Pharmaceutical regulatory round up: January 2023

Catch up with the latest news from around the pharmaceutical industry with our January 2023 regulatory review, curated by Dr Tim Sandle.





Faecal microbiota for transplantation


The U.S. FDA has updated its guidance for faecal transplantation therapies. This is a finalised guidance. Faecal microbiota transplantation is the administration of a solution of faecal matter from a donor into the intestinal tract of a recipient in order to directly change the recipient’s gut microbial composition and confer a health benefit.


The FDA guidance is aimed at the medical and scientific community regarding the investigational new drug application (IND) requirements for the use of faecal microbiota for transplantation (FMT) to treat Clostridioides difficile (C. difficile) infection not responding to standard therapies.


The policy does not apply to FMT that is obtained from a stool bank. A stool bank is defined, for the purpose of this guidance, as an establishment that collects, prepares, and stores FMT product for distribution to other establishments, health care providers, or other entities for use in patient therapy or clinical research. An establishment that collects or prepares FMT products solely under the direction of licensed health care providers for the purpose of treating their patients (e.g., a hospital laboratory) is not considered to be a stool bank under the guidance.





Establishment of a guideline on the development and manufacture of synthetic oligonucleotides

European Medical Agency (EMA) has recently published concept papers with the view to establish guidelines on the development and manufacture of synthetic oligonucleotides and peptides.


This concept paper addresses the need to establish a Guideline on the Development and Manufacture of Synthetic Oligonucleotides. The number of clinical trial applications for human products and marketing authorisation applications for synthetic oligonucleotides for both human and veterinary products has significantly increased over the last few years.


From an analytical and regulatory perspective, oligonucleotides are interesting since they present a link between products derived from biotechnology and small molecular chemical compounds.




Significant new use rules on certain chemical substances

In the U.S., the Environment Protection Agency has set out significant new use rules (SNURs) under the Toxic Substances Control Act (TSCA) for chemical substances that were the subject of premanufacture notices (PMNs) and are also subject to orders issued by EPA pursuant to TSCA.


The SNURs would require persons who intend to manufacture (defined by statute to include import) or process any of these chemical substances for an activity that is proposed as a significant new use by this rule to notify EPA at least 90 days before commencing that activity. The required notification initiates EPA's evaluation of the use.





Human factors and medical devices

The U.S. FDA has issued a new draft guidance titled “Content of Human Factors Information in Medical Device Marketing Submissions”. For medical devices, the most important goal of the human factors/usability engineering process is to minimise use-related hazards and risks and then confirm that these efforts were successful and users can use the device safely and effectively.


This is to help manufacturers to ensure that human factors are accounted for when medical devices are developed. The goal of the human factors assessment is to ensure that the device user interface has been designed such that errors that occur during use of the device that could cause harm or degrade medical treatment are either eliminated or reduced to the extent possible. The main factors to consider in a risk-based approach including the identification of (i.e., presence of or modification to) critical tasks and the elimination or reduction of use-related hazards.





Generic drug development

The U.S. FDA has issued a draft guidance document titled “Controlled Correspondence Related to Generic Drug Development.”


The guidance provides information regarding the process by which generic drug manufacturers can submit to FDA controlled correspondence requesting information related to generic drug development. This guidance also describes the Agency’s process for providing communications related to such correspondence.


Once final, this guidance will replace the December 2020 FDA guidance on the subject. The December 2020 guidance was issued as part of FDA’s implementation of the Generic Drug User Fee Amendments of 2017 (GDUFA II).





The FDA Modernization Act 2.0

The FDA Modernization Act 2.0 officially passed through the United States House of Representatives on December 23, 2022. The FDA Modernization Act gives drug sponsors the option to use scientifically rigorous, proven non-animal test methods when they are suitable.


