Issue 14: Pharmaceutical regulatory roundup




Catch up with the latest news from around the pharmaceutical industry with issue 14 of our regulatory review, curated by Dr Tim Sandle.


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Manufacturing changes and comparability for human cellular and gene therapy products


The U.S. FDA has issued a new draft guidance, titled “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products”.


The guidance notes that the management of manufacturing changes presents many challenges for human cellular therapy or gene therapy (CGT) products due to their complexity. The objective of the guidance is to provide advice to the sponsors of Investigational New Drug Applications (INDs) and applicants of Biologics License Applications (BLAs) for CGT products.


This takes the form of recommendations regarding product comparability and the management of manufacturing changes for investigational and licensed CGT products.


The purpose of this guidance is to provide FDA’s current thinking on management and reporting of manufacturing changes for CGT products based on a lifecycle approach, and comparability studies to assess the effect of manufacturing changes on product quality.


The guidance can be accessed here:





European pharmacopoeia water monographs


Ph. Eur. Supplement 11.4 comes into force 1st April 2024.


There are two changes that will take place for the monographs for water for injection (WFI 0169) and purified water (PW 008):

•    The deletion of the test for nitrate if the test for conductivity meets the pharmacopoeial requirement for WFI. This will harmonise WFI and PW testing with the USP
•    It will be permissible to use recombinant factor C (rFC) for testing for endotoxins, under chapter 2.6.32, for pharmacopeial grade water. That is either LAL or rFC can be used, provided either chapter 2.6.14 or 2.6.32 is followed.


The timeline is:

•    The amendments were adopted by the Ph. Eur. Commission in March 2023
•    Updated monographs will be issued in October 2023
•    The changes will come into force on 1 April 2024







The USP is proposing to update General Chapter <701> Disintegration and a draft has been published for comments (the comments period ends 30 November 2023). The chapter is to be updated as part of the process of international harmonisation.


If agreed, the texts of the leading pharmacopeia will become interchangeable, hence the methods of the European Pharmacopoeia and/or the Japanese Pharmacopoeia may be used for demonstration of compliance instead of the present general chapter. 


The disintegration test is provided to determine whether tablets, capsules or granules disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions presented below. Compliance with the limits on disintegration stated in the individual monographs is required.


For the purposes of this test, disintegration does not imply complete solution of the unit or even of its active constituent. Complete disintegration is defined as that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core.


The draft text is accessible via the USP website (registration is required).




Volumetric apparatus


The USP is proposing to update its volumetric apparatus chapter (this is chapter <31>):


1.    Clarify that a calibration temperature of 27° C is also performed in other countries that have adopted that reference temperature. Temperature correction might be required when ambient temperature differs from the reference temperature
2.    Calibration of volumetric apparatus is needed to ensure the degree of precision required. Frequency of calibration is risk-based and defined in the user’s manual quality management system
3.    Incorporate reference to the new chapter Use and Calibration of Volumetric Apparatus〈1331〉 to provide theoretical bases for calibration and examples
4.    Provide alternatives when the limits of error are not met or not suitable at the conditions of use
5.    Add a new Table 1 to categorise the volumetric apparatus accuracy classes and the applicable external updated references
6.    Update terminology to the International Vocabulary of Metrology [VIM; (Joint Committee for Guides in Metrology, JCGM) 200] for consistency with equivalent public standards. For example, the section Standards of Accuracy formerly containing “capacity tolerances” is proposed to be changed to ‘limits of error’ (or maximum permissible errors). Limits of error has been defined
7.    Introduce considerations for Piston-Operated Volumetric Apparatus (POVA) in several paragraphs when appropriate. The limits of error for POVAs are included in new columns added to pipettes in Table 3 (0.5 mL) and burettes in Table 4 (5 mL)
8.    For plastic volumetric apparatuses, introduce temperature correction and equilibration, as well as limits of error
9.    Specific references to applicable ISO and American Society for Testing and Materials (ASTM) standards were introduced in the tables for limits of error


In terms of the corresponding updates to chapter <1331>, it is proposed this new chapter covers: 

-    A scope with volumetric apparatus accuracy classes
-    The relevant public standards
-    User considerations
-    Measurement considerations
-    Calibration process
-    Calculations
-    A glossary
-    Useful references used in the proposed text





Analytical balances


The USP is proposing to modify chapter <41> Balances.


