Review of Developments in GMP and the Regulation of Medicines November 2019
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New Guide to the quality and safety of tissues and cells for human application
EMA encourages companies to submit type I variations for 2019 by end of November 2019
European countries increase commitment to responsible antibiotic use in animals
EMA Management Board: highlights of October 2019 meeting
Dialogue with Chinese authorities on medicine regulation
How to ensure that novel analytic methods are fit for decision-making
MHRA Process Licensing: useful information
HRA - Digital Health and Pharma 4.0
Identification of manufacturing establishments in applications submitted to CBER and CDER – Q&A
Drug master files guidance for industry
Demonstrating bioequivalence for veterinary soluble powder oral dosage form products or type a medicated articles manufactured from active pharmaceutical ingredients considered to be soluble in aqueous media
Drug Products Labeled as Homeopathic
TGA Laboratories testing of ranitidine medicines
First vaccine to protect against Ebola
First non-injectable treatment for severe low blood sugar levels
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EDQM
New Guide to the quality and safety of tissues and cells for human application
The EDQM has just released a new edition of its Guide to the quality and safety of tissues and cells for human application. This 4th edition provides healthcare professionals with an extensive overview of the most recent advances in the field, as well as technical guidance to ensure the quality and safety of human tissues and cells for human application.
The Guide provides support to professionals on a practical level with the type of guidance that aims at ensuring the successful clinical application of tissues and cells. It also lays out the ethical principles and guidelines that must be taken into consideration in the context of tissue and cell donation and related human applications.
The guide contains specific information and guidance for:
professionals involved in identifying potential donors;
transplant co-ordinators managing the process of donation after death;
bone marrow and cord blood collection centres;
fertility clinics;
tissue establishments processing and storing tissues and cells;
testing laboratories;
organisations responsible for human application;
inspectors auditing the establishments;
health authorities responsible for tissues and cells for human application.
EMA encourages companies to submit type I variations for 2019 by end of November 2019
EMA is advising marketing authorisation holders to submit type IA and type IAIN variations for 2019 no later than Friday 29 November 2019. This will enable EMA to acknowledge the validity of the submissions before the Agency's closure between 23 December 2019 and 6 January 2020 and within the 30-day timeframe set out in Article 14 of Regulation EC 1234/2008
Marketing authorisation holders planning to report Brexit-related Type IA/IAIN variations in December 2019 will receive the acknowledgment of the validity of the submissions within 30 days as per the usual procedure.
Marketing authorisation holders are advised to submit any type 1B variations or groupings of type IBs and type IAs by 6 December 2019 for a start of procedure in 2019. For submissions received on or after 9 December 2019, the procedure may not start until January 2020.
European countries increase commitment to responsible antibiotic use in animals
European countries continue to reduce the use of antibiotics in animals. The overall sales of veterinary antibiotics across Europe dropped by more than 32% between 2011 and 2017.
In particular, two of the critically important classes of antibiotics for human medicine were used less in animals: sales of polymyxins plummeted by 66% and sales of 3rd- and 4th-generation cephalosporins decreased by more than 20%. These classes include antibiotics used to treat serious infections in humans caused by bacteria resistant to most treatments.
The findings of the report confirm the downward trend seen over the last few years and show that EU guidance and national campaigns promoting prudent use of antibiotics in animals to fight antimicrobial resistance are having a positive effect.
EMA Management Board: highlights of October 2019 meeting
The Board was updated on the Agency’s ongoing preparations for the withdrawal of the UK from the EU. Interim arrangements allowing staff to telework from London have now largely come to an end. The total available workforce is roughly 730 - a further 6% reduction compared to the last update to the Board in June.
Due to these ongoing resource constraints, delivery of EMA’s work programme for Q4 2019 will be challenging for the Agency, particularly in view of the need to implement new legislation for veterinary products and medical devices, which will bring additional workload.
The Board also heard that in accordance with current planning, the construction of the new EMA building in Amsterdam Zuid will be finalised in November 2019 and the building will then be handed over to EMA on 15 November. Between mid-November and January, moving of equipment, IT configuration and testing will take place so that staff can move in during the week starting 13 January 2020.
Dialogue with Chinese authorities on medicine regulation
The Deputy Commissioner of the Chinese National Medical Product Administration visited EMA on 25 October together with a delegation.
