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Review of Developments in GMP and the Regulation of Medicines August 2019

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Vol 24-3 August 2019
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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 and USA regulatory authorities.

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

  • EU / US MRA fully operational

  • Medicine shortages: EU network takes steps to improve reporting and communication

  • Call for all sponsors to publish clinical trial results in EU database

  • EMA takes note of the European Ombudsman’s decision on pre-submission activities

  • MHRA Blog - How the implementation of Safety Features progresses 5 months in

  • UK government - Development of new antibiotics encouraged with new pharmaceutical payment system

  • BP and USP formalize partnership to strengthen quality of medicines and public health

  • CDER office of compliance Annual report FY 2018

  • Instructions for use — content and format

  • Drug Abuse and Dependence section of labeling for human prescription drug and biological products

  • REMS Modifications and revisions guidance for industry

  • Using the Inactive Ingredient Database

  • Cell analysis technique identifies subpopulations of stimulated mesenchymal stromal cells with in vitro immunosuppressive activity

  • Harmonizing compendial standards with drug application approval using the USP pending monograph process guidance for industry

  • TGA strengthens regulation of stem cell treatments

  • Remaking Therapeutic Goods Order No. 78 – (tablets /capsules/pills)

  • Rituzena Withdrawal of the marketing authorisation in the European Union




EU / US MRA fully operational

The European Union and the United States have now fully implemented the MRA for inspections of manufacturing sites for certain human medicines in their respective territories.

This agreement, which means authorities on both sides of the Atlantic will now be able to rely on each other’s inspection results. This in the strategic partnership with the US will support making best use of inspection capacity.

Each year, EU national authorities and the FDA inspect many production sites in the EU, the US and elsewhere in the world, to ensure that these sites operate in compliance with GMP. Under the MRA, EU and US regulators will now rely on each other’s inspections for human medicines in their own territories and hence avoid duplicative work. As a result of the MRA, both the EU and the US will be able to free up resources to inspect facilities in other countries.

The MRA is underpinned by robust evidence on both sides of the Atlantic that the EU and the US have comparable procedures to carry out GMP inspections for human medicines. Since May 2014, teams from the European Commission, the EU national competent authorities, EMA and the FDA have been auditing and assessing the respective supervisory systems. With the positive assessment of Slovakia, this process has now concluded for GMP inspectorates covering human medicines.

From now on, a batch testing waiver will also start to apply. This means that the qualified persons in EU pharmaceutical companies will no longer have to carry out quality controls for products manufactured in and imported from the US when these controls have already been carried out in the US.

The MRA implementation work will continue with a view to expanding the operational scope to veterinary medicines, human vaccines and plasma-derived medicinal products.

[Hurray – it’s been a long time in the making with a broad MRA including a pharmaceutical annex first signed in 1998. Hopefully the Joint Committee which will oversee progress on the MRA will be able to ensure smooth progress and widen this specific very important MRA in a relatively short timeframe. Hopefully steps will also be taken such that when the UK leaves the EU a mechanism will be found to allow similar trade arrangements will be made possible between the 3 territories – EU27/UK/USA. MBH]

Medicine shortages: EU network takes steps to improve reporting and communication

A task force was established by EU regulators to better address potential problems with medicines’ supply and to develop and coordinate actions to facilitate the prevention, identification, management of and communication about shortages.

Both documents lay the foundations for an improved and harmonised EU approach in reporting of and communication on medicines’ shortages and availability issues, a key public health priority for the EU network.

The first document provides guidance to the pharmaceutical industry, to facilitate the detection and early notification to competent authorities. The guidance is based on a common definition of the term ‘shortages’, which should enable a more harmonised and timely approach in the detection and management of issues with the supply of medicines. A proposed template for shortage notification by companies is included in the guidance. The guidance and template will be implemented in a pilot phase, which is currently planned to start in the last quarter of 2019. Further information will be provided nearer the time.

The second document, addressed to EU national competent authorities and EMA, lays out principles and examples of good practices for communication on shortages to the public, including patients and healthcare professionals. These groups require timely, accurate and up-to-date information on availability issues to ensure continuity of care.

Call for all sponsors to publish clinical trial results in EU database

The European Commission (EC), the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) have co-signed a letter reminding all sponsors of clinical trials conducted in the European Union of their obligation to make summaries of results of concluded trials publicly available in the EU Clinical Trials Database (EudraCT).

Transparency and public access to clinical trial results, whether positive or negative, are fundamental for the protection and promotion of public health. It assures trial subjects that their voluntary participation in clinical trials is useful and that the results have been collated and reported for the benefit of all. In addition, for those medicines which are placed on the market or used in further clinical trials, it allows patients and healthcare professionals, or any other citizen, to find out more information about medicines they might be taking or prescribing. Transparency also enhances scientific knowledge and helps to advance clinical research and support more efficient medicine development programmes.

EMA has since September 2018 been identifying trials with missing results on a monthly basis and sending reminders to the sponsors of those trials to ensure compliance with the transparency rules and their follow up on their results reporting obligations.

