Issue 7: Pharmaceutical regulatory round up

Catch up with the latest news from around the pharmaceutical industry with issue 7 of our regulatory review, curated by Dr Tim Sandle.


BY DR TIM SANDLE  |  22 March 2023


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Design and conduct of externally controlled trials for drug and biological products


The FDA has issued new draft guidance that provides recommendations to sponsors and investigators considering the use of externally controlled clinical trials. This is to provide evidence of the safety and effectiveness of a drug product.


The document states that in an externally controlled trial, outcomes in participants receiving the test treatment according to a protocol are compared to outcomes in a group of people external to the trial who had not received the same treatment. The external control arm can be a group of people, treated or untreated, from an earlier time (historical control), or it can be a group of people, treated or untreated, during the same time period (concurrent control) but in another setting.


The guidance addresses considerations for the design and analysis of externally controlled trials to study the effectiveness and safety of drugs, including discussion of threats to the validity of trial results from potential bias.




Pharmaceutical Dosage Forms


The USP is proposing an update to chapter 〈1151〉 Pharmaceutical Dosage Forms. This is the cat-all term for pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration and apportioned into a particular dose.


This proposal is based on the version of the chapter official as of May 1, 2021. The changes made to the revision include:


  • Inclusion of new dosage forms - Cloths, Sponges and Swabs
  • Updates to Suspensions with new suspensions that include Lipid Nanoparticles (LNP), viral vectored vaccines and gene therapies (e.g., adenovirus and adeno-associated virus respectively)
  • Updates to the term "TDS", which includes both transdermal delivery systems and topical delivery systems, under Systems
  • Updates to Tablets to include a tablet with a sensor to detect if it has been administered
  • Updates to Orally Disintegrating Tablets to improve clarity
  • Updates to the Glossary to include new dosage forms and updates to Suspensions


The changes are outlined in Pharmacopeia Forum 49 (1) and comments are open until the end of March 2023.




Residual solvents


The USP is proposing an update to chapter 〈467〉 Residual Solvents. This proposal is based on the version of the chapter official as of September 1, 2022.


Some organic solvents are often used during the synthesis of APIs and excipients. They could also be used during the preparation of drug products to enhance the yield, increase solubility or aid crystallisation. Therefore, the topic of residual solvents applies to certain classes of medicine.


ICH has recently updated its guidelines Q3C(R8) Residual Solvents. The update introduced two new Class 2 residual solvents - cyclopentyl methyl ether (with a permitted daily exposure (PDE) of 15 mg/day) and tertiary butyl alcohol (with a PDE of 35 mg/day). There is also a new Class 3 residual solvent - 2-methyltetrahydrofuran.


As a consequence of incorporating these updates, the USP Residual Solvents Class 2 -Mixture B RS has been changed to include cyclopentyl methyl ether and tertiary butyl alcohol. The following changes to the chapter are proposed:


  • Update Table 3 to include the two new Class 2 residual solvents
  • Update Table 4 to include the new Class 3 residual solvent
  • In 8.2 Screening of Water-Soluble Articles, revise the system suitability requirements of Procedure B to include a resolution of not less than 1.5 between cyclopentyl methyl ether and 1.2-dimethoxyethane in the chromatogram of the Class 2 mixture B standard solution
  • Revise the USP Reference Standards section to include USP class 2-cyclopentylmethyl ether RS, USP class 2-tertiary butyl alcohol RS and USP 2-methyltetrahydrofuran RS


The changes are outlined in Pharmacopeia Forum 49 (1) and comments are open until the end of March 2023.




Laser products


The US FDA has published a guidance update on Laser Products, titled “Laser Products – Conformance with IEC 60825-1 Ed. 3 and IEC 60601-2-22 Ed. 3.1 (Laser Notice No. 56)”.


This guidance describes the Food and Drug Administration’s (FDA) approach regarding manufacturers’ compliance with FDA’s performance standards for laser products.


Laser product refers to any manufactured product or assemblage of components which constitutes, incorporates, or is intended to incorporate a laser or laser system. A laser or laser system that is intended for use as a component of an electronic product shall itself be considered a laser product.


The document states that the FDA recognises that while there are many similarities between International Electrotechnical Commission (IEC) standards 60825-1: Safety of laser products - Part 1: Equipment classification, and requirements, Edition 3.0 and 60601-2-22: Medical electrical equipment - Part 2-22: Particular requirements for basic safety and essential performance of surgical, cosmetic, therapeutic and diagnostic laser equipment, Edition. 3.1 and FDA’s laser performance standards, there are clauses of these IEC standards that differ significantly from FDA’s performance standards for laser products.


