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


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Vol 26-3C Sept 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 UK, EU. USA Australian PIC/s and ICMRA regulatory authorities.


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


UK


MHRA

  • Written Confirmations for export to EEA and Northern Ireland of Active Substances manufactured in Great Britain

  • Recall of contaminated Irbesartan- batches as precautionary measure

  • Batch of metformin oral solution recalled due to nitrosamine impurity

  • Consultation on proposed statutory instrument for the Early Access to Medicines Scheme


EU

  • Joint Audit Programme for EEA GMP inspectorates

  • Big Data Steering Group Workplan 2021-2023

  • Checklist for annual updates for parallel distribution

  • General principles EMA-FDA parallel scientific advice (PSA)

  • Ph Eur reference standards


USA

  • Development and submission of near infrared analytical procedures

  • Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an Abbreviated New Drug Application (ANDA)

  • Conduct of clinical trials of medical products during the COVID-19 public health emergency


International


Australia TGA

  • TGA presentations: Good Manufacturing Practice (GMP) Forum 2021

  • TGA business plan 2021-22

  • Regulation of borderline disinfectant and related products with antiviral claims including COVID-19

  • Advice on the use of tocilizumab (Actemra) intravenous vials post expiry date during the COVID-19 pandemic


International Coalition of Medicines Regulatory Authorities (ICMRA)

  • Recommendations on common technical denominators for traceability systems for medicines to allow for interoperability

PIC/S

  • Seminar on “GMP Assessment Approaches in Post COVID-19 Era"


Products

  • First monoclonal antibody treatment for COVID-19 approved for use in the UK

  • FDA grants full approval to Pfizer-BioNTech COVID vaccine

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


Documents

  • Report on the state of pharmaceutical quality: fiscal year 2020 (US FDA)


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


UK

MHRA

Written Confirmations for export to EEA and Northern Ireland of Active Substances manufactured in Great Britain

This document was updated on 3 Aug 2021

Recall of contaminated Irbesartan- batches as precautionary measure

The MHRA has issued a recall for 25 batches of Irbesartan-containing medicinal products due to contamination with an impurity that could potentially increase the risk of cancer over time. The recall is for pharmacies and wholesalers and is not a patient-level recall. The MHRA continues to work with the Department of Health and Social Care to ensure that an adequate supply of these products remains available for patients. Previous recalls of these types of products in 2018, 2019 and June 2021 are part of an ongoing investigation. The MHRA is working with other medicines regulators on this issue.

Batch of metformin oral solution recalled due to nitrosamine impurity

A recall notice for one batch (10,452 units) of metformin oral solution has been issued by the MHRA as a precautionary measure after it was found to contain a nitrosamine impurity above accepted levels.

The impurity, nitrosodimethylamine (NDMA), has been identified as a risk factor in the development of certain cancers.

At the very low levels that have been detected, nitrosamines only have a potentially harmful effect if consumed over a long period of time and to date there is no evidence that this impurity has caused any harm to patients. The Class 2 recall to wholesaler dealer and pharmacy level is precautionary to prevent further exposure.

Consultation on proposed statutory instrument for the Early Access to Medicines Scheme

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 the UK’s medicines regulatory authority. This consultation seeks views and comments on the proposed legislative changes to clarify the legal basis for EAMS.

The aim of this proposal is to ensure that EAMS remains an attractive option for patients, healthcare professionals and companies, so that cutting-edge therapies are available for patients where there is an unmet clinical need. MHRA aims to make the legal basis for EAMS supply clear and minimise the burden on those supplying EAMS medicines and for those companies wishing to collect real-world data during the scheme. This will be delivered whilst continuing to ensure the safety of EAMS products through pharmacovigilance (safety monitoring), maximising patient access and benefit.

The Government invites responses on the specific questions raised. This consultation will close on 17th September 2021.


