Pharmaceutical regulatory round up: December 2022

Catch up with the latest news from around the pharmaceutical industry with our December 2022 regulatory review, curated by Dr Tim Sandle.





MHRA updates good clinical practice CAPA guidance

The MHRA has issued revised guidance for setting corrective and preventative actions in relation to clinical activities. This has come about after the good clinical practices (GCP) Inspectorate assessed recent responses to GCP inspection reports, revealing concerns about the quality of responses.


Common problems with CAPA, in general terms, include:


  • Lack of cross-functionality
  • Reactive instead of proactive
  • Overuse versus underuse
  • Poor root cause determination
  • Poor definition of a CAPA process


In the document, the MHRA notes that responses requiring amendment/clarification lead to additional time spent by the inspector and the inspected organisation when closing the inspection.


The guidance document aims to give assistance for firms in how to respond to the GCP inspection report findings, plus it seeks to increase awareness of the GCP Inspectors’ expectations and aid formulation of an acceptable response.


The guidance can be found here:




Statistical Approaches to Establishing Bioequivalence

The U.S. FDA has issued a new draft guidance “Statistical Approaches to Establishing Bioequivalence”.


This guidance is intended to encourage the use of science-based approaches when making statistical bioequivalence assessments. Bioequivalence is the biochemical similarity of two (or more) drugs that share the same active ingredient(s) and desired outcome(s) for patients. Pharmacokinetic studies are performed to determine whether a commercially available brand and a potential generic version share core attributes.


Given the evolving nature of statistical approaches and technologies, the FDA seeks to encourage generic and new drug applicants to propose and discuss novel methodologies (e.g., model-based bioequivalence and novel adaptive designs for comparative clinical endpoint bioequivalence studies) with the Agency through appropriate regulatory meetings.


In the document, bioequivalence is defined as relative bioavailability. This involves comparison between a test (T) and reference (R) drug product, where T and R can vary depending on the comparison to be performed (e.g., to-be-marketed formulation versus clinical trial formulation, generic drug versus reference listed drug, originally approved formulation versus post-approval formulation changes).


Read the guidance in full here:




Computerised systems

The European Medicines Agency (EMA) has issued a concept paper, in conjunction with PIC/S, on computerised systems ahead of a planned revision to Annex 11. This document will be titled “Concept Paper on the revision of Annex 11 of the guidelines on Good Manufacturing Practice for medicinal products – Computerised Systems” (reference EMA/INS/GMP/778340/2022).


The new paper signals some of the potential changes ahead of the issuing of a revised Annex for public comment in 2024, with the finalised version of the Annex becoming available in 2026.


Interestingly the document is set to replace relevant parts of the Q&A on Annex 11 and the Q&A on data integrity on the EMA GMP website. The update will include requirements for ‘data in motion’ and ‘data at rest’ (backup, archive and disposal).


The concept paper can be found here:




Quality by Design

The 23rd edition of the British Pharmacopeia comes into effect in 2023. One of the new chapters is ‘Analytical Quality by Design Guidance (AQbD)’. The aim is to provide guidance for applying AQbD concepts with minimal risk. In particular, laboratories will be encouraged to enhance their method understanding by adopting AQbD concepts in analytical methods. 


A good scientific understanding of the analytical environment is essential for the AQbD approach, for example the sample matrix, the process that generated the samples, the characteristics of the analyte, or the characteristics of the measurement.


To develop the chapter, BP scientists worked together with MHRA assessors and inspectors, as well as the Therapeutic Goods Administration of Australia (TGA), multinational biopharmaceutical manufacturers, the generics manufacturing industry and personnel from the field of metrology to provide the content. 


The chapter sets out to ensure the analytical methods are fit for purpose by guiding users to:


  • Ensure implementation of robust methods
  • Save time in the laboratory by targeting experimentation to the relevant method conditions


As an example of how the concepts apply, the Atorvastatin Tablets monograph in the BP 2023 has been developed using AQbD concepts.




Generic drug submissions

The U.S. FDA has issued revised draft guidance titled “ANDAs: Pre-Submission Facility Correspondence Related to Prioritized Generic Drug Submissions”. The purpose of the guidance is to incorporate programme enhancements related to the content, timing, and assessment of a pre-submission facility correspondence (PFC) within the abbreviated new drug application (ANDA) assessment programme.


The guidance can be accessed here:




EMA Regulation (EU) 2019/6 (for certain categories of variations)

A document referred to as a "reflection paper" (EMA/CVMP/64911/2021) has been issued by the European Medicines Agency (EMA) in relation to Regulation 2019/6. Article 40(5) of the Regulation confers four years of data protection for variations involving a change to the pharmaceutical form, administration route or dosage assessed as having demonstrated:


  • a reduction in the antimicrobial or parasiticide resistance, or
  • an improvement of the benefit-risk balance of the veterinary medicinal product (VMP)


The data protection applies to the results of the pre-clinical studies or clinical trials provided in support of the variation. The reflection paper outlines the potential criteria to support the demonstration of a reduction in the antimicrobial or antiparasitic resistance, or an improvement of the benefit-risk balance.


