Review of Developments in GMP and the Regulation of Medicines October 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, UK, PIC/s and USA regulatory authorities.
The topics covered in this edition of the “Update” include:
How incidents with medicines are managed in the EU – a ten-year analysis
Big Data - HMA/EMA Big Data Steering Group
Q&A: Type II variations – veterinary
Q&A: Extension applications
Public consultation on the CEP of the future
EU Exit and Post Transition guidance webinar series
Blog - Investigations in the GMDP environment
ICH M7 Guideline: assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk- Q&A
Control of nitrosamine impurities in human drugs
Resuming Normal Drug and Biologics Manufacturing During the COVID-19 Public Health Emergency
Draft guidance - Geriatric information in human prescription drug and biological product labeling
Health Secretary Azar Asserts Authority Over F.D.A.
Failure to respond to an ANDA complete response letter within the regulatory timeframe
ANDA Submissions – Amendments and requests for final approval to tentatively approved ANDAS
New Early Scientific Advice service to support medicine registrations
Information for medicine advertisers: Additional allergen warnings effective 1 September 2020
Consultation: Compounded medicines and good manufacturing practice (GMP)
2020 PIC/S virtual Seminar
Update on the review by EDQM of the CEP application regarding an impurity in the active substance paracetamol.
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EMA
How incidents with medicines are managed in the EU – a ten-year analysis
EMA, in collaboration with the Heads of Medicines Agencies (HMA) and the European Commission, established the Incident Management Plan (EU-IMP) in 2009 to enable rapid and effective actions across the EU in case of an event or new information on medicines authorised in the EU with a potential serious impact on public health. Such incidents can affect the safety, quality, efficacy or availability of a medicinal product and causes may include the product’s safety profile, manufacturing compliance or supply chain issues.
When an incident is suspected, a group of experts from EMA and its scientific committees, the European Commission and the national competent authorities, called the Incident Review Network (IRN), convenes within the shortest possible time to assess the potential public health impact and recommend the appropriate regulatory pathway and the most appropriate communications.
During the first ten years of operation of the EU-IMP, a total of 78 incidents were managed through the IRN. Of these, 70% were triggered by information that came to EMA from national competent authorities, followed by information from marketing authorisation holders (17%).
During the observation period, more than half of the issues addressed concerned the safety of medicines, while quality and non-compliance with good manufacturing practices accounted for over one third of issues.
Regarding the final outcomes of the incidents managed through the IRN, almost half resulted in a variation to the marketing authorisation and/or risk minimisation measures of the concerned medicine. 22% led to no change to the marketing authorisation, 10% led to the suspension and 9% to the revocation of a medicine’s marketing authorisation.
[A reminder that we don’t always get it right. Continuous improvement and effective Quality Risk Management are essential in the pharmaceutical environment MBH]
Big Data - HMA/EMA Big Data Steering Group
The joint HMA/EMA Big Data Steering Group advises the EMA Management Board and HMA on prioritisation and planning of actions to implement the ten priority recommendations in the Big Data Task Force final report (phase 2).
The Steering Group began its work in May 2020. Its workplan sets out actions for delivery in 2020 and 2021
Q&A: Type II variations – veterinary
EMA has updated Q10 of this Q&A relating to “Which post opinion steps apply to my Type II variation and when can I implement the approved changes?”
Q&A: Extension applications
EMA has revised Q&A 5 “How shall my extension application be handled (timetable)?
Public consultation on the CEP of the future
The content and layout of the current Certificate of Suitability (CEP) remains very similar to the original created in 1992. The EDQM is aware of the far-reaching effects that globalisation, the rise of digital technology and many other major regulatory and scientific developments have had on the pharmaceutical industry and competent authorities over the last three decades and, in response, is launching a project to design the CEP of the future. The aim is to develop a “new-look” CEP that will better fit the emerging needs of stakeholders and offer both enhanced user-friendliness and greater transparency of the information conveyed without, however, increasing the administrative regulatory burden related to their revision.
The consultation will remain open until 31 December 2020 in the form of an online survey
UK
MHRA
EU Exit and Post Transition guidance webinar series
From 1 January 2021, the MHRA will be the UK’s standalone medicines and medical devices regulator.
Stakeholders need to get ready for new rules from 1 January 2021. The agency has now published guidance which will apply following the end of the transition period, from 1 January 2021, and which will be developed further in due course.
To help stakeholders understand the detail of the guidance and to ask any questions, the agency is running a series of free webinars covering many important topics.