Europe


EMA

Joint Audit Programme for EEA GMP inspectorates

This procedure describes how the Joint Audit Programme (JAP) and its audits are performed. This document covers the planning for audits and the audit process of competent authorities (CAs) in charge of the GMP compliance programme as detailed in the ‘Evaluation Guide for GMP Regulatory Compliance Programme - Audit Checklist’ (JAP Audit checklist) as well as the JAP Observed Inspection checklist

Big Data Steering Group Workplan 2021-2023

The 2021-2023 HMA-EMA joint Big Data Steering Group (BDSG) workplan was adopted on 18 June 2021. This document introduces each topic and outlines key deliverables. The plan was prepared based on BDSG mandate, the continuation of the activities launched in 2020-21 and the need to address new topics. The document is structured in line with the key recommendations of the Big Data Task Force. Information security and ethical data governance are at the core of the work of the BDSG.

Implementation of the actions in the BDSG workplan 2021-23 will need to be flexible given uncertainties on the resources that will need to be prioritised towards the regulatory response to the COVID-19 pandemic.

Checklist for annual updates for parallel distribution

EMA has recently updated this checklist and asks its applicants to use it in advance of submission of an annual update for parallel distribution. Applicants should be able to answer “Yes” to every item listed unless a specific point is not applicable (“n/a”) to the application in question. In order to improve the quality of submissions, it is recommended to include the completed checklist with the submission.

General principles EMA-FDA parallel scientific advice (PSA)

The goal of the PSA program is to provide a mechanism for EMA assessors and FDA reviewers to concurrently exchange with sponsors their views on scientific issues during the development phase of new medicinal products (i.e., new human drugs and biologics). Such interactions are expected to increase dialogue between the two agencies and sponsors from the beginning of the lifecycle of a new product, provide a deeper understanding of the bases of regulatory decisions, optimize product development, and avoid unnecessary testing replication or unnecessary diverse testing methodologies. The agencies conduct PSA procedures under the auspices of the confidentiality arrangement between the European Commission, the EMA, and FDA


EDQM

Ph Eur reference standards

The EDQM announces the availability of 6 new and 16 replacement batches for Ph.Eur. reference standards.



United States of America


The US Food and Drug Administration (USFDA)

Development and submission of near infrared analytical procedures

This final guidance provides recommendations to applicants to aid the development, validation, and use of near infrared (NIR)-based analytical procedures in evaluating the identity, strength, quality, purity, and potency of drug substances and drug products. The recommendations apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental NDAs and ANDAs for small molecule drugs. The principles in this guidance also apply to drug substances and drug products covered in Type II drug master files. FDA intends to issue recommendations specific to NIR methods used for biological products under biologics license applications in a future revision to this guidance.

Bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an Abbreviated New Drug Application (ANDA)

This draft guidance provides recommendations to applicants planning to include bioequivalence (BE) information in ANDAs and ANDA supplements. The guidance describes how to meet the BE requirements set forth in FDA regulations. The guidance is applicable to dosage forms intended for oral administration and to non-orally administered drug products in which reliance on systemic exposure measures is suitable for documenting BE. The guidance will be especially useful when planning BE studies intended to be conducted during the postapproval period for certain changes in an ANDA.

Conduct of clinical trials of medical products during the COVID-19 public health emergency

This guidance is being issued to address the Coronavirus Disease 2019 (COVID-19) public health emergency. This guidance is being implemented without prior public comment because the FDA has determined that prior public participation for this guidance is not feasible or appropriate. This guidance document is being implemented immediately, but it remains subject to comment in accordance with the Agency’s good guidance practices. FDA is issuing this guidance to provide general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity for the duration of the COVID-19 public health emergency. This document updates the guidance of the same title issued in January 2021 (previous versions December, September, July, June, May, April, and March 2020). The appendix to this guidance further explains those general considerations by providing answers to questions that the Agency has received about conducting clinical trials during the COVID-19 public health emergency.



