Issue 9: Pharmaceutical regulatory roundup

BY DR TIM SANDLE  |  16 MAY 2023



Catch up with the latest news from around the pharmaceutical industry with issue 9 of our regulatory review, curated by Dr Tim Sandle.


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FDA: Discontinuation of products


The U.S. FDA has issued draft guidance relating to the discontinuation of finished products and active pharmaceutical ingredients, titled “Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act”.


They state: “FDA is issuing this guidance to assist applicants and manufacturers in providing FDA timely, informative notifications about changes in the production of certain finished drugs and biological products as well as certain active pharmaceutical ingredients (API) that may, in turn, help the Agency in its efforts to prevent and mitigate shortages.”


This guidance does not relate to short-term discontinuances or potential manufacturing issues (other protocols exist for these purposes). Examples include interruptions in manufacturing due to matters such as routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of time.


In the context of the guidance, meaningful disruption means a change in production that is reasonably likely to lead to a reduction in the supply of a drug by a manufacturer that is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its product.



Tightening microbial standards for non-sterile pharmaceuticals


The USP is updating several non-sterile mandatory chapters, which are set to be issued in the summer of 2023. These are:


<2> Oral drug products

Oral delivery is the most common route of administration for drug products. All oral drug products lead to systemic and/or local action in the oral cavity and/or gastrointestinal tract. Oral drug products fall primarily into two main categories: solids and liquids. 


<3> Topical and transdermal drug products

Topically applied drug products fall into two general categories: those applied to achieve local action and those applied to achieve systemic effects after absorption through the skin into the blood circulation. 


<4> Mucosal drug products

The mucosal route of drug administration is subdivided into seven membrane surfaces for the purposes of taxonomic distinction of dosage forms by route of administration. These membrane surfaces are characterized as otic, ophthalmic, nasal, oropharyngeal, urethral, vaginal and rectal. 


<5> Inhalation and nasal products

Inhalation drug products deliver drugs into the lungs by oral inhalation and include inhalation aerosols, inhalation powders, inhalation sprays, inhalation solutions, inhalation suspensions, solutions for inhalation and drugs for inhalation solutions dosage forms. Nasal drug products deliver drugs into the nasal cavity and include nasal sprays, nasal solutions, nasal aerosols and nasal powder dosage forms. 


An important change to each of these chapters is in relation to the microbial quality of the dosage form. The chapters have always required an assessment of microbial quality using appropriate validated test(s) and acceptance criteria for total aerobic count, total yeasts and moulds count.


The chapters contain greater clarification of the microbiological tests required: Microbial Enumeration Tests for Specified Microorganisms <62>; Alternative Microbiological Sampling Methods for Nonsterile Inhaled and Nasal Products <610>; Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use <1111>; Bioburden Control of Nonsterile Drug Substances and Products <1115>.


In addition, for inhalation and nasal products there is a new requirement in terms of a specific mention of ‘freedom from specified microorganisms’, with the acceptance criteria to be expressed per-container, per-gram or per-milliliter. There is a specific mention of USP Chapter <60> Microbiological Examination of Nonsterile Products—Tests for Burkholderia cepacia complex.


Burkholderia cepacia and related species are human opportunistic pathogens which can cause pneumonia in immunocompromised individuals (especially when introduced into the air passages of a susceptible population).


The Burkholderia cepacia complex is of concern in relation to many pharmaceutical and healthcare facilities because of their association with water and survival resilience. Moreover, many of the organisms within the group are resistant to organic solvents and antiseptics, and, to a degree, some types of disinfectant agents. Resistance arises from several factors, including efflux pump mechanisms within the bacterial cells.


Additional resistance is conferred through the organisms having a tendency to form biofilms under optimal conditions, especially on plastic materials and components (making plastic water piping a greater risk for biofilm formation than with stainless steel). The production of extracellular polymeric substances within the biofilm community means that chemical biocides cannot easily penetrate to kill community cells within the matrix.


For non-sterile drug product for inhalation use and water-based non-sterile drug products for oral, mucosal, skin and nasal administration, risk management and a control study of Burkholderia cepacia complex should be conducted. Following this, a corresponding control strategy should be developed according to relevant technical requirements and an assessment should be included in the product release/registration specification as necessary. This is unlike most other assessments of unacceptable microorganisms, where research and control can be carried out in combination with the product itself.


This places an additional microbiological focus on non-sterile pharmaceuticals. 



Replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers


The European Medicines agency has provided a Q&A guidance note titled “Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers - scientific guideline”.


The document outlines expected multidisciplinary (including quality, non-clinical and clinical) aspects of oral pressurised metered dose inhalers intended for delivery of the active substance into the lungs for the treatment of conditions affecting the lungs and airways (such as asthma and COPD). 


The document aims at providing advice regarding data requirements for the replacement of hydrofluorocarbons (HFCs) used as excipients (propellants) in oral pressurised metered dose inhalers with low global warning potential propellants (LGWP).



Medicines: notes for applicants and holders of a wholesale dealer licence or broker registration


The MHRA have updated their 2014 guidance aimed at helping applicants and licence holders secure and maintain a wholesale dealer licence (WDA(H)) or broker registration.