EMA takes note of the European Ombudsman’s decision on pre-submission activities

EMA has welcomed the European Ombudsman’s recognition of the value and need for scientific advice and her recommendations are in line with EMA’s ongoing initiatives to further increase transparency. Early interactions with medicine developers and provision of scientific advice are well-established processes with demonstrated added value in medicines regulation and they contribute positively to public health by helping to bring new, safe and effective medicines to patients. At the same time, EMA recognises the importance of guaranteeing the independence of the medicine assessment which takes place at a later stage.


MHRA Blog - How the implementation of Safety Features progresses 5 months in

MHRA will be issuing a series of blog posts regarding the implementation of FMD: Safety Features.

This is the first and looks at robustness of incoming checks.

MHRA has been inspecting for the required new elements and has seen some excellent examples of robust systems that have been brought in line with the FMD safety features requirements. It has also seen some systems that required improvement and examples of systems that failed to identify falsified stock as part of the pharmaceutical quality system requirements.

Systems should be able to identify decommissioned, stolen or recalled stock. This should include not just using the new FMD 2D barcode unique identifier (UI) scanning systems but also identifying stock from Greece and Italy that are yet to implement the 2D barcode UI system.

Where the 2D barcode UI is not yet in use, the MHRA are clear that it is still your responsibility to identify falsified, stolen or recalled stock received into your systems, including those that have already been decommissioned. Inspectors will be looking for this step as part of your incoming goods checks.

UK government - Development of new antibiotics encouraged with new pharmaceutical payment system

The NHS will test the world's first ‘subscription’ style payment model to incentivise pharmaceutical companies to develop new drugs for resistant infections.

The new trial will be led by the National Institute for Health and Care Excellence (NICE) and NHS England and NHS Improvement.

It will test a ‘subscription’ style model that pays pharmaceutical companies upfront for access to drugs based on their usefulness to the NHS.

This will make it more attractive for companies to invest the estimated £1 billion it costs to develop a new drug, as they can be reassured they will still be paid for the drug even though it may be stored for reserves.

Currently, drugs companies are paid by volume of antibiotics sold, while the NHS is trying to reduce their use to prevent antimicrobial resistance (AMR).

Low returns on investment in development mean industry is reluctant to invest in the research and clinical trials necessary to bring new antibiotics to market.

BP and USP formalize partnership to strengthen quality of medicines and public health

The relationship between the British Pharmacopoeia (BP) and United States Pharmacopeia (USP) will be further strengthened following the signing of a Memorandum of Understanding (MoU) between the two parties.

The agreement will enable improved collaboration and knowledge sharing between the BP and the USP in a wide area of standards setting for medicines.

This collective working agreement supports the important role public quality standards play in ensuring the quality of medicines taken by patients every day.

One of the features of this agreement is the commitment from both organisations to provide opportunities for exchange of staff and participation in events and joint working.

The challenges of assuring medicines quality in a world of globalised supply chains and rapid technological developments are best met by working in partnership with the BP and USP’s global peers.

United States of America

The US Food and Drug Administration (USFDA)

CDER office of compliance Annual report FY 2018

In this report CDER highlights several First Time Achievements including

  • issuing an administrative detention order for human drugs held under insanitary conditions at a salvaging warehouse

  • issued a compounding priorities plan

  • leading an opioid workshop to reduce the availability of illicit opioids online

  • developed and implemented a post-marketing adverse drug experience inspection site selection tool

In addition

  • a record number of Warning Letters were issued

  • 24 sartan recall events were coordinated

  • prevention and / or mitigation of a large number of drug shortages by exercising regulatory flexibility

  • Participated in many stakeholder participation and outreach activities

  • Issued 23 final & draft guidances.

Instructions for use — content and format

This draft guidance provides recommendations for developing the content and format of an Instructions for Use (IFU) document for human prescription drug and biological products and drug-device or biologic-device combination products submitted under a new drug application (NDA) or a biologics license application (BLA). The IFU is developed by applicants for patients who use drug products that have complicated or detailed patient-use instructions. The recommendations in this guidance are intended to help develop consistent content and format across IFUs and to help ensure that patients receive clear, concise information that is easily understood for the safe and effective use of such prescription products. Thus, the recommendations in this guidance are ultimately intended to enhance patients’ understanding of IFUs and facilitate the development and approval of IFUs that are clear and helpful to patients.

Drug Abuse and Dependence Section of Labeling for Human Prescription Drug and Biological Products

This draft guidance is intended to assist applicants in writing the DRUG ABUSE AND DEPENDENCE section of labeling, as described in the regulations for the content and format of labeling for human prescription drug and biological products (21 CFR 201.57(c)(10)). , This guidance applies to:

- Prescription drugs controlled under the Controlled Substances Act (CSA)

- Prescription drugs not controlled under the CSA for which there is important information to convey to health care providers related to abuse and dependence

REMS Modifications and revisions guidance for industry

This guidance provides information on how the FDA defines the types of changes to approved risk evaluation and mitigation strategies (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). This guidance is issued pursuant to section 505-1(h)(2)(A)(ii), (iii), and (iv) of the FD&C Act and section 1132(c) of Public Law 112-144.

