• EJPPS

Updated: May 12

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


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Vol 24-4 October-2019
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Europe

  • Ranitidine containing medicinal products

  • Advice to companies on steps to take to avoid nitrosamines in human medicines

  • Change of name of liposomal medicines at high risk of medication errors (update)

  • Implementation of the new Veterinary Medicines Regulation

  • MHRA Blog - Supply chain security: part 1 - introduction


USA

  • NMDA impurity in certain ranitidine products

  • Wholesale distributor verification requirement for saleable returned drug product

  • •Bringing remaining approved OTC medically important antimicrobial drugs used for animals under veterinary oversight

  • Reorganization of the Office of New Drugs with Corresponding Changes to the Office of Translational Sciences and the Office of Pharmaceutical Quality

  • TCPro simulates immune system response to biotherapeutic drugs

  • Evaluation of Internal Standard Responses during Chromatographic Bioanalysis: Q&A


International

Australia

  • Updated Guidelines for making an offer of enforceable undertaking to the TGA

  • TGA business plan 2019-20

PIC/S

  • Focused stakeholders consultation on revised draft PIC/S GMP Guide Annex 2A (Manufacture of Advanced Therapy Medicinal Products for Human Use) and Annex 2B (Manufacture of Biological Medicinal Substances and Products for Human Use)

WHO

  • Proposal to discontinue the test for undue toxicity (chapter 3.7) in the international pharmacopoeia


Products

  • USFDA approves first live, non-replicating vaccine to prevent smallpox & monkeypox


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS


Europe

EMA

Ranitidine containing medicinal products

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 an impurity called N-nitrosodimethylamine (NDMA).

NDMA is classified as a probable human carcinogen (a substance that could cause cancer) on the basis of animal studies. It is present in some foods and in water supplies but is not expected to cause harm when ingested in very low levels.

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.


Advice to companies on steps to take to avoid nitrosamines in human medicines

EMA’s human medicines committee (CHMP) is requesting as a matter of precaution that marketing authorisation holders (MAH) for human medicines containing chemically synthesised active substances review their medicines for the possible presence of nitrosamines and test all products at risk. If nitrosamines are detected in any of their medicines, MAH’s must inform authorities promptly so that appropriate regulatory actions can be taken.

A notice to this effect is being sent out to MAH’s with information on the actions they should take. A Q&A document is also available.

MAH’s are responsible for ensuring that every batch of their finished product is of satisfactory quality, including the active substances (AS) and other ingredients used to make them. They should take into account the published guidance along with knowledge of the manufacturing processes for their products and all other relevant scientific evidence.


Change of name of liposomal medicines at high risk of medication errors (update)

The CHMP and the CMDh have now clarified that for medicines administered topically or by other routes of administration, the qualifier 'liposomal' or 'pegylated liposomal' should only be added to the invented name in those cases when a clear risk of medication errors has been identified. Elements such as route of administration, medication error reporting or long established use should be taken into consideration when assessing the need for the qualifier.

In those cases where a name change is considered necessary, applicants are requested to update the name throughout the product information, including all annexes. This is an addition to the communication from July, in which they were instructed to amend only section 1 of the summary of product characteristics

MAH’s are requested to submit an A.2.a variation before the end of September 2019 to update the name of liposomal medicines in line with the new recommendation from the CHMP and the CMDh.


Implementation of the new Veterinary Medicines Regulation

The new Veterinary Medicines Regulation (Regulation (EU) 2019/6) will modernise the existing rules on the authorisation and use of veterinary medicines in the European Union (EU) when it becomes applicable on 28 January 2022. It contains new measures for increasing the availability and safety of veterinary medicines and enhances EU action against antimicrobial resistance. The European Medicines Agency (EMA) is working closely with the European Commission and other EU partners in preparation for the implementation of the new Regulation.

The main objectives of the new Regulation are to:

  • simplify the regulatory environment and reduce administrative burden for pharmaceutical companies developing veterinary medicines, for example through streamlined pharmacovigilance rules;

  • stimulate the development of innovative veterinary medicines, including products for small markets (minor use and minor species);

  • improve the functioning of the internal market for veterinary medicines;

  • strengthen EU action to fight antimicrobial resistance through specific measures ensuring prudent and responsible use of antimicrobials in animals, including reserving certain antimicrobials for the treatment of infections in people.

MHRA

Blog - Supply chain security: part 1 - introduction

Whether pilfered for personal use or stolen in bulk for diversion, opportunistic or planned, the theft of medicines has a broad impact that increases risk to public health and risks the integrity of the medicine supply chain. Considering the amount of UK medicines distributed, the proportion of theft is low, however, this series of blog posts aims to assist distributors to improve security standards.

