the recommendations described in the guidance are expected to assist the Agency more broadly in its continued efforts to assure the safety and quality of drugs and maintain the drug supply beyond the termination of COVID-19 public health emergency and reflect the Agency’s current thinking on this issue. Therefore, within 60 days following the termination of the public health emergency, FDA intends to revise and replace this guidance with any appropriate changes based on comments received on this guidance and the Agency’s experience with implementation.
Statistical considerations for clinical trials during the COVID-19 public health emergency
FDA is issuing this guidance to provide recommendations on statistical considerations to address the impact of COVID-19 on meeting trial objectives for clinical trials conducted during the duration of the COVID-19 public health emergency. The COVID-19 pandemic has impacted clinical development and ongoing clinical trials across investigational product areas. Public health measures to control the virus may impact the ability to collect data, for example, if trial participants are not able to visit clinical sites for endpoint assessments. The guidance outlines considerations for the statistical analysis of the primary and key secondary endpoints in a trial affected by COVID-19 to help ensure that the trial will provide interpretable findings with correct statistical quantification of uncertainty. This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19
Risk Evaluation and Mitigation Strategies: modifications and revisions
This final guidance provides information on how the FDA defines the types of changes to an approved risk evaluation and mitigation strategy (REMS), how application holders should submit changes to an approved REMS, and how the FDA will process submissions from application holders for changes to REMS. Specifically, this guidance provides information, as described in section 505-1(h) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), on what types of changes to REMS will be considered modifications of the REMS and what types of changes will be considered revisions of the REMS (changes that may be implemented following notification to the FDA).
International
Australia (TGA)
COVID-19 delays to adoption of TGO 91 labels
The transition period from TGO 69 to TGO 91 is due to expire on 1 September 2020. However, due to the pressures of COVID-19, some prescription medicine manufacturers are experiencing difficulty introducing TGO 91 assessed labels into their manufacturing process.
In response, the TGA have implemented a streamlined section 14 process. The new s14 process will provide a decision within 5 days of the application fee being paid and will be available to sponsors from 1 July 2020.
COVID-19 and eligibility to request consent to supply therapeutic goods that do not comply with the new labelling requirements of TGO 92
The COVID-19 pandemic has placed unprecedented pressures and challenges on the pharmaceutical industry, including difficulty in implementing the new medicine labels that comply with the new labelling orders (TGO 91/92) for medicines that come into force on 1 September 2020.
In recognition of these challenges, the TGA has established a temporary process for sponsors of listed, registered complementary, and over-the-counter (OTC) medicines to request consent to supply products that do not comply with TGO 92 due to adverse business impacts of COVID-19. The end date for this consent will be 6 March 2021.
Notice - the implications of adopting the PIC/S Guide to GMP PE009-14
This notice is being issued to assist with the transition period. It is a point-in-time document and TGA are not planning on updating this notice.
TGA will be updating GMP guidance during 2020 to reflect the new requirements.
Readers should particularly note in regard to Reporting deficiencies in Post Inspection Letters (PIL) During the transitional implementation period, TGA will be aiming to assist and encourage implementation of the new requirements. As a result, it will not cite a deficiency when companies demonstrate they are meeting the minimum expectations summarised below. TGA will report a deficiency if the company has not undertaken an appropriate approach to implementing the new requirements or may not achieve compliance in a timely manner. This will usually be cited as an ‘other’ deficiency against the relevant part of the PIC/S Guide to GMP. Major deficiencies will generally be cited only where a manufacturer has not commenced, or significantly progressed, action to implement the new PIC/S Guide to GMP requirements. A major deficiency may also be cited where a manufacturer’s implemented procedures and systems do not meet the requirements of the PIC/S Guide to GMP.
Country of origin and medicine quality
Some medicines make country of origin claims, however there is no requirement for a medicine to display the country of origin on the label.
The manufacture of medicines is often complex and can involve manufacturers in many different countries. For example, the active ingredient in a medicine might be manufactured in one country before the medicine is processed into the finished dosage form in a second country, packaged in a third, tested in a fourth, and then released for supply in a fifth. All of these activities are part of the manufacturing process. The manufacturer involved in any of these steps can also be different for different batches of the same medicine.
No matter how many manufacturers are involved or where they are located, all medicines supplied in Australia must demonstrate quality manufacture:
Australia-based manufacturers must be licensed by the TGA
manufacturing facilities located overseas must be approved by the TGA
manufacturing facilities must be regularly inspected by the TGA or, for some overseas facilities, a partner agency to confirm that standards are being met.
