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Review of Developments in GMP and the Regulation of Medicines May 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 & and USA regulatory authorities.


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


Europe

  • Coronavirus disease (COVID-19)

  • EMA to issue electronic certificates for medicines

  • Qualification of novel methodologies for medicine development

  • Nitrosamine impurities

  • EMA to review ranitidine medicines following detection of NDMA

  • EMA Management Board March 2020

  • Brexit-related guidance for companies

  • EMA publishes ICH guideline Q12

  • Veterinary post-authorisation Q&A

  • Update on the European Pharmacopoeia (PhEur) policy on elemental impurities – Excipients of natural origin

  • Tetanus vaccines – Rationalising toxicity testing requirements

  • Deadline extension to all CEP holders to complete step 1 Risk Assessments regarding presence of nitrosamines

  • MHRA Good Practice (GxP) inspections during the COVID19 outbreak

  • MHRA Coronavirus guidance

  • Advice for Management of Clinical trials in relation to Coronavirus

  • Guidance for Good Laboratory Practice (GLP) facilities in relation to coronavirus (COVID-19)

  • Veterinary post-authorisation Q&A


USA

  • The “Deemed To Be a License” provision of the BPCI Act Q&A

  • Safety Testing of Drug Metabolites

  • Q3D(R1) Elemental Impurities

  • Competitive Generic Therapies

  • Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19)

  • Temporary Policy for Manufacture of Alcohol for Incorporation Into Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19)


International


Australia

Therapeutic Goods Administration (TGA)

  • Physical samples for batch release not required: a reminder for sponsors of biosimilars and biological medicines

  • TGA suspends overseas GMP inspections and QMS audits

  • TGA to expand quality audits for medicinal cannabis


Products

  • Kromeya - Withdrawal of the marketing authorisation in the EU


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe

EMA

Coronavirus disease (COVID-19)

EMA has issued a useful summary of its current positions on this topic, some of which are referenced as individual sections in this edition of the Regulatory Update

The topics covered in the EMA article can be viewed from the hyperlinks below:-

  • What's new

  • Supporting the development of medicines and vaccines

  • Advice on clinical trials

  • Monitoring the impact on medicine supply chains

  • Advice on safety of medicines in COVID-19 patients

  • Working with EU and international partners

  • Impact on EMA activities and meetings

EMA to issue electronic certificates for medicines

EMA has implemented a new system to issue electronic certificates for human and veterinary medicines. The Agency will no longer provide printed certificates but only electronically signed and authenticated certificates to maintain EMA’s ability to provide these documents during the Covid-19 pandemic.

EMA issues certificates on behalf of the European Commission to confirm the marketing authorisation status of products

The new format of the certificates is based on an electronically signed PDF document. It contains an electronic signature fully compliant with the eIDAS Regulation (Electronic Identification, Authentication and Trust Services) that guarantees the unique link to the signatory and the full authenticity and integrity of the document.

The Agency will consider whether the electronic signature should be implemented as a permanent solution as part of its efforts to digitalise its administrative processes for all documents requiring signature.

See:-electronic certificates and section 4.7 of information package


Qualification of novel methodologies for medicine development

The following section of this guidance has changed:-

  • Letter of intent for request of qualification of novel methodologies

In addition, there are 2 new documents in the section concerning “Qualification opinion- Muliple sclerosis clinical outcome assessment.

The full listing of these guidance documents can be retrieved from:-


full list


Nitrosamine impurities

EMA has updated its guidance on this topic. This follows reports of the challenges encountered in meeting the original deadline of 26 March 2020 to complete step 1 (risk evaluation) of the review of manufacturing processes, and the impact of the severe restrictions in place to combat the COVID-19 pandemic. The deadline is now extended to 1 October 2020.

EMA also encourages marketing authorisation holders to submit the outcome of step 1 before 1 October 2020 if they complete the risk evaluation or identify a risk in their products.

See:-nitrosamine impurities & udated Q&A


EMA to review ranitidine medicines following detection of NDMA

At the request of the European Commission, EMA is to start a review of ranitidine medicines after tests showed that some of these products contained the impurity N-nitrosodimethylamine (NDMA). EMA is evaluating the data to assess whether patients using ranitidine are at any risk from NDMA and will provide information about this as soon as it is available.

See:-ranitidine containing medicines


EMA Management Board March 2020

EMA’s first Management Board meeting of 2020 was held virtually in view of the rapidly changing situation in the context of the COVID-19 pandemic. The Board was shortened to one and a half hours to allow EMA and Member States to continue to focus resources on the response to the pandemic.

See:-highlights


Brexit-related guidance for companies

The EMA has updated its guidance in relation to centrally authorized products.