For the manufacturers that conform to the clauses of IEC 60825-1 Ed. 3 and IEC 60601-2-22 Ed. 3.1 that FDA identifies as comparable with 21 CFR 1040.10 and 1040.11, FDA does not intend to enforce the applicable requirements in 21 CFR 1040.10 and 1040.11.


The guidance describes the Agency’s current thinking on a topic and the FDA states it should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.




Abbreviated new drug applications


The US FDA has issued draft guidance providing recommendations to industry on Product-Specific Guidance (PSG) meetings between FDA and a prospective applicant preparing to submit to FDA or an applicant that has submitted to FDA an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)).


The guidance provides information on requesting and conducting PSG meetings with FDA (PSG teleconferences, pre-submission PSG meetings and post-submission PSG meetings), as

contemplated in the Generic Drug User Fee Amendments (GDUFA) Reauthorization

Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter).


The guidance is intended to provide procedures that will promote well-managed PSG meetings and help ensure that such meetings are scheduled and conducted in accordance with the time frames set forth in the GDUFA III commitment letter.


To receive approval for an ANDA, an applicant must demonstrate that its proposed drug product is bioequivalent to the Reference Listed Drug (RLD). As noted in 21 CFR 320.24, in vivo and/or in vitro methods can be used to establish Bioequivalence (BE).


FDA recommends that applicants consult published PSGs when considering an appropriate BE study and/or other studies for a proposed drug product. PSGs provide recommendations for developing generic drug products and describe FDA’s current thinking on the evidence needed to demonstrate that an ANDA is therapeutically equivalent to a specific RLD product.




Drug Supply Chain Security Act – get ready


According to The Regulatory Affairs Professionals Society, the US FDA is incorporating compliance with the Drug Supply Chain Security Act (DSCSA) into routine inspections. This is being phased in during 2023 (the Act comes into effect on 27th November 2023).


The primary areas from the briefing are:


  • Inspectors will be looking to see whether firms have systems in place for determining that they are only accepting products from authorised trading partners (ATPs)
  • DSCSA mandates that pharmaceutical manufacturers only accept drug products from ATPs, or parties that are properly licensed or registered to receive or transfer products
  • ATPs include manufactures, repackagers, dispensers, wholesale distributors and third-Party Logistics (3PL) providers
  • Firms should have effective systems to prevent suspect and illegitimate products from entering the supply chain e.g., products having tamper-proof product identifiers
  • Inspectors will be checking to see that firms have systems in place for exchanging data with trading partners at the time the product moves through the supply chain
  • Inspectors will assess how well firms are serialising products
  • Inspectors will assess if firms have systems for responding to verification requests and systems for handling returned goods


Overall, FDA inspectors will be looking for Standard Operating Procedures (SOPs) for DSCSA compliance.






Regulators in Egypt have issued new guidance on the use of heparin. Heparin is one of the most widely used medicines in the world - it has been described as lifesaving, as it plays a vital role in many serious conditions such as kidney dialysis, surgery, cardiac-invasive, heart attack, cardiac arrhythmia, acute coronary syndrome, pulmonary embolism, stroke, deep vein thrombosis, blood clot prevention and many other related conditions.

The guideline addresses the marketing authorisation registration requirement of unfractionated heparins drug substance and drug product. This is regardless of the origin of tissues (either bovine or porcine origin), in order to ensure safety, quality or efficacy of products to be used in humans.


The requirements cover:


  • Control of starting materials
  • Control of manufacturing process
  • Control of drug substance and drug product




Sterilisation alternatives


The Sterility and Infection Control Program in the FDA’s Center for Devices and Radiological Health (CDRH) conducts regulatory scientific research to help ensure patients have access to safe and effective medical devices that are free of microbial and biochemical contamination.


The programme consists of two sub-programme areas: Alternatives to Ethylene Oxide Sterilization and Device Related Infections. These are part of the research programmes in CDRH’s Office of Science and Engineering Laboratories (OSEL).


There have long been concerns with ethylene oxide, not least because of residuals and the fact the chemical is a mutagen. There is also an environmental impact and a related goal to reduce emissions to as close to zero as possible from the ethylene oxide sterilisation process. In the North American market, it is estimated that about 50% of single-use medical device are terminally sterilised by ethylene oxide.