The FDA Modernization Act 2.0 removes a mandatory requirement from the original Food, Drug, and Cosmetic Act of 1938 (FDCA) that mandates animal testing to ensure it will not be toxic. The Food, Drug, and Cosmetic Act of 1938 was originally passed in response to the sulphanilamide tragedy of 1937, where sulphanilamide was one of the first antibiotics in the class of “sulpha” drugs. Essentially, the pills were intolerable for patients and ended up causing damage to their blood, kidneys, nervous system and liver. This pressure caused the FDCA to get passed rapidly.


According to Laboratory Roots, the original act held clauses mandating animal testing, which resulted in the killing of countless animals around the world to further drug development. There have even been data that shows that animal testing may not be a great indicator of drug toxicity. With how developed human biology science is, animal testing may not even be necessary in many cases now.





Specifications for Pharmaceutical Preparations

The World Health Organisation (WHO) has updated parts of its “Specifications for Pharmaceutical Preparations”, relating to:


  • Guidelines and guidance texts adopted by the Expert Committee on Specifications for Pharmaceutical Preparations
  • Points to consider when including Health Based Exposure Limits (HBELs) in cleaning validation
  • Good manufacturing practices
  • Water for pharmaceutical use
  • Guideline on data integrity


The update includes the adoption of EU GMP Annex 1 by WHO.




Global antimicrobial resistance and use surveillance system

The WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) was launched in 2015 to foster AMR surveillance and inform strategies to contain AMR. The system started with surveillance of AMR in bacteria causing common human infections and has expanded its scope to include surveillance of antimicrobial consumption (AMC), invasive fungal infections, and a One Health surveillance model relevant to human health. As of the end of 2022, 127 countries, territories and areas participate in GLASS.


The fifth GLASS report has been issued. This summarises 2020 data on AMR rates in common bacteria from countries, territories and areas. The report includes analyses of population testing coverage or AMR trends.


A new interactive dashboard allow users to explore AMR and AMC global data, country profiles and download the data.


Patterns of antimicrobial consumption are presented by country with a particular focus on antibacterials. The report also presents the antimicrobial consumption according to the WHO AWaRe antibiotic classification, for penicillins and cephalosporines.





Global atlas of medical devices

WHO has issued a Global Atlas to consider the status of medical device topics. A focus is with supporting the increased access to priority medical devices (including in vitro diagnostics) for emergencies, wellbeing, and universal health coverage (UCH). The country profiles incorporate facts indicating the national status of medical devices in areas such as: medical device policies, regulations, incorporation, lists, inventories, nomenclature, health technology assessment, management and biomedical engineering resources.





Containment: methodologies, processes and technologies

A new ISPE document of interest has been published – “Good Practice Guide: Containment for Potent Compounds”. The guideline covers pharmaceutical containment, including background to safe working levels, the mechanisms of exposure and how such exposure can be controlled.


The guidance has been issued to reflect the increasing number of highly potent compounds that are handled within the pharmaceutical industry. Many modern products require some degree of containment or other exposure control to maintain safety.


Developed by a multinational team of experts consisting of engineers, toxicologists, hygienists and analysts from major pharmaceutical companies and suppliers, the guideline aims to consolidate this widely dispersed knowledge base into one document. It describes and discusses the containment methodologies, processes, and technologies commonly used in the pharmaceutical industry when handling potent compounds.





Strategies for Vaccine Development and Lifecycle Management

The PDA has issued “Technical Report No. 89: Strategies for Vaccine Development and Lifecycle Management”. The new report describes different strategies that can be applied to manage the development and lifecycle of vaccine products. The concepts covered are intended to apply to different types of vaccines, for which “real world” examples are provided.


Building product and process knowledge and including control strategy elements are particularly important for such complex biological products as vaccines. This report addresses that issue by including strategies that can be applied in early development to licensure and those that are focused on lifecycle management of marketing products.


Specific aspects of control strategies that are particularly relevant to both prophylactic and therapeutic vaccines are covered, including setting and managing specifications, managing process parameters with respect to classification and lifecycle management and considering comparability requirements.