See:-updated guidance


EMA publishes ICH guideline Q12

This guideline provides a framework to facilitate the management of post-approval CMC changes in a more predictable and efficient manner. A harmonised approach regarding technical and regulatory considerations for lifecycle management will benefit patients, industry, and regulatory authorities by promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance and improving supply of medicinal products. The concepts outlined in prior ICH Quality Guidelines (ICH Q8(R2), Q9, Q10 and Q11) provide opportunities for science-and risk-based approaches for use in drug development and regulatory decisions. These guidelines are valuable in the assessment of Chemistry, Manufacturing and Controls (CMC) changes across the product lifecycle. ICH Q8(R2) and Q11 guidelines focus mostly on early stage aspects of the product lifecycle (i.e., product development, registration and launch). This guideline addresses the commercial phase of the product lifecycle (as described in ICH Q10); and it both complements and adds to the flexible regulatory approaches to post-approval CMC changes described in ICH Q8(R2) and Q10 Annex 1

See:-ICH Q12 EU posting & note on EU implementation


Veterinary post-authorisation Q&A

This guidance addresses a number of questions marketing-authorisation holders may have on post-authorisation procedures. It provides an overview of the Agency's position on issues which are typically addressed in discussions or meetings with marketing-authorisation holders in the post-authorisation phase.

It is updated regularly to reflect new developments. New or Revised topics will be marked by “New” or “Rev” upon publication.

See:-updated Q&A


EDQM

Update on the European Pharmacopoeia (PhEur) policy on elemental impurities – Excipients of natural origin

Since 2017, the group of experts dealing with inorganics – Group 9 – has continued to work on the individual monographs for excipients of natural origin. The Group deleted specific elemental impurity tests when the contaminant was found to be process-related or where batch data showed that it was not actually present in the substance. Specific tests were kept for elemental impurities that continued to be detected in production batches or were added for any new elemental impurities found. In both cases, appropriate limits were set based on available batch data.

While assessing individual elemental impurities, Group 9 took into consideration the control threshold of 30% of the established permitted daily exposure (PDE) for oral dosage forms laid down in the ICH Q3D guideline. When completed, draft revised monographs on excipients of natural origin are published in Pharmeuropa for public consultation. To date, 11 monographs describing new elemental impurities and two showing updated limits for existing impurities have been published. Group 9 still has 17 monographs left on its work programme to be discussed in the framework of the Ph.Eur. policy on elemental impurities.

See:-excipients of natural origin


Tetanus vaccines – Rationalising toxicity testing requirements

The Ph. Eur Commission adopted 16 revised monographs on tetanus vaccines, following a re-assessment of toxicity testing requirements. The revisions include the suppression of three tests and the harmonisation, as far as possible, of the Ph. Eur.’s toxicity testing requirements for tetanus vaccines for human and veterinary use.

The Ph. Eur. Commission is committed to phasing out the use of animal tests by continuously reviewing in vivo tests described in Ph. Eur. texts and applying, whenever possible, the 3Rs principles set out in the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS No. 123). The re-assessment of toxicity testing requirements for tetanus vaccines and the decision to delete three animal tests is an illustration of this commitment.

See:-Tetanus vaccine testing


Deadline extension to all CEP holders to complete step 1 Risk Assessments regarding presence of nitrosamines (now 31st July 2020).

CEP holders will be aware that the European medicines regulatory network has agreed to extend the deadline to complete step 1 (risk evaluation) for marketing authorisation holders to 1 October 2020. EDQM has chosen the extended deadline for CEPs in advance of this date to ensure that information on drug substances which are subject of CEPs is available in a timely manner to allow for marketing authorisation holders to meet the extended deadline for their medicinal products.

See:-CEP step 1 risk assessment nitrosamines


MHRA

MHRA Good Practice (GxP) inspections during the COVID19 outbreak

A new Blog post, “MHRA Good Practice (GxP) inspections during the COVID19 outbreak” has been published on the MHRA Inspectorate blog.

The COVID19 pandemic presents an unprecedented challenge to healthcare, the pharmaceutical industry’s supply chain and personnel movement. MHRA understands the impact of its work on industry, NHS and patients. This is not just in terms of our regulatory support to bring new technologies and products quickly and safely to market, but also the personnel and resources required to support the regulatory inspection programmes necessary to protect public health.

Until further notice, MHRA will only conduct on-site inspections linked to the UK Government’s COVID19 response or any other potential serious public health risk, and where remote assessment is not possible. Other inspections will be temporarily replaced with alternative regulatory supervision approaches such as office-based assessment. This will support the industry and NHS to focus on service continuity, and essential clinical trial authorisation applications will not be affected.

During this period of disruption, MHRA’s remote assessment procedures and its communication with the international regulatory network will maintain protection of public health.

Office based inspections will involve organisations being asked to provide electronic copies of documents and other information for review off-site, with teleconferences and email to follow up.