The paper can be found here:




ATMP Guidance

New guidance has been issued which can be downloaded for free covering ‘Advanced Therapy Medicinal Products Guidance – Flow Cytometry and Vector Copy Number’. This comes from the British Pharmacopoeia (BP, as part of the MHRA), in partnership with experts from the cell and gene therapy community including industry, NHS and academia.


This best practice guidance offers a practical and phase-appropriate validation tool to help to develop a cell and gene therapy programme.
The content includes:


  • Reliable, phase appropriate support to every stage of assay development
  • Practical translation of regulation to support both new and experienced users
  • The development of robust internal procedures for data acquisition and documentation
  • Flexibility in how the user applies the guidance to their own environment
  • Harmonisation with – and links to – existing industry guidance for an understanding of regulatory expectations


The guidance can be downloaded here:




BAN book 2022

Every 5 years the British Pharmacopeia publishes the British Approved Names (BAN) book, with supplements published annually. The most recent 5-year update was in 2022.


British Approved Names (BAN) are the non-proprietary name or generic name for an active pharmaceutical ingredient (API) for use in the UK; distinctive names for use with medicines in the UK harmonised with the English form of the recommended international non-proprietary name (rINN).


The BAN publication is the official dictionary of drug names for regulatory use in the UK. Each entry includes:


  • The official pronunciation guide
  • Systematic name
  • Molecular formula
  • Molecular structure
  • CAS registry number
  • Pharmacological action and/or medicinal use


The latest publication can be obtained here:




Biotechnology and viruses

ICH has released a new draft guidance titled “Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin”, which closes for public comment on 14 January 2023 (the expected date of issue of the finalised version is November 2023). The core content covers:


  • Selecting and testing cell lines and other raw materials
  • Assessing the capacity of the production process to clear infectious viruses
  • Testing the product at appropriate steps of production. This includes sections on next generation sequencing (NGS) methods






11th edition of the European Pharmacopeia – first supplement

As we reported last month, the 11th edition of the European Pharmacopeia comes into force 1st January 2023. The first supplement has already been issued. Below is a full list of texts that have been technically revised since their last publication. They will be implemented on 1 April 2023 at latest.


General chapters


  • 2.27. Thin-layer chromatography
  • 2.28. Gas chromatography
  • 2.29. Liquid chromatography
  • 2.30. Size-exclusion chromatography
  • 2.45. Supercritical fluid chromatography
  • 8.2. Foreign matter
  • 9.5. Uniformity of mass of single-dose preparations
  • 9.38. Particle-size distribution estimation by analytical sieving
  • 2.9. Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders
  • 2.2. Chicken flocks free from specified pathogens for the production and quality control of vaccines
  • 21. Chemometric methods applied to analytical data
  • 22. Names of herbal drugs used in traditional Chinese medicine




  • Radiopharmaceutical preparations (0125)
  • Vaginal preparations (1164)
  • Avian infectious bronchitis vaccine (live) (0442)
  • Avian infectious bursal disease vaccine (live) (0587)
  • Avian infectious encephalomyelitis vaccine (live) (0588)
  • Avian infectious laryngotracheitis vaccine (live) (1068)
  • Avian viral tenosynovitis vaccine (live) (1956)
  • Duck viral hepatitis type I vaccine (live) (1315)
  • Fowl-pox vaccine (live) (0649)
  • Infectious chicken anaemia vaccine (live) (2038)
  • Newcastle disease vaccine (live) (0450)
  • Rabies vaccine (inactivated) for veterinary use (0451)
  • Radiopharmaceutical preparations and starting materials
  • For radiopharmaceutical preparations
  • Flumazenil (N-[11C]methyl) injection (1917)
  • Gallium (68Ga) chloride (accelerator-produced) solution for
  • Radiolabelling (3109)
  • L-Methionine ([11C]methyl) injection (1617)
  • Raclopride ([11C]methoxy) injection (1924)
  • Sodium acetate ([1-11C]) injection (1920)
  • Herbal drugs and herbal drug preparations
  • Coriander oil (1820)
  • Lavender oil (1338)
  • Rhubarb (0291)
  • Monographs
  • Amylmetacresol (2405)
  • Benzydamine hydrochloride (2759)
  • Cefalotin sodium (0987)
  • Colistimethate sodium (0319)
  • Colistin sulfate (0320)
  • Crotamiton (1194)
  • Dexpanthenol (0761)
  • Diclazuril for veterinary use (1718)
  • Enoxolone (1511)
  • Erythromycin lactobionate (1098)
  • Estriol (1203)
  • Etanercept (2895)
  • Everolimus (2918)
  • Felodipine (1013)
  • Fructose (0188)
  • Glucose (0177)
  • Glucose monohydrate (0178)
  • Infliximab concentrated solution (2928)
  • Isoniazid (0146)
  • Lactose (1061)
  • Lactose monohydrate (0187)
  • Levomepromazine hydrochloride (0505)
  • Mefloquine hydrochloride (1241)
  • Moxonidine (1758)
  • Octreotide (2414)
  • Ondansetron hydrochloride dihydrate (2016)
  • Pivmecillinam hydrochloride (1359)
  • Quinine hydrochloride dihydrate (0018)
  • Raltegravir potassium (2887)
  • Regorafenib tablets (3023)
  • Rifaximin (2362)
  • Risedronate sodium 2.5-hydrate (2572)
  • Sevoflurane (2269)
  • Teriflunomide (3036)
  • Theophylline-ethylenediamine (0300)
  • Theophylline-ethylenediamine hydrate (0301)
  • Tibolone (1739)
  • Tilidine hydrochloride hemihydrate (1767)
  • Water for injections (0169)





