Review of Developments in GMP and the Regulation of Medicines November 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 EU, UK, USA and PIC/S regulatory authorities.
The topics covered in this edition of the “Update” include:
Nitrosamine impurities – update
ICH guideline M7 Q&A - comments received
IRIS Guide -create and submit scientific applications, for industry and individual applicants
Qualification of novel methodologies for drug development:guidance to applicants
Veterinary pre-submission Q&A: 21-40
ICH guideline Q3D (R2) on elemental impuritiesStep 2b
EU Big Data Stakeholder Virtual Forum
EMA encourages companies to submit type I variations for 2020 by end of November
Launch of public consultation on the CEP of the future
New general text on implementation of pharmacopoeial procedures
Friability of uncoated tablets
New Rules from January 2021
The use of physiologically based pharmacokinetic analyses — biopharmaceutics applications for oral drug product development, manufacturing changes, and controls
Annual status report information and other submissions for postmarketing requirements and commitments: using forms FDA 3988 and FDA 3989 Guidance for Industry
Referencing Approved Drug Products in ANDA Submissions
Wholesale distributor verification requirement for saleable returned drug product and dispenser verification requirements when investigating a suspect or illegitimate product
International
PIC/S Seminar 2020
PIC/S Expert Circle on Quality Risk Management (QRM) webinar
First long-acting injectable antiretroviral therapy for HIV recommended for approval
First CAR-T cell medicine for mantle cell lymphoma
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EMA
Nitrosamine impurities – update
As of October 2020, EMA and the national competent authorities are asking marketing authorisation holders for metformin-containing medicines to test their medicines before releasing them onto the market.
This is a precautionary step to ensure patient safety while the investigation is ongoing.
EMA and the national competent authorities will carefully monitor responses to this request and take action if necessary.
Furthermore EMA and HMA have issued a new Implementation Plan from the Lessons learnt
ICH guideline M7 Q&A - comments received
Six Interested parties (organisations or individuals) commented on the draft document as released for consultation. The comments will be sent to the ICH M7(R2) Maintenance EWG/IWG for consideration in the context of Step 3 of the ICH process.
IRIS Guide -create and submit scientific applications, for industry and individual applicants
This guide has been produced to show applicants how to use the IRIS platform to prepare and submit an application for a scientific procedure (e.g. orphan designation application, scientific advice, or Inovation Task Force (ITF) briefing meeting request) and related activities. For Parallel Distribution procedures separate user access roles are needed and separate guidance is available on the IRIS home page.
Qualification of novel methodologies for drug development:- guidance to applicants
Revision 4 of this document relates mainly to the submission process i.e.to the requirement that Applicants should use EMA's secure online IRIS platform to apply for qualification from EMA.
Veterinary pre-submission Q&A: 21-40
This page lists questions 21 to 39 of the European Medicines Agency's Q&A on pre-submission guidance for veterinary medicinal products Q21- 21.8 relating to Active Substance Master File issues (ASMF) issues are all subject to revision.
The page is updated regularly to reflect new developments, to include guidance on further pre-authorisation procedures and to reflect the implementation of new European legislation. New or revised topics are marked as “New” or “Rev.” on publication.
ICH guideline Q3D (R2) on elemental impurities Step 2b
This document for public consultation is comprised of extracts of the Q3D(R2) Guideline with the revisions to the Q3D(R1) Guideline
Part 1 - Extract of Appendix 2: Correction of PDEs for Gold, Silver and Nickel
Part 2 - Extract of Appendix 3: Correction of Gold monograph
Part 3 - Extract of Appendix 3: Correction of Silver monograph
Part 4 - New Appendix 5
Comment is due by 25 December 2020
EU Big Data Stakeholder Virtual Forum
The objectives of this meeting are to:
Inform on implementation of the HMA-EMA Big Data Task Force priority recommendations.
Understand stakeholders’ perspectives.
Discuss opportunities for stakeholder collaboration and priorities.
