Issue 8: Pharmaceutical regulatory roundup




Catch up with the latest news from around the pharmaceutical industry with issue 8 of our regulatory review, curated by Dr Tim Sandle.


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Biological reactivity tests


The USP is planning to update chapter 〈87〉 “Biological Reactivity Tests, In Vitro”. The objective of this proposed revision, along with the updates of Biological Reactivity Tests, In Vivo 〈88〉, The Biocompatibility of Pharmaceutical Packaging Systems and Their Materials of Construction 〈1031〉, and the omission of Sensitization Testing 〈1184〉, is to reduce the amount of redundant testing and to refine the type of testing performed to align with the potential risk. It also aims to replace in vivo testing with in vitro testing or utilise other information using a risk-based approach focused on the knowledge of the material and pharmaceutical application.


The key changes proposed are as follows:


•    Remove the Agar Diffusion Test from the list of 3. Cytotoxicity Tests and add the 3.5 Neutral Red Uptake (NRU) Test.
•    Add 4. Skin Irritation Test
•    Add the following genotoxicity tests: 5.2 Ames Bacterial Reverse Mutation Assay, 5.3 Mammalian Cell Genetic Toxicity Tests, 5.3.1 Chromosomal Aberration Test, 5.3.2 Gene Mutation Test, and 5.3.3 Micronucleus (MNvit) Test


With chapter <88>, the USP intends to:


•    Delete Classification of Plastics as the distinction of plastic materials into six classes (Class I to Class VI) no longer serves a purpose - in practice only Class VI is utilised by vendors and end users
•    Delete Intracutaneous Test
•    Delete Implantation Test
•    Delete Safety Tests–Biologicals as the relevant FDA Code of Federal Regulations, 21 CFR §610.11, was revoked on August 3, 2015


Furthermore, in section 2.2 Apparatus, the aim is to add the requirement that the autoclave has the ability to connect to a calibrated resistance thermometer or a calibrated thermocouple. The autoclave must be calibrated before first use.






The USP is proposing to update its chapter for pH determination: 〈791〉 pH. 


The proposal is based on comments received regarding a discrepancy in a mathematical symbol impacting the introductory equation that defines pH when compared to internationally recognised bibliography (e.g., IUPAC and other pharmacopoeias). 


Also, a value in Table 2 is revised based on updated international references and its uncertainty assigned. A chemical formula has also been corrected in the Buffer Solutions for Calibration of the pH Measurement System section.




Plastic packaging


A revised USP chapter - 〈661.2〉 “Plastic Packaging Systems for Pharmaceutical Use” – is set to become official from December 1, 2025.


The change includes errata revisions that were incorporated on December 1, 2020. Here, the General Chapters - Packaging and Distribution Expert Committee -  is proposing the following changes:


•    In Physicochemical Tests, revise the extraction time and temperature for Solution C1 to address the concern that some plastic packaging materials start to melt and deform at the low temperature currently outlined in the chapter (70°)
•    The revision includes an additional extraction time and temperature of 50 ± 2° for 72 h
•    In the Total Organic Carbon test, revise the acceptance criteria to align with that in Total Organic Carbon 〈643〉, which was revised in 2021




Biocompatibility of meterials


The USP has issued a draft of chapter 〈1031〉 “The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants”. The following changes are being considered:


•    Change the title to "The Biocompatibility of Pharmaceutical Packaging Systems and Their Materials of Construction"
•    Expand the scope of the chapter to encompass plastic materials of construction and plastic and elastomeric components for pharmaceutical packaging/delivery systems and for packaging of combination products
•    Add an overview of the USP classification of plastics, as described in “Biological Reactivity Tests, In Vivo” 〈88〉, which identified six different classes of plastics (Classes I–VI). The classes were differentiated by the number, the types of solvent used for extraction and the biological reactivity tests performed. A review of the utilisation of the classification system found that typically only the most stringent category (Class VI) was used by suppliers of plastic materials of construction and components, as well as pharmaceutical manufacturers. This classification system has been replaced by the term "pharmaceutical grade polymeric materials", which is defined as materials that are in compliance with specific in vitro tests
•    Include the following significant additions:
o    A risk-based approach to biocompatibility evaluation
o    Assessment of test methods
o    Chemical characterisation as a key part of the overall safety assessment process
o    Biological reactivity test failure analysis
o    Overall biocompatibility evaluation




Supplier qualification


A new USP Chapter <1083> “Supplier Qualification” is set to be issued during August 2023.