Blog - Investigations in the GMDP environment
In this post, MHRA shares some common issues that the inspectorate often sees whilst out on inspection at companies of all sizes and of all operating models, so you can consider your own company’s systems and practices and improve investigation outcomes.
The concepts outlined in this post are equally applicable to deviations, customer complaints and several other Pharmaceutical Quality System (PQS) activities.
The strength of investigations, and the subcomponents that together make them effective, has been an ongoing area of challenge in deficiency data published by MHRA since 2010. The most recently published dataset from 2018 shows that roughly 10% of deficiencies raised in that period were directly attributable to poor investigations, though it is important to consider whether they could also be the root cause of other deficiencies too.
It is also worthy of note that some of those deficiencies have been classified by the inspector as Critical. When things do not go to plan or systems do not work as intended, a state of control is not maintained and the risk of product that is not of the right quality, efficacy or is not safe being produced increases. If such products reach the market this may have a significant impact on public health.
[Remember also that a perfect data set – particularly in contamination control / microbiological monitoring may mean that you are not looking hard enough! Don’t necessarily accept the status quo MBH]
United States of America
The US Food and Drug Administration (USFDA)
ICH M7 Guideline: assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk- Q&A
FDA has now formally published this Q&A as draft guidance for comment by 27 Nov.2020.
Since the ICH M7 Guideline was finalized, worldwide experience with implementation of the recommendations for DNA reactive (mutagenic) impurities has given rise to requests for clarification relating to the assessment and control of DNA reactive (mutagenic) impurities. This Question and Answer (Q&A) document is intended to provide additional clarification and to promote convergence and improve harmonization of the considerations for assessment and control of DNA reactive (mutagenic) impurities and of the information that should be provided during drug development, marketing authorization applications and/or Master Files. The scope of this Q&A document follows that of ICH M7.
Control of nitrosamine impurities in human drugs
This guidance is for immediate implementation and recommends steps manufacturers of APIs and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities. The recent unexpected finding of nitrosamine impurities, which are probable human carcinogens, in drugs such as angiotensin II receptor blockers (ARBs), ranitidine, nizatidine, and metformin, has made clear the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence.
Because the nitrosamine impurity issue extends beyond the U.S. drug supply, FDA and other regulatory authorities have partnered to share information, coordinate inspection efforts, communicate effective analytical methods to detect and identify various nitrosamines, and to develop rapid solutions to ensure the safety and quality of the drug supply.
Resuming Normal Drug and Biologics Manufacturing During the COVID-19 Public Health Emergency
FDA is issuing this guidance to help drug and biological product manufacturers during the COVID-19 public health emergency plan and prioritize CGMP activities as they transition from operations impacted by the public health emergency to normal manufacturing operations. This guidance describes how to evaluate and prioritize the remediation of CGMP activities that were necessarily delayed, reduced, or otherwise modified during the public health emergency in order to maintain production and the drug supply.
Except as noted in this guidance, this policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19
Draft guidance - Geriatric information in human prescription drug and biological product labeling
This draft guidance is intended to assist applicants of human prescription drug and biological products in determining the appropriate placement and content of geriatric information in labeling as described in the regulations for the content and format of labeling for human prescription drug and biological products. , The goal of this guidance is to provide recommendations to help ensure that appropriate information on the use of prescription drugs in geriatric patients is consistently placed in the proper sections and subsections within labeling so that the information is clear and accessible to health care practitioners and includes content that guides the safe and effective use in geriatric patients.
Submit Comments by 11/16/2020 identified with this document's docket number:. FDA-D-1621202 to ensure that the FDA considers your comment on a draft guidance before it begins work on the final version of the guidance,
[A sobering thought that under FDA’s age-based definition your author would be considered geriatric! MBH ]
Health Secretary Azar Asserts Authority Over FDA
According to The New York Times, “In a stunning declaration of authority, Alex M. Azar II, the secretary of health and human services, this week barred the nation’s health agencies, including the FDA, from signing any new rules regarding the nation’s foods, medicines, medical devices and other products, including vaccines.”
Failure to respond to an ANDA complete response letter within the regulatory timeframe
FDA has issued this draft guidance to assist applicants of abbreviated new drug applications (ANDAs), which were submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act, in responding to complete response letters (CRLs) from FDA. As described in regulation, ANDA applicants are required to take action after receiving a CRL. This guidance provides information and recommendations regarding potential courses of action for an ANDA applicant after issuance of a CRL, as well as the actions that FDA may take if the applicant fails to respond to that CRL.