International


Australia TGA


TGA presentations: Good Manufacturing Practice Forum 2021

TGA has published the 15 presentations from this May 2021 GMP Forum. These presentation papers are provided on the TGA's website solely for the purpose of indicating or suggesting what TGA representatives spoke about to the various conferences and seminars to which it relates. The papers are not legislative in nature and should not be taken to be statements of any law or policy in any way.

[Well worth a look if you didn’t attend the Forum in May or as a refresher if you did! MBH]

TGA business plan 2021-22

The TGA, as part of the Australian Government Department of Health, is responsible for enabling therapeutic goods available for supply in Australia to be safe and fit for their intended purpose. These include goods Australians rely on every day, such as analgesics and sunscreens, through to goods used to treat and prevent serious conditions, such as prescription medicines, vaccines, blood products and surgical implants.

The TGA Business Plan provides details on TGA’s key deliverables in relation to the regulation of therapeutic goods, and should be read in concert with TGA’s performance reporting.

Regulation of borderline disinfectant and related products with antiviral claims including COVID-19

This guidance has been published to assist sponsors and manufacturers of borderline disinfectants and related products that make antiviral claims. Such products often sit at the interface between consumer goods and therapeutic goods.

The COVID-19 pandemic has led to increased enquiries about the regulation of borderline disinfectant and related products with claims that the products can remove, kill or inhibit viruses (such as the virus that causes COVID-19).

Guidance is provided to assist sponsors and manufacturers of a range of borderline products to determine their regulatory obligations, with specific examples provided for clarity. The guidance explains the application of the therapeutic goods legislation for these products, and whether antiviral claims (including in relation to COVID-19) would require the product to be listed or included in the Australian Register of Therapeutic Goods (ARTG) to be legally imported and/or supplied in Australia.

Advice on the use of tocilizumab (Actemra) intravenous vials post expiry date during the COVID-19 pandemic

Due to the current shortages of tocilizumab (Actemra) and the current COVID-19 pandemic, the TGA is advising that it has assessed that tocilizumab vials continue to be stable for a further six months past their labelled expiry date.

Roche Products Pty Limited (Roche), the sponsor of tocilizumab (Actemra), has notified the TGA that the shortage of tocilizumab intravenous vials will continue until January 2022.

Some states and territories have advised TGA that they have tocilizumab vials which will soon expire. The approved shelf-life for tocilizumab vials is 30 months with storage conditions at 2°C to 8°C.

Due to the shortage, and considering tocilizumab is a lifesaving medicine in the treatment of conditions such as cytokine release syndrome (CRS) and the off-label treatment of hospitalised COVID-19 patients, TGA requested stability data from Roche to assist clinicians in making decisions about use of recently expired stock.

TGA assessed the additional stability data provided by Roche and based on this information, considers there is sufficient evidence to indicate tocilizumab intravenous vials are stable for up to a total of 36 months with storage conditions at 2°C to 8°C (i.e. 6 months post the expiry date of tocilizumab vials). There is no available stability data beyond 36 months. This advice is being given due to the COVID-19 situation and there will be no changes to the approved shelf-life of tocilizumab products included in the product information.

Given the additional stability information provided above, clinicians should consider the risks and benefits of treating patients when only expired tocilizumab vials are available.

[This looks like very sensible Risk based decision making from TGA. Could it also possiblyquickly lead to a formal more long-term change to the product’s shelf life after further evaluation? If not, why not? MBH]


International Coalition of Medicines Regulatory Authorities (ICMRA)

Recommendations on common technical denominators for traceability systems for medicines to allow for interoperability

Supply Chain Integrity has been identified as an ICMRA priority area, and the ICMRA work has focussed on alignment of existing and planned Track and Trace (T&T) systems for medicines, with a view to facilitating their interoperability as, to date, existing traceability systems for medicines have been designed with a national or regional focus only. ICMRA published a paper on this subject in 2017, which built on previous work carried out by the World Health Organisation (WHO). This paper was developed by regulators from ICMRA participating authorities. The 2017 document provided high-level recommendations on future interoperability of T&T systems, including some limited details on common technical features that traceability systems should present to enable interoperability. After publication, it was agreed that more detailed technical recommendations were needed to make a real impact, and that complementary expertise from the private sector was necessary, in addition to that of regulators. A joint regulators/industry working group was formed, which has developed the present paper. Regulators from ICMRA participating authorities could volunteer to be part of the group, while experts from the private sector were selected through a public call for expression of interest. Although the present document has been developed by the joint working group, final adoption was by ICMRA member regulatory authorities.

