Issue 10: Pharmaceutical regulatory roundup




Catch up with the latest news from around the pharmaceutical industry with issue 10 of our regulatory review, curated by Dr Tim Sandle.


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ICH guidance on biodistribution


An important step in the development process with many products (including gene therapy products) is assembling biodistribution data in relation to the intended clinical population. Developing an accurate biodistribution profile is influenced by factors such as the route of administration, dose level(s), dosing regimen and the animal immune response to the gene therapy product.


While animal models remain important, biotechnology firms are reducing their use of animal models for the targeting of viral vectors and, at the same, are seeking more efficient nonclinical assessment methods. A new ICH guidance S12 (adopted by the US FDA in May 2023 and by the EMA during September 2023) provides the regulatory expectations around these nonclinical approaches. This is the first internationally harmonised guideline that specifically addresses an important nonclinical development component of gene therapy products. This article reviews the key points from the guidance.


The guidance can be found here: 




Guidance on Qualified Person responsible for pharmacovigilance


The MHRA have updated their ‘Guidance on qualified person responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF)’.


New guidance replaces the section: 'Notification of QPPV and PSMF details to the MHRA by existing holders of UK marketing authorisations'. The revision replaces the previous requirement to submit a Type IA(IN) variation and an accompanying eCTD sequence to make these changes. This has been simplified and only an update notification is required - there is no requirement to submit an eCTD sequence.






Changes to clinical trials regulation


The MHRA is seeking views on the Good Clinical Practice (GCP) guideline revised by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The ICH E6(R3) GCP guideline seeks to maintain patient safety, alongside enabling and encouraging innovation and risk-proportionate regulation of clinical trials.


The ICH papers plan to update the guidance to further encourage a proportionate, risk-based approach to the quality management of clinical trials. They focus on addressing innovation in trial design and conduct. This includes the increasing use of new technologies, as well as the protection of the rights, well-being and safety of trial participants and the reliability of the trial results. The ICH Principles of GCP (in section II of the guidance) will form part of the revised UK legislation. The consultation will inform the UK Clinical Trials Regulations.


The consultation will close on Thursday 31 August 2023. See: 




Oral drug products


The USP is proposing an update to Chapter 〈2〉 “Oral Drug Products—Product Quality Tests.” A revision to the chapter appears in the third issue of Pharmacopeial Forum #49. 


The revision was initiated to align the section of extractables of this chapter with corresponding information contained in ICH Guideline Q6A—Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. 


The relevant official texts on dissolution and nitrosamines were also incorporated. Additional alignment with current guidance from FDA on chewable tablets was also introduced. References to general chapters on extractables and leachables were incorporated for completeness.  Other sections were updated for better flow and consistency within the chapter.


Accessing the USP requires registration, via: 




Titrimetry with Automated Instruments


The USP has published a stimuli article titled “Titrimetry with Automated Instruments”. 


Quantitative determinations by titrimetric analysis can be automated using motor-driven piston burets in combination with appropriate sensors to monitor the course of the titration reaction and to determine the endpoint. A mathematical evaluation of the resulting titration curve allows for the calculation of the equivalence point.


Control and evaluation of titrimetric analyses can be automatically achieved by means of microprocessor-controlled instruments.


The stimuli article describes working principles of titration (e.g., reaction types, endpoint vs. equivalence point and endpoint indication). Manual titration is compared to automated titration and recommendations are given for the migration of manual to automated titration methods.


Accessing the USP requires registration, via:




Subvisible particles


Subvisible particles are commonly defined as particles smaller than those that are visible to the unaided eye (e.g., approximately 100 µm or smaller). These particles may lead to occlusions in blood capillaries and certain particle types have potential immunogenicity concerns for biologic DPs. Therefore, subvisible particles are monitored at drug product release and during stability testing to ensure product quality and patient safety.


The USP has published a new stimuli article. For small volume therapeutics (≤100 mL), subvisible particulate (SbVP) matter limits are generally set at no more than 6000 particles per container for ≥10 µm particles, and no more than 600 particles per container for ≥25 µm particles per compendia.


A volume multiplier needs to be selected for calculating the particles per container value from the light obscuration (LO) analytical testing results of particles per millilitre. In liquid products (liquid in vials or syringes), multiple nomenclatures exist to describe drug product volumes at various steps in delivering liquid products to patients. For example, the fill volume or total volume in a container, measured deliverable volume and label claim volume, are all applicable options - it is unclear which of these terms is best suited for use as the volume multiplier.


Moreover, lyophilized drug products are uniquely challenging as the label dose is typically in mass and not volume and the solid contents need to be reconstituted. Several options are available for selecting the volume multiplier, such as the fill volume (pre-lyophilized total volume), reconstitution volume, total volume after reconstitution and minimum deliverable volume. In the article, the USP clarifies the nomenclature of drug product volumes and discusses the preferred choice in selecting a volume multiplier for the subvisible particles per container calculation. This is described as a patient-centric hybrid approach, by which the drug product volume selected as the volume multiplier is closest to what is intended for the patient.