Attendance will be organised through EU associations and by direct invitation. To enable a wide participation the Forum will be broadcast and a recording made public.
EMA encourages companies to submit type I variations for 2020 by end of November
EMA is advising MA holders to submit type IA and type IAIN variations for 2020 no later than Monday 30 November 2020. This will enable EMA to acknowledge the validity of the submissions before the Agency's closure between 24 December 2020 and 4 January 2021 and within the 30-day timeframe.
EDQM
Launch of public consultation on 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 EDQM wishes to gather general feedback from stakeholders in the industry and from National Competent Authorities worldwide on various aspects connected with the CEP, particularly its content, layout, format and use.
The consultation will remain open until 31 December 2020 in the form of an online survey. The responders are also given access to a “read only” version of the survey to help them prepare their answers in advance.
All the information provided will help shape the CEP of the future.
New general text on implementation of pharmacopoeial procedures
The European Pharmacopoeia (Ph.Eur.) is seeking feedback on its new general text on the implementation of pharmacopoeial procedures (5.26).
The draft text elaborates on the requirement expressed more succinctly in the Ph.Eur. General Notices, according to which “a user must assess whether and to what extent the suitability of the method [i.e. pharmacopoeial procedure] under the actual conditions of use needs to be demonstrated in compliance with relevant monographs, general chapters and quality systems”.
This new general text would represent a major addition to the Ph.Eur. as it provides more detailed information on one of the key processes underpinning correct use of Ph.Eur. monographs.
Friability of uncoated tablets
This draft corresponds to Revision1, Stage2, ver.1 (based on revised PDG working procedure) within the Pharmacopoeial harmonisation process (Ph.Eur., JP, USP). The coordinating pharmacopoeia is the USP. The original text submitted to the Pharmacopoeial Discussion Group is published in the Pharmacopoeial harmonisation section. Compared to the monograph published in the 10th Edition of the Ph.Eur., the following changes are proposed:–
Equipment: uniform presentation of the dimensional requirements for the apparatus.–
Procedure: clarification of the test criteria and other minor wording changes for clarity (e.g. specification in case of effervescent and chewable tablets)
UK
MHRA
New Rules from January 2021
The UK has left the EU, and the transition period after Brexit comes to an end this year.
From 1 January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) will be the UK’s standalone medicines and medical devices regulator.
Transition from the EU allows the UK to offer fully independent regulatory decisions for both devices and pharmaceuticals, both nationally and in joint work with other international regulators.
Stakeholders need to get ready for new rules from 1 January 2021.
The MHRA has published details of what you what you'll need to do from 1 January 2021. The information will be updated if anything changes.
Readers may also be interested to see comment on the changes from The Association of British Pharmaceutical Industries (ABPI)
[To help stakeholders understand the detail of the guidance and to ask any questions the MHRA, ran a series of free webinars covering several important topics during October MBH]
United States of America
The US Food and Drug Administration (USFDA)
The use of physiologically based pharmacokinetic analyses — biopharmaceutics applications for oral drug product development, manufacturing changes, and controls
This guidance provides general recommendations regarding the development, evaluation, and use of physiologically based pharmacokinetic (PBPK) analyses for biopharmaceutics applications employed by sponsors of investigational new drug applications, and applicants for new drug applications, or abbreviated new drug applications, and supplements to these applications, for oral drug product development, manufacturing changes, and controls. PBPK analyses use models and simulations that combine physiology, population, and drug substance and product characteristics to mechanistically describe the pharmacokinetic (PK) and/or pharmacodynamic behaviors of a drug product.
Although the pharmaceutical industry has in some cases been successful in developing in vitro/in vivo correlations (IVIVCs) to support biowaiver requests in lieu of in vivo BE studies for major manufacturing changes, development of an adequate IVIVC for regulatory submission remains challenging. FDA recognizes this challenge and encourages the development and use of new tools and approaches for linking pharmaceutical quality to clinical performance. Advances in modelling and simulation have enabled the integration of factors such as the physicochemical properties of the active pharmaceutical ingredient (API), dissolution data, and the physiology of the GI tract into the development of PBPK models. As such, PBPK modeling has become a promising tool in predicting systemic drug exposure and has been used for dose selection, food effect assessment, and drug interaction potential evaluation.