Finding alternatives is not easy and changes in sterilisation modality currently require significant revalidation testing including biocompatibility, chemical characterisation, and material/device performance testing.


Alternative technologies include:


  • Supercritical carbon dioxide sterilisation
  • Nitrogen dioxide sterilisation
  • Accelerator-based radiation sterilisation
  • Vaporised hydrogen peroxide sterilisation
  • Vaporised hydrogen peroxide-ozone sterilisation


For details, see:  




Dissolution of tablets and capsules


The European Pharmacopoeia has launched public consultation on: Revision of the harmonised general chapter 2.9.3. Dissolution of tablets and capsules.


The text on dissolution testing of oral solid dosage forms, already harmonised within the Pharmacopoeial Discussion Group (PDG), has been revised to provide a more detailed description of the two possible ways of operating Apparatus 3 – reciprocating cylinder. The PDG also took this opportunity to edit the text for greater clarity and to harmonise the terminology used. In particular, the number of significant digits for pH and temperature has been corrected.




Characterisation of powder behaviour during compression


The European Pharmacopoeia has launched public consultation on: New general chapter 2.9.55. Characterisation of powder behaviour during compression.


Powder compression is a critical process in tablet manufacturing. Problems during compression are numerous and include capping and lamination, friability or powder sticking to punch surfaces of the die wall. It is important to characterise tablet compression in order to control the compression process well.


The detailed new general chapter on characterisation of powder behaviour during compression provides guidance for standardised compression test procedures such as evaluation of compressibility, tabletability and compactibility profiles.





Pharmacopeial harmonisation


The current work programme for the European, Japanese and U.S. pharmacopeia indicates that they are collaborating on revisions of the general chapters:

  • Bulk density of powders
  • Powder flow
  • Peptide mapping


With corrections to the excipient monographs:

  • Carmellose calcium
  • Hydroxypropylcellulose, low substituted
  • Hypromellose
  • Lactose, Anhydrous
  • Lactose, Monohydrate
  • Methylcellulose




Pyrogen testing


Plans continue to abolish pyrogen testing throughout Europe in 2025 and manufacturers still undertaking the pyrogen test have been directed to ensure that their plans to adopt alternatives are on course. In 2025, there will no longer be a British or European monograph for the pyrogen test.


This course of action was re-emphasised at a joint meeting between the European Directorate for the Quality of Medicines & HealthCare (EDQM) and the European Partnership for Alternative Approaches to Animal Testing (EPAA) to phase out the Rabbit Pyrogen Test (RPT) for the testing of pharmaceuticals. This direction was supported by regulatory agencies.


The aim was also to make the adoption of the Monocyte Activation Test (MAT) easier by presenting it as a straightforward in vitro alternative to the RPT.


The ending of pyrogen testing fits into the wider 3R goals (replacement, reduction and refinement of animal testing) and it will contribute to a significant reduction in the number of rabbits used for experimental purposes in Europe.


Pharmacopoeias from other regions (Brazil, China, India, Japan and the United States) also joined the event and all committed to progressively phase out animal tests from their respective standards, including the RPT.




Manufacture of Investigational Medicinal Products


The MHRA have issued a ‘Frequently Asked Questions’ blog post in relation to the manufacture of Investigational Medicinal Products (IMPs). It is written by Alan Moon.


As the blog explains, GMP and GCP Inspectors work closely with MHRA clinical trials and regularly provide support to help answer a wide range of stakeholder queries which relate to the manufacture, import, labelling, licencing requirements and general handling of IMPs.


The FAQs are an update of a previous positing, containing new information about the introduction of an import oversight process for QP certified IMPs into Great Britain from approved countries.




Good Distribution Practice


The European Medicines Agency has amended its Good Distribution Practises (GDPs) advice in relation to how the rules apply to brokers operating outside of the European Economic Area (EEA).​


Two new areas of focus are:


  • Whether a broker can broker operations between parties outside the EEA
  • Whether a broker can broker activities for medicinal products without an EEA marketing license but with an EEA marketing authorisation?


The answer to both of the above is ‘no’.



PIC/S have issued an ‘Aide-Memoire: Inspection of Good Distribution Practice (GDP) for medicinal product in the supply chain’ (PI 044-1). This is a guidance note for GMDP inspectors.


The structure of the document makes for a good self-inspection aid. See: 


There is also a companion document, titled ‘Questions & Answers document regarding the PIC/S GDP Guide (PE 011-1)’. See:


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