The guidance covers:

•    wholesale dealing or distribution
•    brokering
•    how to register as a broker
•    persons requiring a wholesale dealer licence
•    how to apply for a wholesale dealer licence
•    wholesale dealers’ obligations
•    responsible person
•    inspection
•    falsified and diverted medicines
•    regulatory action
•    fees for wholesale dealer licence applications


The update is with section 9 - 'Responsible Person'.






Evaluation guide for GMP regulatory compliance programme


The European Medicines Agency has updated its guidance on GMP inspections, which is in the form of an audit checklist. This is the third revision to document EMA/INS/GMP/119415/2023.



Comments on ICH guideline Q5A (R2) Viral safety evaluation


The EMA has posted an overview of comments received on ‘ICH guideline Q5A (R2) on Viral safety evaluation of biotechnology products derived from cell lines for Human or Animal origin’.


This refers to testing and evaluation of the viral safety of biotechnology products derived from characterised cell lines of human or animal origin. The guidance outlines data that should be submitted in the marketing application/registration package.





European Health Union: Commission proposes pharmaceuticals reform


The European Commission is proposing a revision of the EU pharmaceutical legislation. As a consequence, the role of the Qualified Person (QP), regulated in Article 48 of Directive 2001/83/EU, will move into Annex 3 of the proposed new Directive 2023/132.


This will take the form of a new Regulation and a new Directive, which are designed to achieve the following objectives:


  • Create a single market for medicines, ensuring that all patients across the EU have timely and equitable access to safe, effective and affordable medicines
  • Continue to offer an attractive and innovation-friendly framework for research, development and production of medicines in Europe
  • Drastically reduce the administrative burden by speeding up procedures and significantly reducing authorisation times for medicines, so they reach patients faster
  • Enhance availability and ensure medicines can always be supplied to patients, regardless of where they live in the EU
  • Address antimicrobial resistance (AMR) and the presence of pharmaceuticals in the environment through a One Health approach
  • Make medicines more environmentally sustainable


The revision is the first major review of the pharmaceutical legislation since 2004. It will adapt the legislation to the needs of the 21st century.


There are two legislative proposals: a new Directive and a new Regulation which constitute the EU regulatory framework for all medicines (including those for rare diseases and for children).


  • The Directive contains all the requirements for authorisation, monitoring, labelling and regulatory protection, setting the standard and other regulatory procedures for all medicines authorised at EU and national level.  See: 


  • The Regulation sets specific rules (on top of the ones in the Directive) for medicines authorised at EU level, in particular the most innovative ones. It sets out the rules on coordinated management of critical shortages and security of supply of critical medicines. It also sets out the rules governing the European Medicines Agency (EMA). See: 


This means Directive 2001/83 (Directive 2001/83/EC and Directive 2009/35/EC) are to be replaced.


Included within the changes, is a commitment that, for medicines for rare diseases, the standard duration of market exclusivity will be nine years. 


The regulation also aims to improve transparency on research and development (R&D) costs or public contributions to these costs. While R&D costs are not relevant for the assessment of a medicine's benefit-risk balance, it is hoped that more transparency on public support for the development of medicines may strengthen the negotiating position of authorities responsible for pricing and reimbursement of medicines when negotiating prices with the pharmaceutical companies. This could help reduce prices and thereby improve access to medicines.


Pharmaceutical companies will therefore be required to publish information on all direct financial support for the research and development of medicines received from public authorities or publicly funded bodies. This information will be easily accessible to the public on a dedicated webpage of the company and through the database of medicinal products for human use authorised in the Union.


An EU list of critical medicines - i.e. medicines considered to be most critical for health systems at all times - will be established. Recommendations on measures to be taken will be made to companies and other relevant stakeholders to strengthen the supply chains of those medicines, to ensure continuity and security of supply for EU citizens. The legislation will also allow the Commission to introduce, through an implementing act, measures to strengthen security of supply, including requirements to establish contingency stocks.


An environmental risk assessment (ERA) to limit the potential adverse impacts of medicines on the environment and public health is required. The ERA is mandatory for all pharmaceutical companies placing their medicines on the EU market. Marketing authorisation may be refused when companies do not provide adequate evidence that environmental risks were evaluated and risk mitigation measures were taken.





WHO good manufacturing practices for excipients used in pharmaceutical products 

The World Health Organization (WHO) has issued a draft guidance document titled “WHO good manufacturing practices for excipients used in pharmaceutical products”. 


As excipients are sometimes used in large quantities in pharmaceutical dosage forms, and may contain impurities, they can affect the quality of a finished pharmaceutical product. The manufacturer of the finished pharmaceutical product is normally dependent on the manufacturer of the excipient to supply excipients meeting the required specification. An appropriately established and implemented quality management system evaluating and controlling risks in the production and quality control of such excipients is therefore required.




Assessing the sensitization potential of transdermal and topical delivery systems 


The US FDA has issued a draft guidance document titled “Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs”. 


The guidance provides recommendations for the design and conduct of studies to evaluate the in vivo skin irritation and sensitisation (I/S) potential of a proposed transdermal or topical delivery system (collectively referred to as TDS). 


The recommendations in the guidance relate to studies submitted in support of an abbreviated new drug application (ANDA). The document clarifies recommendations for the design and conduct of studies to evaluate the in vivo skin (I/S) potential of a proposed TDS. The document also clarifies when an in vivo study to assess the sensitisation potential of a TDS product may not be needed.




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