The aim of this and the subsequent planned Blogs on the topic is to share best practice within industry of developing a good security culture to help maintain the strong reputation of the UK medicine supply chain. The Blogs will cover prevention of theft concerned with all types of medicine, and security associated with storage and transportation.


United States of America

The US Food and Drug Administration (USFDA)

NMDA impurity in certain ranitidine products

FDA has learned that some ranitidine medicines, including some products commonly known as the brand-name drug Zantac, contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables.

The FDA has been investigating NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year. In the case of ARBs, the FDA has recommended numerous recalls as it discovered unacceptable levels of nitrosamines.

When the agency identifies a problem, it takes appropriate action quickly to protect patients. The FDA is evaluating whether the low levels of NDMA in ranitidine pose a risk to patients. FDA will post that information when it is available.

Subsequently FDA is alerting health care professionals and patients of a voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., used to decrease the amount of acid created by the stomach. This recall is due to a nitrosamine impurity, N-nitrosodimethylamine (NDMA), which was found in the recalled medicine. NDMA is classified as a probable human carcinogen (a substance that could cause cancer).

FDA is continuing it’s investigation along with international counterparts, and will keep the American public informed of any additional recalls as well as the potential risks from taking ranitidine products.

The agency is testing ranitidine products from multiple manufacturers and assessing the possible effect on patients who have been taking ranitidine, as well as what manufacturers can do to reduce or eliminate nitrosamine in drugs.


Wholesale distributor verification requirement for saleable returned drug product

In the years since passage of the Drug Supply Chain Security Act (DSCSA), including most recently within the past year, FDA has received comments and feedback from wholesale distributors as well as other trading partners and stakeholders expressing concern with industry-wide readiness for implementation of the verification of saleable returned product requirement for wholesale distributors. Specifically, stakeholders have described challenges with implementation of verification of the product identifier on saleable returned drug product packages or sealed homogenous cases due to a number of factors, including: (1) the very large volume of saleable returned product requiring verification; (2) the need to refine and test verification systems during actual production using real-time volumes of saleable returned product rather than simply in pilots; and (3) the complexities of building an interoperable, electronic system with the capabilities to timely and efficiently verify the large volume of saleable returned products amid immature technologies. Through FDA’s DSCSA pilot project program, FDA is aware that several pilot participants are in the early stages of developing and testing interoperable, electronic systems to enable verification and achieve interoperability between networks. Given the concerns expressed, FDA recognizes that some wholesale distributors (in collaboration with other trading partners) may need additional time beyond November 27, 2019, before they can begin verifying returned products prior to resale or other further distribution as required by the FD&C Act in an efficient, secure, and timely manner. To minimize possible disruptions in the distribution of prescription drugs in the United States, FDA does not intend to take action before November 27, 2020, against wholesale distributors who do not verify a product identifier prior to resale or other further distribution of a package or sealed homogenous case of product as required by section 582(c)(4)(D) of the FD&C Act. Additionally, section 582 of the FD&C Act requires certain trading partners (manufacturers, repackagers, wholesale distributors, and dispensers) to exchange transaction information, transaction history, and a transaction statement when engaging in transactions involving certain prescription drugs.6,7 Section 581(27)(E) of the FD&C Act requires that the transaction statement include a statement that the entity transferring ownership in a transaction had systems and processes in place to comply with verification requirements under section 582. FDA recognizes that wholesale distributors may not have systems in place by November 27, 2019, to enable the wholesale distributor to timely and efficiently comply with the verification of saleable returned product requirements under section 582(c)(4)(D) of the FD&C Act without potentially causing a disruption to the pharmaceutical distribution supply chain. Therefore, prior to November 27, 2020, FDA does not intend to take action against a wholesale distributor for providing a transaction statement to a subsequent purchaser of product on the basis that such wholesale distributor does not yet have systems and processes in place to comply with the saleable return verification requirements under section 582(c)(4)(D).


Bringing remaining approved OTC medically important antimicrobial drugs used for animals under veterinary oversight.

FDA has released draft guidance for industry (GFI) #263 to explain the recommended process for voluntarily bringing remaining approved animal drugs containing antimicrobials of human medical importance (i.e., medically important) under the oversight of licensed veterinarians by changing the approved marketing status from over-the-counter (OTC) to prescription (Rx).

This is part of the FDA’s Five-Year Plan for supporting antimicrobial stewardship in veterinary settings and builds upon the momentum generated by the implementation of GF#213. Under GFI #213, animal drug sponsors worked in collaboration. with FDA over a 3-year period to voluntarily change OTC medically important antimicrobials used in the feed or drinking water of food-producing animals to VFD/Rx marketing status and eliminated the use of these products for production purposes (e.g., growth promotion). These changes took effect in January 2017.