The EMA has endorsed these recommendations.

[it is always, in my opinion, good to see industry and regulators cooperating to develop such guidance. MBH]


PIC/S

Seminar on “GMP Assessment Approaches in Post COVID-19 Era"

The Ministry of Food and Drug Safety (MFDS) of the Republic of Korea will host the 2021 PIC/S Virtual Seminar from 9 to 11 November 2021.

The Seminar on “GMP Assessment Approaches in Post COVID-19 Era” will consist of presentations, interactive panel discussions, and workshops for GMP Inspectors from around the world.

As the COVID-19 pandemic has put restrictions on GMP on-site inspections, various alternative GMP assessment approaches have been taken by Regulatory Authorities to ensure the quality of pharmaceuticals. As we face the post COVID-19 era, there is a need to explore the current and future status of these GMP assessment approaches. There is also a need to be prepared for the changes that will likely be seen in post COVID-19. Therefore, in this Seminar, PIC/S looks forward to valuable presentations and discussions regarding different experiences in distant assessment from regulatory and industry experts; and regarding the status of GMP assessment based on reliance.

The Seminar is open to the participation of Inspectors from Medicines Regulatory Authorities around the world.


Products


First monoclonal antibody treatment for COVID-19 approved for use in the UK

MHRA has approved Ronapreve as the first monoclonal antibody combination product indicated for use in the prevention and treatment of acute COVID-19 infection for the UK.

Developed by Regeneron/Roche, the drug is administered either by injection or infusion and acts at the lining of the respiratory system where it binds tightly to the coronavirus and prevents it from gaining access to the cells of the respiratory system.

Ronapreve may be used to prevent infection, promote resolution of symptoms of acute COVID-19 infection and can reduce the likelihood of being admitted to hospital due to COVID-19.

FDA grants full approval to Pfizer-BioNTech COVID vaccine

FDA full approval of the Pfizer-BioNTech COVID-19 vaccine for people age 16 and older makes it the first coronavirus vaccine fully approved by the FDA.

In the U.S., more than 92 million have already received the shot, which will now be marketed as Comirnaty.

The vaccine has been authorized for emergency us in the USA since December 2020 for people age 16 and older. The authorization was later extended to those 12 and older.

Now with full approval for those 16 and up, the vaccine will continue to be available under emergency use authorization for individuals 12 through 15 years of age and for the administration of a 3rd dose in certain immunocompromised individuals.

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

EMA’s human medicines committee (CHMP) has adopted recommendations that will increase manufacturing capacity and supply of COVID-19 vaccines in the EU. These recommendations do not require a European Commission Decision and the sites can become operational immediately.


Documents


Report on the state of pharmaceutical quality: fiscal year 2020 (US FDA)

This report presents information on quality in the U.S. drug supply chain. Like the rest of the world, FDA and pharmaceutical industry were together forced to adapt in FY2020, due to the COVID-19 public health emergency, to assure quality medicines were available to the American public. his information is limited to FDA- registered human drug manufacturers and drugs regulated by CDER legally marketed in the U.S. Here FDA reports on the evolving global pharmaceutical landscape examining manufacturing site demographics, impacts of COVID-19, manufacturing site compliance, drug product demographics, drug product quality, and regulatory innovations. FDA provides information on, for example, inspectional classification out-comes, product performance, product testing results, and recalls. FDA uses the State of Pharmaceutical Quality, in part, to inform regulatory decision making and surveillance activities. This information is provided to the public so that all stakeholders can better understand the quality of the U.S. drug supply, an especially important consideration during a global public health emergency.



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.