Review of Developments in GMP and the Regulation of Medicines Aug 2019
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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 and USA regulatory authorities.
The topics covered in this edition of the “Update” include:
EMA activities, other than the highest priority activities, that will continue in 2019
Variations to Marketing Authorisations
BREXIT
EU-US mutual recognition agreement for inspections
Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines
How to prepare and review a summary of product characteristics
Quality requirements for drug-device combinations
Q&A on the use of OOS batches of authorised cell/tissue-based ATMPs
MHRA The 2018 Good Distribution Practice (GDP) and GMP Symposia
Formal Dispute Resolution: sponsor appeals above the division level
ANDA Submissions — content and format of abbreviated new drug applications
Providing regulatory submissions in electronic and non-electronic format — promotional labeling and advertising materials for human prescription drugs
Opioid Analgesic Drugs: considerations for benefit-risk assessment framework
guidance for industry
Modernizing FDA's New Drugs Regulatory Program
CDER Conversation: Ensuring that standardization does not impede biological product innovation
FDA poliovirus assay is faster and more versatile than current assays
Additional safety protections regarding use of fecal microbiota for transplantation
Guidance Documents CBER is Planning to Publish During Calendar Year 2019
Bioanalytical method validation M10
CBER Advanced Technologies Program
Excluded autologous human cells and tissues
GMP clearance guidance update (v.18.3)
Products
Premier Pharmacy Labs issues voluntary nationwide recall of all unexpired sterile drug product lots due to lack of sterility assurance
RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS
Europe
EMA
EMA activities, other than the highest priority activities, that will continue in 2019
EMA has published a seven page document updating which activities will included in its work programme through to the end of calendar 2019
Variations to Marketing Authorisations
The EMA has updated guidance for marketing authorisation holders on the regulatory requirements and procedures for the different types of variations for both human and veterinary products.
BREXIT
EMA has updated its guidance on the UK’s withdrawal from the EU and also its BREXIT guidance to companies.
EU-US mutual recognition agreement for inspections
Three additional countries now benefit from the EU-US mutual recognition agreement for inspections. Germany, Luxembourg and the Netherlands have been included into the EU/USA MRA. This means that the FDA will now rely on a total of 27 Member States whose inspection results can replace their own inspections. [Good to see Germany making the list. With so many regulatory bodies involved from the various Lander etc. it was never going to be the most simple of assessments for FDA to complete within the pre-set timelines. mbh]
Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines
The risks associated with the presence of the nitrosamines N-nitrosodimethylamine (NDMA) and Nnitrosodiethylamine (NDEA) in sartan blood pressure medicines (angiotensin II receptor blockers) containing a tetrazole ring have been assessed in a referral under Article 31 of Directive 2001/83/EC within procedure EMEA/H/A-31/1471. Temporary interim limits based on the TD50 values in rat carcinogenicity studies have been set for NDMA and NDEA: acceptable intakes (AI) of 96.0 ng for NDMA and 26.5 ng for NDEA.
Potential contamination with other N-nitrosamines was also considered during this procedure. Such impurities could be generated if different sources of secondary or tertiary amine are present at the same time as nitrite. Some common organic solvents (e.g. N-methylpyrrolidone, which could give rise to 4-(methyl)(nitroso)(amino)butanoic acid [BMSA/NMBA]) and amine bases (e.g. diisopropylethylamine [DIPEA], which could give rise to N-nitrosodiisopropylamine [DIPNA) and Nnitrosoethylisopropylamine [EIPNA]) would present such risks. 4-(methyl)(nitroso)(amino)butanoic acid (BMSA/NMBA) has been detected in losartan batches of Hetero Labs. NMBA may also be referred to as nitrosomethyl-3-carboxypropylamine and 4-(methylnitrosamino) butyric acid (MNBA).
How to prepare and review a summary of product characteristics (SmPCs)
This guidance is intended to enable companies to make sure that the information in SmPCs is of high quality when they submit them to the Agency as part of applications for new, or updates to existing marketing authorisations. It also aims to raise awareness of the information provided in SmPCs among healthcare professionals. It includes both training presentations and scientific guidelines.
Quality requirements for drug-device combinations
This guideline provides dossier requirements for drug-device combinations (DDCs) in the context of a regulatory submission (marketing authorisation application and post-authorisation application). The types of DDCs within the scope of the guideline are medical devices that are integral to the medicinal product, co-packaged with the medicinal product or referenced in the medicinal product information and obtained separately.