The International Council for Harmonisation (ICH) has issued its Q13 “Guideline for Continuous Manufacturing of Drug Substances and Drug Products.” The guideline expands on the FDA Centre for Drug Evaluation and Research's (CDER) draft guidance from February 2019, Quality Considerations for Continuous Manufacturing.


Continuous manufacturing refers to technology that can enable pharmaceutical modernisation by using an integrated process with fewer steps and shorter processing times. This leads to a smaller equipment footprint, supporting an enhanced development approach (e.g., quality by design (QbD) and use of process analytical technology (PAT) and models), enabling real-time product quality monitoring and providing flexible operation to allow scale-up, scale-down and scale-out to accommodate changing supply demands.


The guideline describes scientific and regulatory considerations for the development, implementation, operation and lifecycle management of continuous manufacturing (CM). Building on existing ICH Quality guidelines, this guideline provides clarification on CM concepts and describes scientific approaches and regulatory considerations specific to CM of drug substances and drug products.




Homeopathy: FDA and regulatory action

Homeopathy is a medical system based on the belief that the body can cure itself. Many in the scientific sector and who are advocates of evidence based medicine are sceptical. Nonetheless, homeopathic remedies are sold around the world and used by millions of people. Some of these products are unsuitable for human health and a regulatory framework is required.


The U.S. FDA has issued a new guidance document: “Homeopathic Drug Products Guidance for FDA Staff and Industry”.


The guidance describes how the FDA intends to prioritise enforcement and regulatory actions for homeopathic drug products marketed in the United States without the required FDA approval.


The FDA has developed a risk-based approach involving certain categories of products that potentially pose a higher risk to public health. FDA defines “homeopathic drug product” as a drug product that is labelled as “homeopathic,” and is labelled as containing only active ingredients and dilutions (e.g., 10X, 20X) listed for those active ingredients in the Homeopathic Pharmacopeia of the United States (HPUS).





Clinical protocols for the U.S. market

The U.S. FDA has issued a “Clinical Electronic Structured Harmonised Protocol”


The clinical protocol describes the processes and procedures directing the conduct and analysis of a clinical trial of medicinal product(s) in humans. To date, no internationally adopted harmonised standard has been established for the format and content of the clinical protocol to support consistency across sponsors and for the electronic exchange of protocol information.





Risk assessment of antimicrobials intended for animal use

Prior to approving an antimicrobial new animal drug application, the U.S. FDA determines that the drug is safe and effective for its intended use in the animal. The Agency also determines that the antimicrobial new animal drug intended for use in food-producing animals is safe with regard to human health. The definition of “safe” is if the Agency concludes that there is reasonable certainty of no harm to human health from the proposed use of the drug in food-producing animals.


Risk is based on hazard characterisation, release assessment, exposure assessment and a consequence assessment, in order to produce a risk estimation.


To address the main points, the FDA has developed a draft guidance “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to their Microbiological Effects on Bacteria of Human Health Concern”.


The document provides guidance for industry to evaluate potential microbiological effects of antimicrobial new animal drugs on bacteria of human health concern as part of the new animal drug application process. A risk assessment is required to assess any possible mechanisms in relation to the development of antimicrobial resistance resulting from the use of the drug.




Aluminium toxicity in parenteral nutrition products

Aluminium toxicity in parenteral nutrition (PN) represents a major safety concern, necessitating that PN products meet safety requirements for aluminium content and labelling.


The U.S. has issued a new draft guidance document: “Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations.”


As per the FDA regulation, aluminium content of large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy must not exceed 25 micrograms per litre (mcg/L).


In contrast, the limits for the aluminium content of small volume parenteral (SVP) drug products and pharmacy bulk packages (PBPs) used in PN are not specified by statute or regulation. Further, the International Council for Harmonisation (ICH) has not established a permitted daily exposure (PDE) for aluminium.


To address this lack of information, the draft guidance clarifies the key factors in determining the aluminium content in an SVP drug product and/or a PBP intended as a component of PN and provides FDA’s recommendations regarding the aluminium concentration limits in SVP drug products and PBPs for PN.

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