Accessing the USP requires registration, via:



Optical rotation


The USP is proposing to update Chapter <781> on optical rotation. Many pharmaceutical substances are optically active in the sense that they rotate an incident plane of polarised light so that the transmitted light emerges at a measurable angle to the plane of the incident light. This is a characteristic of some crystals and of many pharmaceutical liquids or solutions of solids.


Optical rotation is an analytical method that utilises a polarimeter to characterise optical isomers. The proposed revisions to 〈781〉 serve one primary purpose - to change the requirements of relative standard deviation (%RSD) to standard deviation in the Repeatability section under Operational Qualification (OQ).


Accessing the USP requires registration, via:




FDA draft guidance on Generally Accepted Scientific Knowledge in Applications for Drug and Biological Products


The U.S. FDA has received an increasing number of questions regarding the extent to which generally accepted scientific knowledge (GASK) may be relied on for drug or biological product approval.


The Agency has issued a draft guidance that describes instances in which it may be appropriate to rely on GASK to meet certain nonclinical safety requirements for new drug applications (NDAs) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)) and biologics license applications (BLAs) under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 262(a)). The information that supports the nonclinical safety of a drug - and that must be submitted in the application - can include references to GASK (when appropriate), instead of or in addition to, specific studies conducted with respect to the drug.


Such information includes the drug’s pharmacology and disposition (pharmacological effects, including mechanism(s) of action; absorption, distribution, metabolism, excretion and toxicology (acute, subacute, and chronic toxicity; developmental and reproductive toxicity; carcinogenicity; and special toxicology, as appropriate). 


This data can come from studies conducted in animals or in vitro. The aim is to:


•    Identify the pharmacological effects, including mechanism(s) of action of the drug in vitro and/or in vivo
•    Identify the absorption, distribution, metabolism, and excretion of the drug in vitro and/or in animals
•    Identify possible consequences of exposure duration (e.g., chronic)
•    Identify risks for special populations (e.g., paediatrics).
•    Identify specific parameters to inform safety in humans
•    Identify the mechanistic understanding of an adverse biological change observed in animals or humans


The guidance can be accessed here:




Screening of donors

The U.S. FDA has issued two documents related to donor screening in relation to blood and blood components.


These are titled:


“Implementation of Acceptable Full-Length and Abbreviated Donor History Questionnaires and Accompanying Materials for Use in Screening Donors of Blood and Blood Components”, see: 




“Recommendations for Evaluating Donor Eligibility Using Individual Risk-Based Questions to Reduce the Risk of Human Immunodeficiency Virus Transmission by Blood and Blood Products”, see: 


Both documents are final versions. 




Ph. Eur. 11.3


The third update to the 11th edition of the European Pharmacopeia goes live on 1st January 2024. Among the chapters of general interest are:


Chapter 2.2.35. Osmolality


The key changes are:


  • Calibration and adjustment. The requirements have been clarified and the zero point
    determination is now avoided
  • Accuracy check. This section has been included to provide additional detail and clarify
    previous requirements. The acceptance criterion has been revised to account for the
    extension of the osmolality reference solutions to values up to 4000 mosmol/kg
  • Reference solutions. This section has been added to provide more guidance on the inhouse preparation of osmolality reference solutions using sodium chloride
  • Table 2.2.35.-1. The preparation of the historical reference solutions in the range
    100-700    smol/kg has been revised according to a new assessment of the scientific data available. The table has also been extended to include osmolality values up to
    4000 mosmol/kg
  • Measurement. The description has been rendered more general


Chapter 2.2.46. Chromatographic separation techniques


The key changes are:

  • Signal-to-noise ratio (S/N): the calculation of the S/N ratio as prescribed in supplements 6.4 to 10.8, i.e., a calculation on a window of at least 5 times the peak width at half height, has been reinstated instead of 20 times (as prescribed in the 11th Ed.). The chromatograms in Figures 2.2.46.-6 and 2.2.46.-7 have been amended accordingly 
  • System sensitivity. The explanation (local requirement) on which solution to use to calculate the S/N ratio has been corrected since the S/N ratio is based on peak height and peak width at half-height, not on peak area. For more clarity, “extrapolate the signal-to-noise ratio” is now stated and the whole recommendation is simplified




Monographs: Pharmaceutical preparations (2619) and Substances for pharmaceutical use (2034), both contain the addition of a paragraph explaining the Ph. Eur. approach for N-nitrosamine impurities.


Soya-bean oil, refined (1473)


Composition of fatty acids. The limits of stearic acid and linolenic acid are updated based
on products on the European market and are aligned with the requirements of the European
legislation for food additives.




Scientific recommendations on classification of advanced therapy medicinal products


The European Medicines Agency (EMA) has updated the list of medicines that the Committee for Advanced Therapies has assessed and recommended classifying as advanced therapy medicinal products (ATMPs) or not. EMA updates the list on a quarterly basis.


The list can be downloaded here: 



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