Q&A on the use of OOS batches of authorised cell/tissue-based ATMPs
EMA has updated its GMP and GDP Q&A in relation to this topic. There are 6 Q&As on this topic.
MHRA
The 2018 Good Distribution Practice (GDP) and GMP Symposia
MHRA has published two blogs covering these events.
United States of America
The US Food and Drug Administration (USFDA)
Formal Dispute Resolution: sponsor appeals above the division level
This final guidance provides recommendations for industry and review staff on the procedures in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) for resolving scientific and/or medical disputes between CDER or CBER and sponsors that cannot be resolved at the division level. This guidance describes the formal dispute resolution (FDR) procedures for sponsors that wish to appeal a scientific and/or medical issue to the office or center level and provides a structured process for resolving disputes.
During the course of review of an investigational new drug application (IND), new drug application (NDA), biologics license application (BLA), or abbreviated new drug application (ANDA), a wide variety of important scientific and/or medical issues are considered that are central to product development. Sometimes, a sponsor may disagree with the Agency on a matter, and a dispute arises. Because these disputes often involve complex scientific and/or medical matters, it is critical to have procedures in place to help ensure open and prompt discussion. The procedures and policies described in this guidance are intended to promote rapid and fair resolution of scientific and/or medical disputes between a sponsor and CDER or CBER.
ANDA Submissions — content and format of abbreviated new drug applications
This final guidance is intended to assist applicants in preparing abbreviated new drug applications (ANDAs) for submission to FDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)). This guidance details the information that should be provided in each section of the common technical document (CTD) format for human pharmaceutical product applications and identifies supporting guidance documents and recommendations issued by FDA to assist applicants in preparing their ANDA submission. This guidance identifies the information that an applicant should include to ensure that a complete, high-quality application is submitted to FDA. FDA has previously published guidance documents on the filing process, including the guidance for industry about refuse-to-receive standards, and common, recurring deficiencies which should be reviewed thoroughly prior to submission of an ANDA.
Providing regulatory submissions in electronic and non-electronic format — promotional labeling and advertising materials for human prescription drugs
This final guidance pertains to submissions of promotional materials for human prescription drugs to the FDA made by manufacturers,
packers, and distributors, whether the applicant or an entity acting on behalf of the applicant. Specifically, this guidance pertains to submissions made to the Office of Prescription
Drug Promotion (OPDP) in the CDER and the
Advertising and Promotional Labeling Branch (APLB) in the CBER. This guidance also explains certain aspects of electronic submission of promotional materials in module 1 of the electronic common technical document (eCTD), using version 3.3 or higher of the us-regional-backbone file. For the purpose of this guidance, the term promotional materials collectively refers to promotional labeling and advertising materials, regardless of the format, manner, or medium by which they are presented. Promotional materials may include, but are not limited to, television advertisements (ads), brochures, booklets, detailing pieces, internet websites, print ads, exhibits, sound recordings, and radio ads.
Opioid Analgesic Drugs: considerations for benefit-risk assessment framework guidance for industry
The purpose of this draft guidance is to describe the benefit-risk assessment framework that the Agency uses in evaluating whether applications for opioid analgesic drugs meet the standard for approval under section 505 of the FD&C Act. This guidance summarizes the information that should be included in a new drug application for an opioid analgesic drug to facilitate the Agency’s benefit-risk assessment.
Benefit-risk assessment is the foundation for FDA’s regulatory review of human drugs and biologics. These assessments capture the evidence, uncertainties, and reasoning used by FDA to arrive at its regulatory decisions. Additionally, these assessments serve as tools for communicating that information to those interested in a better understanding of FDA’s thinking.
FDA assesses risks and benefits of all drugs in the context of the use indicated in the labeling. However, because of the widespread misuse and abuse of prescription opioid analgesic drugs, for this class of drugs, FDA also considers the broader public health effect of opioid analgesic drugs; this involves consideration of the risks related to misuse, abuse, opioid use disorder, accidental exposure, and overdose, for both patients and others. Likewise, FDA considers any properties of a drug expected to mitigate these risks. This guidance describes the various factors that FDA will consider in evaluating the benefits and risks of an opioid analgesic drug. FDA encourages applicants to provide information relevant to these factors.