This proposal is based on the version of the chapter official as of August 1, 2019. On the basis of comments received from stakeholders and to align with USP Weighing on an Analytical Balance 〈1251〉 and the Balances chapter in the European Pharmacopoeia, it is proposed to make the following changes to this general chapter:

1.     Introduce the relationship among calibration and performance checks with the life cycle approach to ensure fitness for purpose
2.    Include the concept of the risk-based approach with respect to the frequency of calibration and performance checks
3.    Add a new section for Calibration, clarifying its purpose and considerations for uncertainty and frequency
4.    Introduce clarifications for compliance with respect to the repeatability test
5.    Minimum weight is aligned with that in 〈1251〉 and the European Pharmacopoeia with regards to the standard deviation. Examples of calculation have been introduced
6.    A clarification note has been introduced to differentiate minimum weight from the smallest net weight
7.    Clarifications of criteria are stated to comply with the accuracy during the performance test and calibration, including the uncertainty of the test weights
8.    Additional applicable references have been incorporated into the text.


In terms of the update to <1251>, it is proposed to:


1.    In the Introduction, clarification is provided on the group of instruments in which balances are included as per Analytical Instrument Qualification 〈1058〉 and its relationship with the analytical target profile (ATP) described in Analytical Procedure Life Cycle 〈1220〉
2.    Introduce the new section for Principle, defining weight and units.
3.    Under Performance Qualification, the risk of the weighing application is explained with regards to the user’s quality management system in order to define the frequency and the type of performance qualification activities
4.    Add clarifications in Table 1 to provide additional guidelines for the test examples of the balance properties, based on questions received
5.    Include discussion of the frequency of each of the individual tests, as well as the relationship between calibration and performance qualification
6.    Delete the section Balance Checks and integrate it into the Performance Qualification section
7.    Simplify the definition of Minimum Weight and add clarifications about the tare vessel and examples to address frequently asked questions
8.    Introduce a safety factor that addresses critical performance changes of the balance during routine usage
9.    Introduce a buoyancy correction when needed as well as other clarifications in the section Operation of the Analytical Balance
10.    Add Glossary to clarify the use of specific terms
11.    Add Additional Sources of Information to ensure alignment of concepts and terminology






The USP is proposing to update the microbiological test chapter for probiotics (chapter <64>). This is to provide additional options for the types of electrophoresis systems recommended for the analysis of the PCR amplification products in Identification. The proposal is also to add specific stomacher conditions (rpm and time) for both Lactobacillus and Bifidobacterium under Sample preparation in Enumeration. The changes also include adding specific incubation conditions (temperature and time) for both Lactobacillus and Bifidobacterium under Analysis in Enumeration.





Light diffraction measurement


The USP has issued a draft version of chapter <429> Light Diffraction Measurement of Particle Size. Here the intention is alignment with the European Pharmacopoeia.


The major revisions to this chapter are:

1.    Change the chapter title to "〈429〉 Particle Size Analysis by Laser Light Diffraction"
2.    A figure is added to illustrate optical arrangements in laser light diffraction instrument
3.    Change the section title "Development of the Method" to "Development of the Procedure" and clarify the scope and acceptance criteria
4.    Revise the Measurement section to add precautions and clarifications
5.    Change the section title "Control of Instrument" to "Instrument Qualification", and substantially revise the section content
6.    Change the section title "Qualification of the System" to "Performance Qualification", and add clarification to the section content



Fats and oils


The USP is planning to update chapter 〈401〉 Fats and Fixed Oils. This proposal is based on the version of the chapter official as of May 1, 2022. On the basis of comments received and the suitability study performed by USP, it is proposed to make the following changes:


•    In the Fatty Acid Composition section, introduce USP FAME Standard Mixture RS as one of the commercial sources for the standard solution preparation
•    Add USP FAME Standard Mixture RS to the USP Reference Standards section


Nuclear magnetic resonance

The USP has redrafted chapter 〈761〉 Nuclear Magnetic Resonance Spectroscopy. 


Nuclear magnetic resonance (NMR) spectroscopy is an analytical method that uses the electromagnetic properties of nuclei placed in a magnetic field to characterise molecules qualitatively and quantitatively. 


The proposed revisions serve three primary purposes: 
1. To update the content with modern technologies and contemporary practices of NMR spectroscopy
2. To expand coverage of quantitative NMR (qNMR) applications to better reflect the established utility and growing use of qNMR in pharmaceutical analysis and metrology
3. To explain essential concepts that underlie advanced methodologies for both qualitative and quantitative NMR analyses.