Annual status report information and other submissions for postmarketing requirements and commitments: using forms FDA 3988 and FDA 3989 Guidance for Industry
This guidance is intended for applicants that are required to report annually on the status of postmarketing studies and clinical trials for human drug and biological products under section 506B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356b) and its implementing regulations at 21 CFR 314.81(b)(2)(vii) and 601.70. In other words, this guidance is intended for applicants that are required by statute or regulation, or that have agreed in writing, to conduct postmarketing studies or clinical trials concerning a product’s clinical safety, clinical efficacy, clinical pharmacology, and nonclinical toxicology as postmarketing requirements (PMRs) or postmarketing commitments (PMCs). This guidance describes the purpose and content of Form FDA 3988, Transmittal of PMR/PMC Submissions for Drugs and Biologics, and Form FDA 3989, PMR/PMC Annual Status Report for Drugs and Biologics; when to use these forms; and how to submit these forms. Submission of completed Form FDA 3989 will meet the reporting requirements for postmarketing studies or clinical trials described in section 506B of the FD&C Act and its implementing regulations.
Referencing Approved Drug Products in ANDA Submissions
This guidance is intended to provide information to potential applicants on how to identify a reference listed drug (RLD), a reference standard, and the basis of submission in an abbreviated new drug application (ANDA) submission. A variety of factors has led to confusion among stakeholders on what the terms RLD, reference standard, and basis of submission mean, and how ANDA applicants should use them. These factors include the discontinued marketing of many approved drug products and FDA’s past practice of identifying reference standards with the RLD symbol (“+”) in the printed version, and with a “Yes” under the “RLD” column in the electronic version, of FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book).The purpose of this guidance is to address this confusion by explaining what these terms mean and by clarifying the differences among them. This guidance provides recommendations on how applicants can accurately use these terms in an ANDA, how persons can request FDA designation of an RLD, and how persons can request FDA selection of a reference standard. Because of the confusion regarding use of these terms up until now, previously issued CDER guidances may not use these terms as CDER is now clarifying them in this guidance.
Wholesale distributor verification requirement for saleable returned drug product and dispenser verification requirements when investigating a suspect or illegitimate product
On September 24, 2019, FDA published the Wholesale Distributor Verification Requirement for Saleable Returned Drug Product—Compliance Policy guidance (the 2019 Compliance Policy), where FDA announced a 1-year delay in enforcement of the requirement for wholesale distributors to verify saleable returned product as required under section 582(c)(4)(D) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The 2019 Compliance Policy explained that the Agency intended to delay enforcement of this requirement until November 27, 2020. This guidance announces FDA’s extension of such delay in enforcement. It also sets forth the Agency’s enforcement policy with respect to section 582(d)(4)(A)(ii)(II)and (d)(4)(B)(iii)of the FD&C Act (21 U.S.C. 360eee-1(d)(4)(A)(ii)(II)and (d)(4)(B)(iii)), which generally provide that, beginning November 27, 2020,a dispenser must verify the product identifier of suspect or illegitimate product in the dispenser’s possession or control. This guidance addresses the readiness of wholesale distributors to comply with the requirement to verify the product identifier upon receipt of a returned product that the wholesale distributor intends to further distribute under section 582(c)(4)(D) of the FD&C Act. The requirement under section 582(c)(4)(D) of the FD&C Act for wholesale distributors to verify saleable returned products prior to redistribution went into effect on November 27, 2019. FDA does not intend to take action against wholesale distributors who do not, prior to November 27, 2023, verify the product identifier prior to further distributing returned product as required under section 582(c)(4)(D) of the FD&C Act. This represents an additional 3-year delay from the delay set forth in the 2019 Compliance Policy in enforcement of the requirement for wholesale distributors to verify the product identifier prior to further distributing that returned