The expectations on the part of regulatory authorities are that pharmaceutical products will be fitted for their intended use and be of the required quality. This means that active ingredients, excipients, components, other raw materials and packaging components used in the end product have been manufactured to the appropriate standards and comply with regulations, pharmacopeial monographs, and/or all approved specifications. It also means that the processes in the supply chain for a material or service will also be compliant and will not increase risks to the product.


Reliable suppliers provide benefits through established risk management processes. Supplier qualification is a process to systematically evaluate suppliers based on:


•    The risk to the quality of the product or service supplied
•    Compliance of their quality systems to applicable regulations and requirements of the supply contract or quality agreement
•    The reliability of the supplier to avoid quality deviations and shortages of components and/or products


The chapter provides a quality risk-based approach on how to select, assess, approve and monitor suppliers of ingredients, packaging materials and other components and services. This includes:


•    Materials (such as active pharmaceutical ingredients, excipients and other components and materials)
•    Packaging materials (such as primary, secondary and tertiary packaging)
•    Service providers (such as contract manufacturers, packers, or re-packers, transportation and storage services, calibration and qualification services, analytical services and software services)





Biological product and HCT/P deviation reports: Annual summary for fiscal year 2022


The FDA has issued an annual summary report which provides an overview of Biological
Product Deviation reports submitted during the fiscal year encompassing October 1, 2021, through to September 30, 2022 (FY22). This includes detailed information regarding the number and types of deviation reports. 




FDA: Investigations operations manual


The US FDA has updated its “Investigations Operations Manual”. The manual provides advice for FDA inspectors across all areas of operations (the appendix contains information ranging from blood serum levels to the types of insects that can contaminate grain). A new chapter has been added in relation to sampling (providing advice to inspectors on the types of samples to take when evidence gathering – this even extends to taking samples of mould). 

The FDA states: “Although primarily used internally by FDA staff, it is available publicly so that regulated industry and other external stakeholders can better understand FDA operations.”

The manual is large and detailed, and best serves as a reference aid rather than something to be read cover-to-cover.





EMA: Europe and UK acceptance of international units


The European Medicines Agency has updated the table “Acceptability of IU as abbreviation for International Units in the strength of human medicinal products”. This relates to the measurement of the effect of a drug. 

The table lists each member state (and the UK, for Northern Ireland).





Guideline on computerised systems and electronic data in clinical trials


The European Medicines Agency has issued guidance relating to data integrity and computerised systems as used in clinical trials.


Computerised systems are being increasingly used in clinical research. The complexity of such systems have evolved rapidly in the last few years from electronic Case Report Forms (eCRF) and electronic Patient Reported Outcomes (ePROs), to various wearable devices used to continuously monitor trial participants for clinically relevant parameters and ultimately to the use of Artificial Intelligence (AI). 


There is a need to provide guidance to all stakeholders involved in clinical trials reflective of these changes in data and trial types on the use of computerised systems and on the collection of electronic data. This is important to ensure the quality and reliability of trial data, as well as the rights, dignity, safety and wellbeing of the trial participants. This would ultimately contribute to a robust decision-making process based on such clinical data.


The guideline describes some generally applicable principles and definitions of key concepts. It also covers requirements and expectations for computerised systems, including validation, user
management, security and electronic data for the data life cycle. In addition, requirements and expectations are covered relating to specific types of systems, processes and data.






New edition of the WHO International Pharmacopeia


The International Pharmacopoeia (Ph. Int.) constitutes a collection of recommended procedures for analysis and specifications for the determination of pharmaceutical substances and dosage forms that is intended to serve as source material for reference or adaptation by any WHO Member State wishing to establish pharmaceutical requirements. 


A new edition has been issued – the 11th edition. 


The pharmacopoeia, or any part of it, has legal status, whenever a national or regional authority introduces it into appropriate legislation. 





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