If on-site inspection is required, MHRA will continue to operate to normal procedures, including the possibility of an unannounced visit if considered necessary to protect public health. MHRA inspectors will take all possible steps to protect the inspected organisation and themselves from COVID19 transmission risks, including strict hygiene measures in line with UK Government advice.

See:-inspections blog


MHRA Coronavirus guidance

Further guidance has been published in relation to Managing Clinical Trials and Clinical Trial Applications. MHRA addresses issues such as paperwork for temporary halts, providing IMP by post and remote monitoring. There is also guidance on submitting applications for COVID-19 trials.

See:-guidance


Advice for Management of Clinical trials in relation to Coronavirus

MHRA recognises the difficulties created for managing trials and offers some advice.

There will be an increase in protocol deviations; and MHRA requests that they are well documented, to enable appropriate evaluation for the trial.

It notes that an increase in protocol deviations in relation to Coronavirus will not constitute a serious breach, therefore there is no need to report this to MHRA (unless of course patients are being put at risk).

See:-clinical trials advice


Guidance for Good Laboratory Practice (GLP) facilities in relation to coronavirus (COVID-19)

Following previous posts, further guidance has been published on the MHRA website in relation to GLP Amendments & Deviations, QA and a reminder on when to contact MHRA.

MHRA continue to add guidance as the situation develops.

See:- blog and MHRA Website



United States of America

The US Food and Drug Administration (USFDA)


The “Deemed To Be a License” provision of the BPCI Act Q&A

This guidance is intended to provide answers to common questions about FDA’s implementation of the “transition” provision of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) under which an application for a biological product approved under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) as of March 23, 2020, will be deemed to be a license for the biological product under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262) on March 23, 2020 (the transition date). This guidance also describes FDA’s compliance policy for the labeling of biological products that are the subject of deemed biologics license applications (BLAs). This guidance is intended to facilitate planning for the transition date and provide further clarity regarding the Agency’s implementation of this statutory provision. Although the majority of therapeutic biological products have been licensed under section 351 of the PHS Act, some protein products historically have been approved under section 505 of the FD&C Act. On March 23, 2010, the BPCI Act was enacted as part of the Patient Protection and Affordable Care Act (Public Law 111-148). The BPCI Act clarified the statutory authority under which certain protein products will be regulated by amending the definition of a “biological product” in section 351(i) of the PHS Act to include a “protein (except any chemically synthesized polypeptide),” and describing procedures for submission of a marketing application for certain “biological products.” Section 605 of the Further Consolidated Appropriations Act, 2020, further amended the definition of a “biological product” in section 351(i) of the PHS Act Contains Nonbinding Recommendations to remove the parenthetical “(except any chemically synthesized polypeptide)” from the statutory category of “protein.” The BPCI Act requires that a marketing application for a biological product (that previously could have been submitted under section 505 of the FD&C Act) must be submitted under section351 of the PHS Act; this requirement is subject to certain exceptions during a 10-year transition period ending on March 23, 2020(see section 7002(e)(1)-(3) and (e)(5)of the BPCI Act). On March 23, 2020(i.e., the transition date), an approved application for a biological product under section 505 of the FD&C Act shall be deemed to be a license for the biological product under section 351 of the PHS Act (see section 7002(e)(4)(A)of the BPCI Act; see also section 7002(e)(4)(B) of the BPCI Act).

See:-final guidance


Safety testing of drug metabolites

This guidance provides recommendations to industry on when and how to identify and characterize drug metabolites whose nonclinical toxicity needs to be evaluated. Drug metabolites may need to be determined in nonclinical studies when they are disproportionate drug metabolites, that is, metabolites identified only in humans or present at higher plasma concentrations in humans than in any of the animal species used during standard nonclinical toxicology testing.

See:-final guidance


Q3D(R1) Elemental Impurities

FDA has now published this final guidance. Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guidance:

  • The evaluation of the toxicity data for potential elemental impurities

  • The establishment of a permitted daily exposure (PDE) for each element of toxicological concern

  • The application of a risk-based approach to control elemental impurities in drug products

This guidance applies to new finished drug products and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or nonrecombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this guidance, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.

This guidance does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts and products, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. This guidance does not apply to products based on genes (gene therapy), cells (cell therapy), and tissue (tissue engineering).

See:-elemental impurities


Competitive Generic Therapies

The FDA Reauthorization Act of 2017, or FDARA, created a new pathway by which FDA may, at the request of the applicant, designate a drug with “inadequate generic competition” as a competitive generic therapy (CGT). At the request of the applicant, FDA may also expedite the development and review of an abbreviated new drug application (ANDA) for a drug designated as a CGT.