The proposed changes are:

•    Introduce the life cycle approach to analytical procedure validation, aligned with Analytical Procedure Life Cycle 〈1220〉, which contains concepts such as analytical target profile and target measurement uncertainty
•    Expand the elements of qualification of NMR instruments beyond installation qualification, operational qualification and performance qualification to include user requirements specifications, design qualification and system suitability testing
•    Update instrument qualification tests and establish acceptance criteria for intended use and application
•    Revise the Qualitative and Quantitative NMR Analysis section by updating procedure requirements and providing additional details on sample preparation, certified reference material selection, acquisition parameters and post-acquisition data analysis


Mass spectrometry for therapeutic proteins


The USP is planning a new general chapter: Mass Spectrometry-Based Multi-Attribute Method for Therapeutic Proteins <1060>.


The draft chapter is intended to provide users with principles and practical guidance regarding the LC-MS-based peptide mapping approach of the multi-attribute method (MAM) for therapeutic proteins. 


The chapter details sample preparation, system readiness, general considerations and case studies for MAM. Guidance for assay validation and method transfer is provided. In addition to the peptide mapping MAM approach, intact and subunit-level LC-MS analysis and use of MAM in process analytical technology (PAT) is also detailed.





Wetting properties


The USP has proposed a new chapter 〈1243〉 Wetting Properties of Pharmaceutical Systems. In the framework of the pharmaceutical continuous manufacturing processes, this new general chapter was developed to provide guidelines for the evaluation of wetting properties of pharmaceutical systems. The wetting properties of pharmaceutical systems are important in batch and continuous manufacturing, formulations and final product quality.


Therefore, the USP General Chapters–Physical Analysis Expert Committee is proposing this new general chapter to address the needs of the pharmaceutical industry for the standardisation of the analytical technology used in characterisation of wetting properties.


The chapter covers the following topics:

•    Background on wetting properties
•    Applications of wetting properties
•    Approaches to improve or modify wetting properties
•    Relevance of surface tension of liquids in wetting properties
•    Liquid surface tension measurement techniques
•    Factors affecting liquid surface tension
•    Assessment of wetting properties by contact angle
•    Contact angle measurement techniques
•    Factors affecting contact angle
•    Relevance of surface free energy of solids
•    Solid surface free energy measurement techniques





Swiss metric


Swissmedic, the health authority for Switzerland, has established a GMP and GDP database called ‘SwissGMDP’ to act as a parallel EudraGMDP database.


The database will be launched Q1 2024: 





Distribution: Track and trace information


The U.S. FDA has issued a final guidance for exchange of track and trace information for human prescription drugs, titled “DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs - Guidance for Industry”. This is dated September 2023.


This guidance identifies the standards necessary to facilitate adoption of secure, interoperable, electronic data exchange among the pharmaceutical distribution supply chain and clarifies the  trading partners, products and transactions subject to such standards. 


The guidance states that only electronic methods of product tracing will be permitted and verification of product at the packaging level will be required, unless a waiver, exception or exemption applies. 


The guidance is issued subject to sections 582(h)(4)-(5) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360eee-1(h)(4)-(5)), as added by the Drug Supply Chain Security Act (DSCSA) (Title II of Public Law 113-54).


The guidance can be found here: 





Post-marketing commitments


The FDA has published a final guidance on annual status reports and other submissions for post-marketing requirements.


The guidance details the reports required for submissions by drug and biological product application holders to ensure the provision of complete and accurate information relating to post-marketing commitments. 


Through the change, the FDA is seeking improved accuracy and timeliness.


The guidance is titled “Annual Status Report Information and Other Submissions for Postmarketing Requirements and Commitments: Using Forms FDA 3988 and FDA 3989 - Guidance for Industry” and it is dated September 2023.


The guidance can be found here: 





Good practices for QC


The World Health Organization (WHO) has issued a draft document headed "WHO good practices for pharmaceutical quality control laboratories (QAS/21.882)". The document is dated August 2023.


The text is divided:

1.    General considerations
2.    Glossary
3.    Organization and management system
4.    Planning and strategic management
5.    Resources
6.    Technical activities
7.    Safety rules


•    Appendix 1: Equipment for a first-stage and medium-sized pharmaceutical quality control laboratory
•    Appendix 2: Recommendations for the target uncertainty and the maximum admissible uncertainty for normal analytical practice
•    Appendix 3: Examples of the uncertainty estimation on compliance with normal analytical practice (the "worst case") for assay of pharmaceutical substances by chromatography


The document can be found here: 


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