Modernizing FDA's New Drugs Regulatory Program
In 2017, FDA’s CDER embarked on an initiative to modernize the New Drugs Regulatory Program. This will allow CDER to better serve patients and better support staff in their work to carry out the center’s mission – to protect and promote health by making sure that human drugs are safe and effective for their intended use, that they meet established quality standards, and that they are available to patients. CDER are working to build on past successes and strengths by implementing problem-focused, interdisciplinary, team-based approaches so they can meet the challenges of evolving science, new drug platforms, and new drug targets, while incorporating the patient voice in development.
The modernization of the New Drugs Regulatory Program will be a long-term process of continuous improvement involving multiple initiatives. Implementation of some initiatives has begun and will continue over the course of 2020. Additional information will be added as programs and projects progress.
The modernization focuses on six strategic objectives
Scientific Leadership- Grow scientific expertise and clarify pathways to regulatory approval.
Integrated Assessment- Critically, collaboratively, and consistently assess whether information in drug approval applications meets legal and regulatory requirements.
Benefit-Risk Monitoring- Systematically monitor the benefits and risks of approved drugs pre- and post- approval to effectively protect the American public.
Managing Talent- Attract, develop, and retain outstanding people.
Operational Excellence- Standardize workflow, business processes, roles, and responsibilities to improve operational efficiency, and enable FDA scientists to focus on science.
Knowledge Management- Facilitate the identification, capture, distribution and effective use of information.
CDER Conversation: Ensuring that standardization does not impede biological product innovation
The U.S. Pharmacopeia (USP) is an independent, non-governmental, not-for-profit organization that sets quality, purity and strength standards for medicines, food ingredients and other products sold in the United States. The FDA works closely with USP to enforce USP’s standards, which are often called monographs. These monographs, which manufacturers are legally required to follow when applicable, can be vital for many small molecule drug products. However, for biological products, adhering to a monograph may actually hinder progress and does not offer additional quality assurances.
To date, the vast majority of the most highly used biological products do not currently have monographs. It is possible that a maker of an older product could ask USP to write a monograph for its product, and if it were approved, it could impact both existing and future products on the market.
FDA poliovirus assay is faster and more versatile than current assays used in vaccine development and environmental surveillance
FDA has developed a poliovirus assay that is faster and more versatile than those now used to monitor polio vaccine production, assess patient responses to polio vaccines during clinical trials, and do environmental surveillance of vaccine poliovirus. The assay is also the first to measure the amount of several different strains simultaneously in a mixture of polioviruses. the new assay directly measures viral DNA using quantitative multiplex polymerase-chain-reaction (PCR) as an endpoint. In the multiplex PCR-based titration (MPBT) assay, cell cultures are infected with serial dilutions of test samples, lysed after two-day incubation, and subjected to a quantitative multiplex one-step reverse-transcriptase PCR. All three serotypes of poliovirus are identified and quantified in a single assay.
The development of the assay is important because it has key advantages for poliovirus vaccine development and production, as well as public health responses to the virus. The ability to identify and determine the quantity of several different viruses simultaneously enables it to rapidly process the large number of fecal samples collected from subjects during clinical trials, which is more time-consuming using the current techniques.
The assay is also suitable for public health surveillance of vaccine virus in the environment, which could make it easier to track the poliovirus.
Additional safety protections regarding use of fecal microbiota for transplantation
FDA has informed healthcare providers and patients of the potential risk of serious or life-threatening infections with the use of fecal microbiota for transplantation (FMT). Bacterial infections caused by multi-drug resistant organisms (MDROs) have occurred due to transmission of a MDRO from use of investigational FMT, resulting so far in the death of one individual.
Because these serious adverse reactions occurred with investigational FMT, FDA has determined that additional protections are needed for any investigational use of FMT. FDA has notified all Investigational New Drug (IND) holders of these requirements and that they need to implement these new requirements no later than July 15, 2019.
FDA has received inquiries from non-IND holders since the release of the June 13, 2019 safety communication, such as those who may be using FMT under enforcement discretion, regarding the additional screening and testing procedures. To ensure that all stakeholders are fully informed, FDA is providing additional information that has already been communicated to IND holders.
Guidance Documents CBER is Planning to Publish During Calendar Year 2019
This is the updated list of guidance topics CBER is considering for development during Calendar Year 2019. The list includes topics that currently have no guidance associated with them, topics where updated guidance may be helpful, and topics for which CBER has already issued Level 1 draft guidances that may be finalized following review of public comments.