A limited number of other dosage forms of medically important antimicrobials, such as injectables, are currently marketed as OTC products for both food-producing and companion animals. When Draft GFI #263 has been finalized and fully implemented, all dosage forms of all approved medically important antimicrobials for all animal species can only be administered under the supervision of a licensed veterinarian and only when necessary for the treatment, control or prevention of specific diseases.

Comments should be submitted no later than December 24, 2019. FDA is proposing a two-year implementation period that would begin after the agency considers comments on the draft guidance and issues the final guidance.


Reorganization of the Office of New Drugs with Corresponding Changes to the Office of Translational Sciences and the Office of Pharmaceutical Quality

One critical component of the Modernization includes a reorganization of the New Drugs Regulatory Program. The reorganization of the New Drugs Regulatory Program requires restructuring of the Office of New Drugs (OND) and corresponding changes in the Office of Translational Sciences (OTS) and Office of Pharmaceutical Quality (OPQ). The approved changes in OND will create offices that align interrelated disease areas, and divisions with clearer and more focused areas of expertise. The changes increase the number of OND offices that oversee FDA’s review divisions from six to eight—and increases the number of OND clinical divisions from the current 19 divisions to 27, plus six non-clinical review divisions. In addition to enabling greater efficiency, these envisioned changes will help FDA to better understand the diseases intended to be treated by the drugs it evaluates for approval. OND will also create cross-functional support offices of New Drug Policy, Drug Evaluation Sciences, Regulatory Operations, Operations, and Administrative Operations.


TCPro simulates immune system response to biotherapeutic drugs

Scientists at the U.S. FDA have developed a mathematical tool that predicts whether the body will produce antibodies that block the activity of biotherapeutic protein drugs.

The computational tool, called TCPro, simulates the response of the immune system’s CD4+ T cells to specific biotherapeutic drugs. CD4+ cells orchestrate the immune system’s response to biotherapeutic drugs, including the production of antibodies against them by other cells, called B cells.

The new tool is important because most immune responses to biotherapeutic proteins include development of anti-drug antibodies. Therefore, new drugs must be assessed during the early stage of drug development to determine their potential to cause adverse immune reactions (i.e., determine their immunogenicity risk).

TCPro can be used to assess the potential for antibody formation even before the laboratory testing on biotherapeutics that is routinely done to screen for this risk. Such tests, which are done by culturing human T cells in contact with the drug and then measuring the growth of T cells, can be expensive and time-consuming. The FDA tool provides a rapid and inexpensive preliminary way to screen both new biotherapeutic proteins and new protein fragments added while the drug is being bioengineered.


Evaluation of Internal Standard Responses during Chromatographic Bioanalysis: Q&A

This guidance provides recommendations to sponsors, applicants, and contract research organizations regarding internal standard (IS) response variability in chromatographic analytical data submitted in investigational new drug applications (IND), new drug applications (NDA), abbreviated new drug applications (ANDA), biologics license applications, and supplements. Chromatographic analytical methods are commonly used to quantitate analyte concentrations in samples from nonclinical and clinical studies to support regulatory submissions. Depending upon its source, IS response variability may impact the accuracy of analyte concentration measurements. This Q&A document provides the Agency’s current thinking on IS response variability and its potential impact on the accuracy of analyte concentration measurements. It also suggests approaches to determine whether observed IS response variability is likely to impact the accuracy of the data such that further investigation into the root cause(s) is warranted.


International


Australia

Updated Guidelines for making an offer of enforceable undertaking to the TGA

Under section 42YL of the Therapeutic Goods Act 1989 (the Act), the Secretary of the Dep artment of Health can accept an offer of an enforceable undertaking.

An enforceable undertaking is a court-enforceable commitment by an individual or a company to carry out certain activities.

An enforceable undertaking is relatively quick compliance solution. It may include encouraging entities (individuals or companies) to improve their compliance arrangements or restrict the activities they can undertake. This can help entities meet their obligations under the Act and other regulations into the future, which in turn helps protect consumers and public health.

The Therapeutic Goods Administration (TGA) regards the enforceable undertaking as an important compliance tool in situations where there is evidence of a breach of the Act or regulations, but where it may not be in the public interest to take civil or criminal compliance action. Generally, enforceable undertakings are not used in cases involving deliberate misconduct, fraud, or conduct involving a high level of recklessness.

For an individual or company in potential breach of the Act or regulations, entering into an enforceable undertaking can be a cost-effective alternative to criminal or civil compliance action.

