Pharmaceutical regulatory round up: February 2023

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

BY DR TIM SANDLE  |  16 February 2023


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ICH Q9 – Quality Risk Management

Since it was first issued in 2006, ICH Q9 has been a key document within pharmaceuticals and healthcare, providing guidance on ways to approach the management of quality risks. At this stage there were few examples of quality risk management in the pharmaceutical industry. Today, risk management has become commonplace. However, there are weaknesses with the way risk management is being applied, and this is something that regulators have picked up on.  The need to drive further improvements with the quality system has led to some changes to the quality risk management approach, especially in pushing for more formality.


ICH Q9 ‘Quality Risk Management’ has been updated. It now becomes “ICH Q9(R1)”. ICH Q9 is a GMP requirement, with EU GMP and it is adopted by the FDA.


The changes are orientated towards approach and philosophy rather than process (i.e. no new risk tools have been included). Structurally, the changes are:


  • There is a new section “5.1: Formality in Quality Risk Management”.
  • There is a new section “5.2: Risk-based Decision Making”.
  • The title of Annex 1 – ‘Risk Management Methods and Tools’ – has been renamed ‘Quality Risk management Methods and Tools’.
  • A new sub-section II.9 has been added into Annex II (Quality Risk Management as part of Integrated Quality Management). The new sub-section is titled ‘Quality Risk Management as Part of Supply Chain Control’.


In terms of content, the main changes appear to be:


  • The word ‘risk identification’ has changed to ‘hazard identification’ (this means the overall risk approach is more closely aligned to the language used for HACCP and HAZOP tools).
  • There is a requirement to have less subjectivity with risk assessments, which means backing more statements up with supporting data (e.g. rather than saying “it doesn’t happen very often”, there is a requirement to back this up with data).
    • The guidance also recommends a greater use of science-based thinking.
    • The guidance recommends trying to understand bias and seeking to avoid this, and having a process to address different opinions.
  • There is renewed guidance on assessing product availability issues, where the definition of harm includes damage from a ‘loss of product availability’. The update requires risk assessors to address lifecycle risks to manufacturing reliability and quality assurance when assessing supply predictability. Where risk assessments are conducted that relate to issues that do, or could, affect product supply, there is a requirement to include: 
    •  Manufacturing process variation.
    • State of control (internal and external).
    • Manufacturing facilities.
    • The oversight of outsourced activities and suppliers.


  • There is a note on ensuring formality with risk assessments. The guidance indicates that the greater the significance of the risk then more formality is required in the risk management process. It remains acceptance for low risks to be assessed using less formal approaches.
  • There is a recommendation to connect more decisions and decision-making processes to formal risk assessments.
  • There is a recommendation that knowledge from risk assessments is captured, shared and used to improve processes and avoid future risk scenarios.
  • The ‘management’ part of risk management is given additional emphasis (that is it’s OK to identify risks but how are these being managed?)
  • The risk management system needs to account for lifecycle manufacturing performance and quality feedback, and these mechanisms should dictate how often risk assessments are reviewed and updated.


For more details on ICHQ9 visit:



Pyrogen and endotoxin testing

For injectable pharmaceuticals in particular, the presence of pyrogenic substances is a key patient concern. The European Pharmacopeia is undertaking a revision of its general chapter “guidelines for using the bacterial endotoxin test” 5.1.10 (reference note PA/PH/Exp. BET/T (22) 2 ANP). This is part of a broader exercise affecting multiple Ph. Eur. texts and aiming at the complete removal of the pyrogen test in rabbits described in general chapter 2.6.8. Pyrogens (“rabbit pyrogen test”) from the Ph. Eur.


As part of this exercise, the following texts have been published in Pharmeuropa (issue 35.1) for comment:


    1. New general chapter 5.1.13. “Pyrogenicity”, which provides guidance for the selection and implementation of a suitable test for pyrogenicity.
    2. Individual and general monographs on substances/preparations for pharmaceutical use that have been revised to delete the reference to the rabbit pyrogen test.
    3. A reference to general chapter 2.6.32. “Test for bacterial endotoxins using recombinant factor C” has been included in the introduction.


Revision to Chapter 5.1.10


General chapter 5.1.10. has been revised with a section 3 “Risk assessment”, and a section 12 “Implementation of methods described in the Ph. Eur.”. These have been moved to the newly proposed chapter 5.1.13.


Parts of chapter 5.1.10. have been deleted as they were considered to be either no longer applicable or redundant after the publication of 5.1.13. For example:


  • Section 13 “Replacement of a method prescribed in a monograph” has been deleted and this will be the subject of a new general chapter (5.27. “Comparability of alternative analytical procedures”, to be published in Pharmeuropa 34.2).
  • References to the rabbit pyrogen test have been removed.