The visit took place in the context of the ongoing EU-China regulatory dialogue on pharmaceuticals. Topics for discussion included GMP standards for active pharmaceutical ingredients, GCP standards, and the Commission’s strategic approach to pharmaceuticals in the environment.
Discussions were also held around establishing a common training curriculum focused on GMP and GCP standards, in cooperation with other international partners. In addition, EMA introduced the Chinese delegation to EMA’s role and activities in areas like inspection coordination, the evaluation and authorisation of medicines, and safety monitoring.
[It is good to see such dialogue is continuing. On a previous visit some 9 years go the Chinese delegation also met with at least one Industry body (EFPIA) and visited more than one pharma facility in Belgium. The QP system was of particular interest to China at that time and they proposed post visit to hold a trial of such a system in one province. MBH]
How to ensure that novel analytic methods are fit for decision-making
The past decade has seen the increased generation and availability of new data sources such as real-world evidence, as well as patient-level data from completed randomised clinical trials. While these data provide an opportunity to learn more about a medicine’s benefits and risks, and can complement the main body of evidence coming from randomised clinical trials, they will not necessarily translate into credible evidence for regulators and other decision-makers in the absence of adequate statistical methods to extract, analyse, and interpret them.
In an article published in Clinical Pharmacology & Therapeutics, regulators and academics explain how proper methodological validation can ensure the credibility of these data sources and allow authorities to rely on them to draw reliable scientific conclusions. The article is co-signed by a number of EMA staff members, academics and experts from national regulatory authorities.
MHRA
Process Licensing: useful information
The Process Licensing Office sits within the Inspectorate and Process Licensing Group of the Inspection, Enforcement and Standards division. It typically deals with the manufacture, assembly and wholesale distribution of medicinal products under UK and EU legislation, these licences are often called process licences and include:
licences for the manufacture / importation of licensed medicinal products for human use, commonly abbreviated to MIA
'specials' licences for the manufacture / importation of unlicensed medicinal products for human use, commonly abbreviated to MS
authorisations for the manufacture / importation of investigational medicinal products for human use, commonly abbreviated to MIA(IMP)
authorisations for the manufacture / importation of licensed medicinal products for veterinary use (ManA)
'specials' licences for the manufacture of unlicensed medicinal products for veterinary use, (ManSA)
manufacturer's licences for exempt advanced therapy medicinal products (MeAT)
licences for the wholesale distribution of medicinal products for human use, commonly abbreviated to WDA (H) (including those covering unlicensed medicines obtained from another EEA member state)
licences for the wholesale distribution/importation of medicinal products for veterinary use - WDA (V)
blood establishment authorisations (BEA)
non-orthodox practitioners (NOP)
broker registrations
active substance manufacturer, importer or distributor registrations
certificates of Good Manufacturing Practice (GMP)
certificates of Good Distribution Practice (GDP)
MHRA has produced this Blog on the topic.
[As “it says on the tin” it should prove to be a useful source of information as to where to go for any topic in this field MBH]
Digital Health and Pharma 4.0
This blog from Mark Birse looks at some of the exciting pieces of work that he has been involved with in the digital space over the last year and then a look at how the Inspectorate is evolving to support the growth of digital within the pharmaceutical industry, including developments associated with the ‘4th industrial revolution’ and what has been labelled "Pharma 4.0".
United States of America
The US Food and Drug Administration (USFDA)
Identification of manufacturing establishments in applications submitted to CBER and CDER – Q&A
This guidance is intended to clarify Agency expectations regarding facility information that should be included in original new drug application(s) (NDA); abbreviated new drug application(s) (ANDA); original biologics license application(s) (BLA); amendments; supplements; chemistry, manufacturing, and controls (CMC) supplements; and resubmissions to these submission types. This guidance addresses questions related to the inclusion and withdrawal of proposed commercial facilities and development facilities, the appropriate location within an application for facility information, and the type of facility information that should be included in applications. Applications that include appropriate and complete facility information in the establishment information section of Form FDA 356h will reduce the frequency of Information Request (IR), Refusal to File (RTF), and Refuse to Receive (RTR) actions and increase the efficiency of the application assessment process.