product. This guidance also addresses the dispenser requirement in section 582(d)(4)(A)(ii)(II)of the FD&C Act. This provision, which is effective as of November 27, 2020, requires a dispenser to verify whether the product identifier of a suspect product, including the standardized numerical identifier, of at least 3 packages or 10 percent of such suspect product, whichever is greater, or all packages, if there are fewer than 3, corresponds with the product identifier assigned to such product by the manufacturer or repackager. Furthermore, this guidance addresses section 582(d)(4)(B)(iii) of the FD&C Act, which requires dispensers to verify product as described in section 582(d)(4)(A)(ii) of the FD&C Act in response to a notification of illegitimate product from FDA or a trading partner. FDA does not intend to take action before November 27, 2023, against dispensers who do not verify the product identifiers of suspect product as required by section 582(d)(4)(A)(ii)(II) of the FD&C Act. In addition, FDA does not intend to take action before November 27, 2023, against dispensers who do not verify the product identifiers of illegitimate product that are the subject of a notification from FDA or a trading partner as required by section 582(d)(4)(B)(iii) of the FD&C Act. This represents a 3-year delay in enforcement of the requirements for dispensers to verify the product identifier when investigating suspect or illegitimate product.
International
PIC/S
PIC/S Seminar 2020
Registrations for the 2020 PIC/S Seminar on "Distant Assessment of GMP Compliance" which will be hosted virtually from 8-10 December 2020 are now open (for Medicines Regulatory Authorities only). Deadline for registration is 8 November 2020.
PIC/S Expert Circle on Quality Risk Management (QRM) webinar
This PIC/S Expert Circle, currently chaired by Ireland / HPRA, has been active in developing and running advanced QRM training for GMP Inspectors for several years now to enable them to more effectively inspect the application of risk assessment and QRM during inspections in a harmonised manner. It also enables Inspectors to effectively use the PIC/S Recommendation in relation to risk-based GMP inspection planning (PI 037-1).
This webinar, which included some training aspects, was solely for GMP inspectors, and allowed to discuss updates and progress on applicable QRM guidance.
In particular, it led to important developments on:
The revision of the PIC/S Aide Memoire on inspecting the implementation of QRM (PI038-1) including discussions on the revision work in progress and gathering feedback on what the revised Aide Memoire should address;
The QRM Curriculum and the QRM e-Module being developed for the PIC/S Inspectorates’ Academy (PIA) and how these might be used by Inspectorates;
The PIC/S Recommendation Paper on Evaluating and Demonstrating the Effectiveness of the Pharmaceutical Quality System (PQS) with respect to Risk-based Change Management (PI 054-1 (Draft 1)) currently being applied on a trial basis by PIC/S Participating Authorities.
ICH Q12 and its relevance for GMP Inspectors, in particular training under development by the PIC/S Working Group on ICH Q12
Products
First long-acting injectable antiretroviral therapy for HIV recommended for approval
EMA has recommended the granting of marketing authorisations for two new antiretroviral (ARV) medicines, Rekambys (rilpivirine) and Vocabria injection (cabotegravir), to be used together for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection. The two medicines are the first ARVs that come in a long-acting injectable formulation. This means that instead of daily pills, patients receive intramuscular injections monthly or every two months.
The combination of Rekambys and Vocabria injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current ARV treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).
First CAR-T cell medicine for mantle cell lymphoma
EMA has recommended granting a conditional marketing authorisation in the European Union (EU) for Tecartus (autologous anti-CD19-transduced CD3+ cells) for the treatment of adult patients with a rare cancer of white blood cells called mantle cell lymphoma (MCL) when the symptoms or the disease come back (relapse) or when they are not responding (refractory) after two or more lines of systemic therapy.
Tecartus is the third CAR-T cell medicine to be recommended for approval in the EU. CAR-Ts are advanced therapies for cancer, they belong to a new generation of personalised cancer immunotherapies that are based on collecting and modifying patients’ own immune cells to treat their cancer.
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.