Comments close on 31st March 2023.


Discover more here (registration required):  


Chapter 5.1.13


With the proposed new general chapter 5.1.13 “Pyrogencity”, the aim is to provide guidance for the selection and implementation of a suitable test for pyrogenicity (either the test for bacterial endotoxins or monocyte-activation test). This proposed new chapter contains certain parts taken from general chapter 5.1.10. “Guidelines for using the text for bacterial endotoxins”, including considerations on the risk assessment and on the implementation of methods.


It should be noted that the exercise will ultimately lead to the suppression of general chapter 2.6.8. Manufacturers still using the rabbit pyrogen test are strongly encouraged to take the necessary steps to proceed with its replacement by a suitable in vitro alternative (e.g. the monocyte-activation test).


The revision of this general chapter does not call into question strategies involving the test for bacterial endotoxins that are already used by manufacturers to control the pyrogenicity of their products and have been authorised by the competent authority, nor is it intended to prompt a retrospective assessment of pyrogenicity.


Removal of the rabbit pyrogen test


The detailed strategy of the Ph. Eur. Commission for removing the rabbit pyrogen test is described in a document published on Pharmeuropa online:  




UK to introduce framework to make it easier to manufacture innovative medicines at the point of care

Point-of-care testing refers to medical diagnostic testing occurring at or near the point of care, that is, at the time and place of patient care. The UK is to introduce a tailored framework for the regulation of innovative products manufactured at the point where a patient receives care. This will mean that new medicines with very short shelf lives and highly personalised medicines can more easily be made in or near a hospital setting or ambulance and can get to the patients who need them much more quickly.


The new framework will ensure there are no regulatory barriers to innovative manufacturing and that products made via such routes have the same assurances of safety, quality, and effectiveness as those for conventional medicinal products. This follows a public consultation carried out by the MHRA which heard from a range of individuals and organisations across the UK and internationally. In describing their experience with Point of Care (POC) products, responders highlighted the urgent need to establish a regulatory framework for these vital and varied products. 


Once implemented, this innovative framework will apply to all POC products manufactured in the UK, including a range of Advanced Therapy Medicinal Products, such as cell therapy, gene therapy and tissue engineered products; 3D printed products, blood products, and medicinal gasses.


For further details, see: 




REACH data update

To ensure consumer safety, companies make all efforts to identify and manage the risks linked to the substances they manufacture and market in the EU. The Registration, Evaluation, Authorization and restriction of Chemicals (REACH) is the environmental legislation of the European Union, and the regulation extends to pharmaceuticals.


This includes restricted substances, like:


  • 7 phthalates (3phthalates for toys and childcare articles that can be places in the mouth by children)
  • AZO colorants in textiles
  • Nickel release from metal products in direct contact with skin
  • PCTs
  • Benzene
  • Asbestos fibres
  • Arsenic compounds
  • Mercury compounds
  • Cadmium
  • View full list
  • Candidate list of SVHCs (Substances of Very High Concern)


The updated list and associated approvals can be found here:




Swiss Confederation signs mutual recognition agreement with U.S. FDA

The U.S. FDA signed an agreement on Mutual Recognition between the Swiss Confederation and the United States relating to pharmaceutical Good Manufacturing Practice (GMP). The agreement will be able to let FDA and the Swiss Agency for Therapeutic Products (Swissmedic) utilize each other’s GMP inspections of manufacturing facilities, avoiding the need for duplicate inspections.





The European Medicines Agency has updated “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products.”


All MAHs/Applicants of human medicinal products need to work with the manufacturers of their Active Pharmaceutical Ingredients (APIs) and finished products (FPs) in order to ensure that the presence of nitrosamine impurities in their medicinal products is mitigated as much as possible and controlled at or below a limit defined based on ICH M7(R1) principles for substances of the “cohort of concern” reflected in this guideline and calculated considering a lifetime daily exposure and kept as low as possible and that appropriate risk mitigating measures are taken.


The Q&A based guidance can be found here:




ICH guideline M13A on bioequivalence

The forthcoming ICH M13A Guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension.


The ICH M13A Guideline is the first Guideline in a foreseen ICH series describing the scientific and technical aspects of study design and data analysis to support BE assessment for orally administered IR solid oral dosage forms. For more information on harmonisation of BE, please refer to the dedicated ICH M13 page.


Currently, the anticipated finalisation date of ICH M13A is May 2024. Once finalised, the CHMP will implement it as a European guideline superseding the EMA Guideline on the investigation of bioequivalence for these oral dosage forms. Note Appendix III of the EMA guideline is already superseded by the ICH M9 Guideline on biopharmaceutics classification system-based biowaivers.


The guideline can be accessed here:


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