The Agency frequently receives questions regarding expectations for inclusion of manufacturing establishment information in applications (Module 3) and Form FDA 356h. In some instances, this lack of clarity results in FDA receiving applications that contain extraneous information, misplaced information (i.e., not readily accessed by Agency reviewers), or missing information. These issues result in delays to the assessment process and in some instances, unnecessary IR, RTF, and RTR actions. This guidance offers detailed recommendations regarding the placement of facility information in applications.
Drug master files guidance for industry
This guidance provides FDA’s current thinking on drug master files (DMFs), which are submissions to FDA that may be used to provide confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human drug products. DMFs can contain other types of information as well (e.g., toxicology information, shared system REMS (risk evaluation and mitigation strategy))
This draft guidance revises the guidance for industry Drug Master Files: Guidelines that published in September 1989. Most of the information contained in the 1989 guidance has been retained, with significant reorganization.
Demonstrating bioequivalence for veterinary soluble powder oral dosage form products or type A medicated articles manufactured from active pharmaceutical ingredients considered to be soluble in aqueous media
This draft document for comment describes how the Center for Veterinary Medicine (CVM) intends to evaluate requests for waiving the requirement for performing in vivo bioequivalence studies (biowaivers) for animal drugs administered orally as soluble powders or as Type A medicated articles manufactured from active pharmaceutical ingredients (APIs) considered to be soluble in aqueous media (water soluble APIs). This document expands upon CVM’s Guidance for Industry (GFI) #35, “Bioequivalence Guidance,”1 to include biowaivers for soluble powder oral dosage form products as well as Type A medicated articles manufactured from active pharmaceutical ingredients considered to be soluble in aqueous media, and it offers particular focus on criteria for the waiver of the requirements for submitting in vivo bioequivalence study data. This guidance does not address Type A medicated articles manufactured from active pharmaceutical ingredients considered to be insoluble in aqueous media.
This guidance is applicable to generic investigational new animal drug (JINAD) files and to abbreviated new animal drug applications (ANADAs). Although the recommendations in this guidance refer to ANADAs, the general principles described may also be applicable to new animal drug applications (NADAs), supplemental NADAs, and investigational new animal drug (INAD) files.
Drug Products Labeled as Homeopathic
This revised draft guidance for FDA staff and industry describes how FDA intends to prioritize enforcement and regulatory actions for homeopathic drug products marketed in the United States without the required FDA approval. FDA has developed a risk-based approach under which the Agency intends to prioritize enforcement and regulatory actions involving certain categories of such products that potentially pose a higher risk to public health.
The Agency anticipates that many homeopathic drug products will fall outside the categories of drug products that FDA intends to prioritize for enforcement and regulatory action.
For the purposes of this draft guidance, FDA defines a “homeopathic drug product” as a drug product that is labeled as “homeopathic,” and is labeled as containing only active ingredients and dilutions (e.g., 10X, 20X) listed for those active ingredients in the Homeopathic Pharmacopeia of the United States (HPUS).
Comments were to be submitted online by 24 Dec 2019
International
Australia
TGA Laboratories testing of ranitidine medicines
In response to reports of contamination of ranitidine medicines with an impurity called N-nitrosodimethylamine (NDMA), which is associated with an increased risk of cancer, the TGA Laboratories have tested samples of these products currently marketed in Australia.
The purpose of this testing was to determine if NDMA was present in these medicines and to quantify the amounts present. A testing report has been issued.
The report identifies batches tested that contained levels of NDMA above the internationally agreed limit of 0.3 parts per million (ppm) and those with levels below this limit. All products with levels of NDMA at or above 0.3 ppm have been recalled and removed from retailer shelves, while all batches with levels below 0.3 ppm are still available for sale.
Products
First vaccine to protect against Ebola
EMA’s human medicines committee (CHMP) has recommended granting a conditional marketing authorisation in the European Union for Ervebo (rVSVΔG-ZEBOV-GP), the first vaccine for active immunisation of individuals aged 18 years and older at risk of infection with the Ebola virus.
First non-injectable treatment for severe low blood sugar levels
EMA’s human medicines committee (CHMP) has recommended granting a marketing authorisation in the European Union for Baqsimi (glucagon), the first treatment for severe hypoglycaemia (low blood sugar levels) that can be administered without an injection to patients with diabetes aged four years and older.
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.