The USP has proposed a change to the chapter on ‘Dissolution’ <711>, which appears in draft form in edition 48 (6) of the Pharmacopeial Forum.


The proposal is based on the version of the chapter official as of May 1, 2022. The aim is to Performance Verification Standard-Prednisone RS, to qualify the Dissolution Apparatus 1 (basket) and Dissolution Apparatus 2 (paddle).






Biological Assay Validation

As outlined in Pharmacopeial Forum 48 (6), the USP is planning to revise chapter <1033> ‘Biological Assay Validation’. This revision is based on the version of the chapter official prior to 2013 and intends to make changes based on feedback from stakeholders received since the last revision of the chapter.


Bioassays are an integral part of the quality assessment required for the manufacturing and release of biological products: biotherapeutics, vaccines, and cell and gene therapies.


Bioassays commonly used for potency estimation can be distinguished from chemical tests by their reliance on a biological substrate (e.g., animals, living cells, functional complexes of target receptors, and immunological reagents). Because of multiple operational and biological factors arising from this reliance on biology and biochemical reactions, they typically exhibit a greater variability than chemically-based tests, produce measures of functional activity relative to a standard, and rely heavily on a fundamental assumption that the test and standard contain the same active constituents.


The chapter has been rearranged for better flow and readability. A total error approach to out-of-specification (OOS) results is introduced with examples and additional references. Additionally, minor editorial changes have been made to update the chapter to current USP style.






Elemental impurities

The USP is seeking to update chapter 〈232〉 ‘Elemental Impurities—Limits’, as per a draft published in Pharmacopeial Forum 48 (6). This proposal is based on the version of the chapter which became official as of December 1, 2020.


Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container–closure system).


The chapter is being revised to align with ICH Q3D (R2) from the ICH Q3D Expert Working Group. The revisions are proposed to add permitted daily exposures (PDEs) for the cutaneous and transcutaneous route. Furthermore, revisions to the PDEs for nickel (inhalation), gold (oral, parenteral, inhalation), and silver (parenteral) have been made to correct calculation errors. Additionally, minor editorial changes have been made to update the chapter to current USP style.






ICH Q3C (R8) Residual solvents

ICH has updated its guidance on residual solvents: “ICH guideline Q3C (R8) on impurities: guideline for residual solvents. Step 5.” The guidance was originally issued in 2021 and it has been updated in November 2022.


The document recommends acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The text recommends the use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents, providing guidance relating to specifications for class 1 and class 2 residual solvents in active substances and residues of solvents used in the manufacture of finished products.


Residual solvents in pharmaceuticals are defined here as organic, volatile chemicals that are used or produced in the manufacture of drug substances or excipients, or in the preparation of drug products. The solvents are not completely removed by practical manufacturing techniques.


The focus is with forming a global policy for limiting metal impurities in drug products and ingredients. This approach provides clear regulatory guidance on specification limits for elemental impurities worldwide and logically should have an impact on the work of the national regulatory bodies in having transparent and comparable results.


The guidance can be found here:




European Medicines Agency structure

The European Medicines Agency (EMA) has released an updated organisational structure of the Human Medicines Division following their 2020-2022 reorganization.


This replaces the previous EMA Human Medicines structure. The distribution of responsibilities has now been allocated by so-called therapeutic areas; plasma-derived medicinal products now fall under the therapeutic area of ‘Oncology and Haematology’.


The therapeutic areas are as follows:


  1. Oncology and Haematology
  2. Vaccines and therapies for infectious diseases
  3. Therapies for neurologic and psychiatric disorders
  4. Endocrine and cardiovascular diseases
  5. Therapies for immune and inflammatory diseases
  6. Advanced Therapies


The EMA working parties to the CHMP (Committee on Human Medicinal Products) largely remain the same, the previous Blood Products Working Party (BPWP) is now re-named as ‘Haematology Working Party’ (HAEWP)’.


The revised structure can be found here:


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