Factors that may be relevant to the TGA accepting an offer of enforceable undertaking can include:

  • whether the individual or company is prepared to publicly acknowledge that their conduct has breached the legislation and corrective action is necessary

  • whether the conduct was inadvertent

  • whether the conduct was undertaken with the knowledge of senior officers of a company

  • the entity's level of cooperation with the TGA's investigations of the conduct

  • whether the entity has any history of breaching the legislation or regulations or been the subject of complaints

  • whether compliance with the enforceable undertaking will protect the public from the risk of potentially harmful conduct

  • the likelihood or ability of the individual or company to comply with the enforceable undertaking

  • the prospect of a timely resolution of the matter.

Under delegation from the Secretary, the TGA has the power to accept an enforceable undertaking, consent to the withdrawal or variation of an enforceable undertaking, or make an application to the Federal Court to seek orders in relation to a breach of the terms of an enforceable undertaking.

In appropriate cases (for instance involving small companies, or where individuals are directors of a number of small companies), the TGA may accept an enforceable undertaking from both the company itself and from the director/s to ensure that all those likely to be involved in future activities involving therapeutic goods are bound by the relevant provisions.

In order to be enforceable, the undertaking has to be sufficiently specific for the promisor to know exactly what is expected of them and so that any failure to comply will be readily apparent.


TGA business plan 2019-20

The Business Plan sets out TGA’s product regulation, regulatory reform, international engagement and regulatory compliance agenda for 2019-20 and the steps it will take to achieve its vision.

TGA Business Plan is updated annually and is a central part of our activity planning and performance monitoring framework.


PIC/S

Focused stakeholders consultation on revised draft PIC/S GMP Guide Annex 2A (Manufacture of Advanced Therapy Medicinal Products for Human Use) and Annex 2B (Manufacture of Biological Medicinal Substances and Products for Human Use)

A draft revision of the PIC/S GMP Guide Annex 2 (Manufacture of biological medicinal substances and products for human use) has been prepared by the PIC/S Working Group on revision of Annex 2 established with WHO.

This revision is subject to a focused stakeholder consultation which includes both consultation questions and an opportunity to comment on:

- a draft Annex 2A (PS/INF 25/2019 (Rev. 1)): Manufacture of Advanced Therapy Medicinal Products for Human Use; and

- a draft Annex 2B (PS/INF 26/2019 (Rev. 1)): Manufacture of Biological Medicinal Substances and Products for Human Use.

Draft Annex 2A takes into account the international development in the regulation of Advanced Therapy Medicinal Products (ATMP) with particular attention to the European Commission guideline on GMP for ATMP which has been published since the latest revision of the EU Annex 2, while addressing at the same time concerns of PIC/S Participating Authorities with regard to patient safety and proportionate regulation for ATMPs. Draft Annex 2B is the revised version of EU Annex 2 for biologics (excluding ATMPs).

The consultation period will last 3 months and run from 20 September 2019 to 20 December 2019. (Please note PHSS is not currently one of the organisations providing feedback. A list of such organisations and additional information including the draft guidances can be found on the ‘News’ section of the PIC/S website.


WHO

Proposal to discontinue the test for undue toxicity (chapter 3.7) in the international pharmacopoeia

A draft document has been issued to a limited audience following the decision of the WHO Expert Committee on Biological Standardization (ECBS), it is proposed to omit chapter 3.7, “Undue Toxicity” in The International Pharmacopoeia and its reference in the monographs on Kanamycin acid sulfate and Kanamycin monosulfate. (Note PHSS will not be submitting comment on this document)


Products

USFDA approves first live, non-replicating vaccine to prevent smallpox & monkeypox

USFDA has announced the approval of Jynneos Smallpox and Monkeypox Vaccine, Live, Non-Replicating, for the prevention of smallpox and monkeypox disease in adults 18 years of age and older determined to be at high risk for smallpox or monkeypox infection. This is the only currently FDA-approved vaccine for the prevention of monkeypox disease.

Although naturally occurring smallpox disease is no longer a global threat, the intentional release of this highly contagious virus could have a devastating effect. This approval reflects the U.S. government’s commitment to preparedness through support for the development of safe and effective vaccines, therapeutics, and other medical countermeasures.

Jynneos will be available for those determined to be at high risk of either smallpox or monkeypox infection. This vaccine is also part of the Strategic National Stockpile (SNS), the nation’s largest supply of potentially life-saving pharmaceuticals and medical supplies for use in a public health emergency that is severe enough to cause local supplies to be depleted. The availability of this vaccine in the SNS will help ensure that the vaccine is accessible in the U.S. if needed.


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.