Using the Inactive Ingredient Database

This draft guidance describes the FDA’s Inactive Ingredient Database (IID) and provides recommendations for how to use the IID in the development of drug products. The guidance also describes how the IID can be used in evaluating excipient safety, which can affect application filing and scientific review. In addition, this guidance discusses how the IID is structured; the data regarding excipients in the IID; and how nomenclature, maximum potency levels, and units of measure are presented in the IID. Lastly, the guidance is intended to give IID users a clearer understanding of the database’s benefits and limitations.

Cell analysis technique identifies subpopulations of stimulated mesenchymal stromal cells with in vitro immunosuppressive activity

Scientists at the U.S. FDA have developed a strategy that may improve the ability to identify batches of cells with a particular desired function for use as human therapies.

The new technique, called functionally-relevant morphological profiling (FRMP), enabled the FDA scientists to predict how much a population of stimulated mesenchymal stromal cells (MSCs) would be able to suppress key types of immune cells. This prediction is based on the appearance of distinct changes in cell shape that happen after MSCs are exposed to a growth factor called interferon-gamma (IFN-gamma).

The development of FRMP is important because it could help scientists more readily identify which MSC batches will be safe and effective. This information will also help scientists refine their manufacturing methods to make MSCs more consistent and reliable. Moreover, FRMP might be useful for figuring out how other types of cells respond to a variety of different growth factors.

Harmonizing compendial standards with drug application approval using the USP pending monograph process guidance for industry.

This guidance assists applicants and drug master file (MF) holders in the initiation of either revisions to an existing monograph(s) or development of a new monograph(s) under the United States Pharmacopeial Convention Pending Monograph Process (USP-PMP) during FDA’s evaluation of a drug master file or drug product application.2 This guidance describes the process that allows for the revision of compendial standards that are harmonized with the approved quality and labeling requirements for a drug product application.



TGA strengthens regulation of stem cell treatments

TGA has strengthened the regulation of stem cell treatments in Australia. The new regulations maintain consumer access to established stem cell treatments while protecting consumers from unproven and harmful treatments. The new regulations came into force on 1 July 2019 following a one-year transition period.

In the past, the TGA excluded a broader range of treatment providers from its regulatory requirements. In response to concerns about some providers offering unproven and harmful treatments, the TGA has expanded its oversight of stem cell treatments.

Under the new regulations, all providers of cell and tissue products who operate outside of hospitals will need to meet the TGA's requirements for safety, quality and effectiveness. Providers who fail to meet the requirements may face criminal penalties.

Stem cell treatments that are offered in hospitals are likely to remain excluded from TGA regulations. It is up to the hospital to decide the suitability and safety of the stem cell treatments they may offer.

Remaking Therapeutic Goods Order No. 78 – (tablets /capsules/pills)

The TGA thanks respondents who provided submissions in response to the public consultation paper.

There was general support for the remaking of the order but divergent views on the proposed scope.

The majority of submissions expressed support for:

  • The proposal to expand the scope of the order to include pills (having been included in TGO 56 but omitted from TGO 78).

  • A transition period of 12 months for pills.

  • Recognition of multiple default standards and the option to use Australian-specific requirements, even where an applicable monograph is available.

  • Widening of the default content limits from 92.5-107.5% to 90-110% and for wider overages for vitamins and minerals to be applied to registered as there was general support for the remaking of the order but divergent views on the proposed scope.

Feedback was sought on elemental impurity limits for herbal preparations and options for how this could be applied were included. A variety of views was offered, including support of the proposal, although one proposed option was noted to carry a risk of unnecessary regulatory burden. Other responses questioned the different approach taken for herbal medicines with respect to other medicines.

In response to submissions, the order was amended to allow herbal preparations not following an applicable monograph the option of adopting elemental impurity limits in either the USP dietary supplements chapter or the ICH requirements, consistent with recognising multiple default standards for all medicines.

Consultation feedback identified a need for a transition period for impurity limits in all medicines, and clarity on the requirement regarding safe levels. This was to allow manufacturing documentation to be updated. In response, a 2-year transition period was applied to all medicines for these requirements. Clarity on the need for consideration of safe levels of exposure to impurities, regardless of content in a particular batch of medicine, was provided in the guidance.

One submission questioned the exclusion of unapproved goods and information outlining the requirements for these goods has now been included in the guidance.

Further redrafting of the proposed order was undertaken to better clarify alignment between default standards and the Order. The draft was also amended in response to feedback that unintended changes had been made to dissolution requirements and to correct some minor typographical errors.

The remade order TGO 101 came into effect in March 2019. Any feedback received post-implementation will be considered in the context of future revisions to the guidance or amendments to the order.


Rituzena Withdrawal of the marketing authorisation in the European Union

The European Commission has withdrawn the marketing authorisation for Rituzena (rituximab) in the European Union (EU). The withdrawal was at the request of the marketing authorisation holder, Celltrion Healthcare Hungary Kft., which notified the European Commission of its decision not to market the product in the EU for commercial reasons.

Rituzena is a biosimilar of MabThera. There are other biosimilar medicinal products of MabThera authorised and marketed in the EU.

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.


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