If a medicine has an AUST number on the label, it is regulated by the TGA and must meet the requirements above, regardless of its country of origin.
China
Newly Revised Provisions for the Supervision and Administration of Drug Production
The Provisions for the Supervision and Administration of Drug Production (SAMR Order No. 28, hereinafter referred to as the Production Provisions) will come into force on July 1, 2020. For better supervision of drug production, NMPA has made a number of announcements including:-
From July 1, 2020, applicants engaged in the production of preparations, APIs, and traditional Chinese medicines (TCM) slices should follow the relevant provisions of the Production Provisions while applying new for drug production licenses.
Applications for drug production licenses that have been accepted before July 1, 2020 but not yet approved afterwards shall be processed in accordance with the relevant provisions of the new Production Provisions.
The standards for on-site inspection and acceptance of production licenses shall comply with the relevant provisions of the Drug Administration Law of the People's Republic of China and its implementation regulations, and the relevant regulations of the Good Manufacturing Practice for Drugs. The scope of the Drug Manufacturing Certificate (License) shall specify the dosage form in the originals, and the workshop and production line in the copies.
Where the workshops or production lines involved in the entrusted production have not passed the compliance inspection of the Good Manufacturing Practice for Drugs drug production quality management standards (hereinafter referred to as GMP compliance inspection), the local provincial drug administration department should conduct a GMP compliance inspection.
International Coalition of Medicines Regulatory Authorities (ICMRA)
Supporting the development of COVID-19 vaccines and treatments
Medicine regulatory authorities worldwide are cooperating under the umbrella of ICMRA with the aim of expediting and streamlining the development of COVID-19 vaccines and treatments. ICMRA members have committed to strengthening global collaborative efforts in order to facilitate the rapid development, approval and global roll-out of safe and effective medicines to prevent and treat COVID-19. The efforts focus in particular on increasing the efficiency of regulatory processes and decision-making.
ICMRA is holding bi-weekly meetings to allow medicine regulatory authorities worldwide to discuss COVID-19-related policy approaches and regulatory flexibility, with the aim of expediting COVID-19 medicine and vaccine development and approval and avoiding medicine shortages. EMA and the FDA are taking turns in chairing the meetings.
PIC/S
Entry into Force of New PIC/S Guidance Documents (PI 052-1 and PI 053-1)
The following new PIC/S guidance documents have been successfully adopted:
PI 052-1 Aide-memoire - Inspection of Health Based Exposure Limit (HBEL) Assessments and Use in Quality Risk Management
PI 053-1 Questions and Answers on Implementation of Risk-based Prevention of Cross-contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities’
PIC/S virtual meetings
PIC/S virtual Seminar 2020
The Finnish Medicines Agency (FIMEA) will host virtually the 2020 PIC/S Seminar on “Distant Assessment of GMP Compliance" on 8-9 December 2020.
The Seminar is the main annual international training event by PIC/S which is open to GMP Inspectors from PIC/S Participating Authorities, (Pre-)Applicants, Partners and non-PIC/S Member Medicines Regulatory Authorities.
The Turkish Medicines and Medical Devices Agency (TMMDA) will host virtually by webinar the next PIC/S Expert Circle on Quality Risk Management (QRM) meeting on 24 September 2020.
For further detail on these two events which are open to regulators only,
Products
The value of safe and effective vaccines
In recent years, vaccination coverage has dropped to sometimes dangerously low levels in some countries, which increases the risk of the disease spreading and affecting the unvaccinated. International regulators from around the world ICMRA (an international coalition of 29 medicines regulatory authorities from every region in the world, with WHO as an observer.) have jointly developed two statements one for healthcare professionals and one for the general public to give assurance that the regulatory processes for the authorisation and safety monitoring of vaccines are robust, independent and focus firmly on public health. The two ICMRA statements aim to reassure healthcare professionals and the public around the globe that medicines regulators only allow vaccines onto the market that fulfil the highest standards of safety, efficacy and quality.
Levothyroxine product - specific bioequivalence guidance (EU)
This draft document for public consultation provides product-specific guidance on the demonstration of the bioequivalence of levothyroxine.(a critical dose drug)
Documents
From laboratory to patient: -the journey of a medicine assessed by EMA
This booklet covers medicines for human use that are authorised via EMA through the EU centralised procedure. It does not cover medicines authorised through national procedures (including the decentralised procedure and the mutual recognition procedure) by national medicines authorities in the EU Member States
[A useful and informative read MH]
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.