FDA has seen a steady increase of ANDAs pending with industry for more than a year. Historically, FDA, in its discretion, has liberally granted requests for multiple extensions to respond to an individual CRL to the detriment of the ANDA assessment process. Lengthy response times because of multiple extensions, which can result in applicants submitting an amendment addressing deficiencies years after the initial assessment of the ANDA and issuance of the CRL, are disruptive to the assessment process and can create additional assessment cycles. Assessing an amendment submitted years after the initial ANDA assessment and issuance of the CRL diverts the Agency’s limited resources from the review of other applications.
FDA’s regulations provide that if an applicant wishes to continue pursuing approval of its ANDA, an applicant should submit all materials needed to fully address all deficiencies identified in the CRL within 1 year of issuance of the CRL. If an applicant wishes to continue to seek approval in this manner and determines it will be unable to address the deficiencies within 1 year of issuance of the CRL, the applicant should submit an amendment to its ANDA requesting an extension of time to address those deficiencies. The applicant should submit its request for an extension on or before the date the response to the CRL is due.
ANDA Submissions – Amendments and requests for final approval to tentatively approved ANDAS
This final guidance is intended to assist applicants in preparing and submitting amendments to tentatively approved abbreviated new drug applications (ANDAs), including requests for final approval. This guidance provides recommendations on the timing and content of amendments to tentatively approved ANDAs to facilitate submission in a timely fashion to enable final approval on the earliest date on which the ANDA may lawfully be approved based on patent and/or exclusivity protections
International
Australia
New Early Scientific Advice service to support medicine registrations
TGA has launched a new initiative - the Early Scientific Advice service - that enables applicants to request scientific advice on specific data before they apply to register a medicine.
In 2020, therapeutic goods legislation was changed to allow the TGA to provide scientific advice on higher risk medicines. Initially, this service will provide advice to applicants on 'biowaiver' justifications.
While there is a range of information on the TGA website to help companies understand what data is needed to show bioequivalence, the highly technical nature of these requirements means it may not always be clear whether specific data would support a biowaiver justification. Applicants may invest considerable time and resources into developing data that is not needed, or may leave out data that is needed. In either case, this may delay access to new medicines for consumers.
In these situations, the Early Scientific Advice service can help applicants to reduce their costs associated with developing their product.
Information for medicine advertisers: Additional allergen warnings effective 1 September 2020
TGA is reminding advertisers that additional mandatory health warnings for medicines containing specific allergens are required in certain advertising from 1 September 2020. The allergens, including tree nuts and tree nut products, are specified in Part of 4 of Schedule 1 of the Therapeutic Goods Advertising Code (No.2) 2018 (the Code).
Consultation: Compounded medicines and good manufacturing practice (GMP
TGA’s Manufacturing Quality Branch (MQB) regulates the manufacture of therapeutic goods, including goods that are extemporaneous compounded, dispensed, or repackaged. Following updates to the Manufacturing Principles in July 2020, and the receipt of feedback regarding opportunities for improvement, the MQB has produced a draft of updated guidance and has issued a draft consultation to seek input from stakeholders.
This draft guidance paper includes proposed enhancements to the interpretation of current GMP requirements specified in the PIC/S Guide to GMP, PE009, specifically in relation to:
The allocation of expiry dates for compounded goods.
Expiry dating of compounded goods manufactured from biological medicines, e.g. monoclonal antibodies.
The manufacture of non-sterile goods and re-packaged goods in dose administration aids (DAA)
The consultation closes on 18 Dec 2020.
PIC/S
2020 PIC/S virtual Seminar
The 2020 PIC/S Seminar on ”Remote Assessment of GMP Compliance” will be taking place on-line (virtually) on 8-10 December 2020, hosted by the Finnish Medicines Agency Fimea. More information will be available soon. This event will be restricted to regulators only
Products
Update on the review by EDQM of the CEP application regarding an impurity in the active substance paracetamol.
The EDQM has concluded its investigation following reports that paracetamol manufactured by a specific company holding a certificate of suitability could be contaminated with the impurity 4-chloroaniline (PCA).
PCA is a known impurity which may be formed under certain conditions during the manufacturing process of paracetamol, and which should be removed or limited by a suitable control strategy. The levels of PCA reported by the media are well below the Acceptable Intake (AI) of 34 μg/day defined in the addendum of the guideline ICH M7
Since the safety of paracetamol is not compromised, as the reported results did not show 4-chloroaniline to be above the internationally agreed acceptable limit, no action has been taken on the concerned certificate, which hence remains valid.
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.