This guidance provides a description of the process that applicants should follow to request designation of a drug as a CGT and the criteria for designating a drug as a CGT. It also includes information on the actions FDA may take to expedite the development and review of ANDAs for drugs designated as CGTs. Finally, it provides information on how FDA implements the statutory provision for a 180-day exclusivity period for certain first approved applicants that submit ANDAs for CGTs.

FDARA created a new type of 180-day exclusivity, different from 180-day patent challenge exclusivity, for the first approved applicant.

This new 180-day exclusivity under FDARA (hereafter, CGT exclusivity) is intended to incentivize competition for drugs that are not protected by patents or exclusivities and for which there is inadequate generic competition. 14 of a drug with a CGT designation for which there were no unexpired patents or exclusivities listed in the Orange Book at the time of original submission of the ANDA.

See:-competitive generic therapies


Temporary Policy for Preparation of Certain Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19)

FDA is issuing this guidance in response to a number of queries from entities that are not currently licensed or registered drug manufacturers that would like to prepare alcohol-based hand sanitizers, either for public distribution or for their own internal use. The Agency is issuing this guidance to communicate its policy for the temporary preparation of certain alcohol-based hand sanitizer products by firms that register as over-the-counter (OTC) drug manufacturers to prepare alcohol-based hand sanitizers under the circumstances described in this guidance for the duration of the public health emergency. At such time when the public health emergency is over, as declared by the Secretary, FDA intends to discontinue this enforcement discretion policy and withdraw this guidance.

See:-hand sanitizer products


Temporary Policy for Manufacture of Alcohol for Incorporation Into Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19)

FDA is issuing this guidance in response to a number of queries from entities that are not currently registered drug manufacturers that would like to produce alcohol for incorporation into alcohol-based hand sanitizers. This policy does not extend to other types of active ingredients for incorporation into alcohol-based hand sanitizers, such as isopropyl alcohol.

The Agency is issuing this guidance to communicate its policy for the temporary manufacture of ethanol products by firms that manufacture alcohol for incorporation into alcohol-based hand sanitizer products under the circumstances described in this guidance (alcohol production firms) for the duration of the public health emergency, At such time when the public health emergency is over, as declared by the Secretary, FDA intends to discontinue this enforcement discretion policy and withdraw this guidance.

See:- manufacture of alcohol



International


Australia

Australia Therapeutic Goods Administration (TGA)


Physical samples for batch release not required: a reminder for sponsors of biosimilars and biological medicines

TGA is reminding sponsors of biological medicines and biosimilars that physical samples are not required for batch release until further notice.

This reminder follows on from email communication from the TGA to sponsors, informing them of this change, which will be reassessed in June 2020.

This change in process is to facilitate batch release of biological medicines during the COVID-19 pandemic.

Sponsors should still supply protocols for products on batch release. Batch release will be performed via an assessment of the protocols only, with the aim of reducing turnaround times during the pandemic.

This only applies to biological medicines and biosimilars that are currently on batch release.

See:-biosimilars - batch release


TGA suspends overseas GMP inspections and QMS audits until further notice

Consistent with the Australian Government's latest travel restrictions, TGA has suspended all overseas GMP inspections and QMS (Quality Management System) audits until further notice.

In addition to its commitment to ensuring that overseas manufacturers meet GMP and QMS requirements, TGA is also mindful of the need to provide transparent information to sponsors affected by these delays. Sponsors immediately affected by the suspension to GMP inspections have been contacted and, where applicable, advised about maintaining the validity of their existing GMP clearances.

Currently there is no impact on domestic inspections and audits; however, TGA continues to monitor the situation and will provide timely updates should there be any change to this position.

See:-suspension of overseas inspections


TGA to expand quality audits for medicinal cannabis

In the coming months, the TGA will expand the number of quality audits of medicinal cannabis products imported or supplied under the Special Access Scheme (SAS) and other unapproved product access pathways.

Most medicinal cannabis products being supplied in Australia are 'unapproved', that is, they are not included in the Australian Register of Therapeutic Goods (ARTG), but they must still comply with relevant quality standards

Currently, the TGA is approving more than 3,000 SAS applications for medicinal cannabis each month. Unlike other products accessed through the SAS, unapproved medicinal cannabis products are usually not approved or registered overseas.

While manufacturers of imported unapproved medicines are not required to undergo GMP inspections or clearances unless further steps of manufacture occur in Australia, importers or suppliers of products that do not comply with applicable standards, such as TGO 93, may be subject to a range of regulatory compliance actions, including civil and criminal penalties.

See:-audits for medicinal cannabis


Products

Kromeya - Withdrawal of the marketing authorisation in the EU

The withdrawal was at the request of the marketing authorisation holder, Fresenius Kabi Deutschland GmbH, which notified the European Commission of its decision not to market the product in the EU for commercial reasons.

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

See:-public statement


And finally…

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.

GMP Update is compiled by Malcolm Holmes an independent GMP Consultant