Bioanalytical method validation M10
This guideline is intended to provide recommendations for the validation of bioanalytical assays for chemical and biological drug quantification and their application in the analysis of study samples. Adherence to the principles presented in this guideline will improve the quality and consistency of the bioanalytical data in support of the development and market approval of both chemical and biological drugs.
The objective of the validation of a bioanalytical assay is to demonstrate that it is suitable for
its intended purpose. Changes from the recommendations in this guideline may be acceptable if appropriate scientific justification is provided. Applicants are encouraged to consult the regulatory authority(ies) regarding significant changes in method validation approaches when an alternate approach is proposed or taken.
Concentration measurements of chemical and biological drug(s) and their metabolite(s) in biological matrices are an important aspect of drug development. The results of pivotal nonclinical toxicokinetic (TK)/pharmacokinetic (PK) studies and of clinical trials, including comparative bioavailability / bioequivalence (BA/BE) studies, are used to make regulatory decisions regarding the safety and efficacy of drug products. It is therefore critical that the bioanalytical methods used are well characterised, appropriately validated and documented in order to ensure reliable data to support regulatory decisions.
CBER Advanced Technologies Program
The development of advanced technologies is critical to modernizing biopharmaceutical manufacturing and improving quality and patient access, CBER also recognizes that the implementation of advanced technologies could present challenges to both industry and CBER. By the very nature of an approach being new or innovative in the biopharmaceutical industry, a limited knowledge and experiential base about the technology may exist.
CBER has established the CBER Advanced Technologies Team (CATT) to promote dialogue, education, and input among CBER staff and between CBER and prospective innovators / developers of advanced manufacturing technologies that are intended to be implemented in CBER-regulated products. As part of this remit, the CATT will facilitate responses to inquiries from developers of these innovative technologies. Through this inquiry program, interested parties have access to early interactions with CBER prior to filing a regulatory submission.
International
International
Australia
Excluded autologous human cells and tissues
This guidance, which is part of the Australian Regulatory Guidelines for Biologicals (ARGB), is for sponsors of autologous human cells and tissues (HCT) products. It will help you work out if your product is excluded from TGA regulation.
The level of regulation for autologous HCT products is based on the level of risk to the public associated with the manufacturing processes and intended use of the product. If your product is not excluded from TGA regulation, go to Autologous HCT products guidance for information on levels of regulation.
The TGA considers that there are circumstances in which there is sufficient regulation by other bodies to mitigate possible risks that may arise as a result of manufacturing and use of autologous HCT products.
update (v.18.3)
GMP clearance guidance material has been reviewed to reflect the current processes and provide additional information for sponsors and applicants. TGA has published an updated version of the GMP clearance guidance (version 18.3) on TGA website. This version includes the following updates:
Target processing timeframes for Compliance Verification (CV) applications submitted from 1 July 2019
Additional information on prioritisation requests
The previous version of the guidance will be archived and will no longer be accessible.
Products
Premier Pharmacy Labs issues voluntary nationwide recall of all unexpired sterile drug product lots due to lack of sterility assurance
Premier Pharmacy Labs is voluntarily recalling all unexpired products, intended to be sterile, due to a lack of sterility assurance. The Unexpired Sterile Drug Product Lots (include dates dispensed) are being recalled due to concerns presented during the latest FDA inspection including insufficient environmental controls, potential cross contamination and lack of product specific process validations. The nationwide recall includes lots of sterile drug products to the consumer/user level.
The scope of this recall is all commercially distributed product lots compounded in the Weeki Wachee, FL location currently within their labeled expiration date in response to an FDA concerns raised during the most recent inspection carried out from 29 April, 2019 to 12 June, 2019. (Note A number of such incidents have occurred at compounding pharmacies in recent years, some with extremely serious consequences for patients. USFDA continues to issue new rules and to tighten its control over compounding. In a recent Email to Staff Dr.Janet Woodcock, Director of CDER indicated the intention to institutionalize oversight of compounding regulatory programme by centralizing it in the Office of Compliance which is responsible for enforcing Quality Regulations to stop sub-standard products from harming patients part of which specifically includes protecting consumers from unsafe compounded drugs. -mbh)
And finally…
Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website and on the websites of the relevant regulatory bodies and international organisations.
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 and member of the PHSS Management Committee
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