Issue 19: Pharmaceutical regulatory roundup

BY DR TIM SANDLE  | 20 March 2024



Catch up with the latest news from around the pharmaceutical industry with issue 19 of our regulatory review, curated by Dr Tim Sandle.


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Microbiological Methods for the Detection of Contamination in Short-Life Products


The United States Pharmacopeia (USP) is considering introducing a new chapter titled “Respiration-Based Microbiological Methods for the Detection of Contamination in Short-Life Products”.


This chapter is intended to be used as a risk-based test for the detection of microbial contamination in short-life products and encompasses short shelf-life products and/or short manufacturing times where the product must be administered as soon as possible.


The chapter could also be used as an in-process control for the testing of product intermediates, cell media or process solutions. Growth-based methods that use detection signals other than visible signs of microbial growth or precipitation within the media (i.e., turbidity, pellicle formulation or floccular growth) have been used to test a variety of products. Instrumentation for respiration-based methods is based on blood culture systems used in the clinical setting that utilise colorimetric or fluorometric sensors to detect an exponential increase in carbon dioxide as an indicator of microbial growth. The application of respiration-based methods for the detection of contamination in a variety of short-life products, such as cell therapy products, has been published in the peer-reviewed literature.


The chapter has been published in draft form in the Pharmacopeial Forum (registration is required for access).


In addition, the USP has issued a draft chapter titled “ATP Bioluminescence-Based Microbiological Methods for the Detection of Contamination in Short-Life Products”.


With this second chapter, growth-based methods using detection signals other than visible signs of microbial growth or precipitation within the media (i.e., turbidity, pellicle formation, or floccular growth) include adenosine triphosphate (ATP) bioluminescence measurement for the detection of growth in microbiological growth media (nutrient broth) or the detection of colonies on membranes placed on solid media. All viable cells, including microorganisms, contain ATP at various levels. ATP bioluminescence detection of microorganisms is based on the luciferin-luciferase cascade emitting light that is measured with a luminometer. Measured light is interpreted as relative light units (RLU).


A third chapter has also been drafted. Intended as a guidance chapter, this is titled “Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach.”


With the guidance chapter, it is widely recognised that the current growth-based sterility tests with an incubation period of at least 14 days are not suitable for products with a short shelf-life or for products prepared for immediate use, which are usually infused into patients due to clinical needs before completion of the sterility test. These products may include compounded sterile preparations (CSPs), nuclear medicine products and autologous cells.




Bioburden testing


The USP is considering a new chapter titled “〈1119〉 Bioburden Monitoring”. This chapter provides guidance for the monitoring and testing of bioburden, including recommended limits. The chapter distinguishes the differences from Microbial Enumeration Tests, which is purposed for the testing and release of nonsterile products and nonsterile substances for pharmaceutical use in accordance with ‘Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use’.


Although an existing chapter, “Monitoring of Bioburden 〈1229.3〉” suggests that appropriately modified and qualified versions might be used for testing bioburden, there are no details or directions on how to achieve this. The new draft chapter and 〈1119.1〉 provide a solution.


The scope of this chapter includes any material subject to a test for bioburden that is not used for the release testing of a finished product. This includes, but is not limited to, in-process samples, drug substances, components and water. The purpose of bioburden monitoring is to ensure that an item consistently meets the required acceptable limit for bioburden.




Therapeutic Goods Amendment (2024 Measures No. 1) Regulations 2024


Australia has made an amendment to its GMP guidance. The reference is: F2024L00260 (dated 29 February 2024). The updates can be accessed here: 




Analytical procedures


The US FDA has announced the availability of the final guidances for industry entitled “Q2(R2) Validation of Analytical Procedures” and “Q14 Analytical Procedure Development.”


The guidances were prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).


  • The guidance entitled “Q2(R2) Validation of Analytical Procedures” provides a general framework for the principles of analytical procedure validation, including validation principles that cover the analytical use of spectroscopic data.  
  • The guidance entitled “Q14 Analytical Procedure Development” provides harmonised guidance on scientific approaches for analytical procedure development and describes principles to facilitate more efficient, science-based and risk-based post-approval change management.


The guidances are intended to facilitate regulatory evaluations and potential flexibility in post-approval change management of analytical procedures when scientifically justified.


See: and: 




Clinical Pharmacology Considerations


The US FDA has issued guidance (“Clinical Pharmacology Considerations for Antibody-Drug Conjugates Guidance for Industry”) that provides recommendations to assist industry and other parties involved in the development of antibody-drug conjugates (ADCs) with a cytotoxic small-molecule drug or payload.


Specifically, the guidance addresses the FDA’s current thinking regarding clinical pharmacology considerations and recommendations for bioanalytical methods, dosing strategies, dose- and exposure-response analysis, intrinsic factors, QTc assessments, immunogenicity and drug-drug interactions (DDIs).


The principles discussed in this guidance might not be applicable to the development of other types of ADCs (e.g., ADCs with payloads other than cytotoxic small molecule drugs and/or for indications other than oncology).








The European Pharmacopoeia is planning to revise the chapter 2.5.42 titled “N-Nitrosamines In Active Substances And Medicinal Products”.


This chapter describes analytical procedures for the detection of various N-nitrosamines in particular active substances.


For this there are different procedures: Procedure B has been validated as a limit test (30 ppb). Procedures A and BC have been validated as limit tests (30 ppb). Procedure C has been validated as a quantitative test.


The scope of each procedure is defined in Table 2.5.42.-1 within the chapter. With these three procedures, it is possible to analyse the following N-nitrosamines: N-nitroso-dimethylamine (NDMA); N-nitroso-diethylamine (NDEA); N-nitroso-dibutylamine (NDBA); N-nitroso-N-methyl-4-aminobutyric acid (NMBA); N-nitroso-diisopropylamine (NDiPA); N-nitroso-ethyl-isopropylamine (NEiPA) and N-nitroso-dipropylamine (NDPA).


The revised chapter is accessible via Pharmeuropa (requires registration). 






This European Pharmacopeia general chapter for mycoplasmas continues to undergo review. The chapter been further revised to take into account the current knowledge in the field:


  • The culture method and the indicator cell culture method (or alternatively a NAT method) are to be used conjointly to ensure the detection of both “cultivable” and “non-cultivable” mycoplasmas, unless otherwise justified and authorised based on a risk assessment.
  • Given that mycoplasma contaminants may adhere to or be present in the cells, samples should contain both cells and supernatant. However, alternative approaches (culture supernatants alone) may also be acceptable.
  • Selection of the strains (including additional strains) to be considered as positive controls during the routine test and the interfering substance evaluation should be based on a risk assessment.
  • An important revision has been made to the guidelines on the validation of nucleic acid amplification techniques (NAT) for the detection of mycoplasmas in order to adapt the content to the state of the art in science and technology (e.g. strains to be included, characterisation of the viable reference strains, acceptance criterion for the GC/CFU ratio).


The general chapter has been amended and republished for public consultation with the modifications published in Pharmeuropa 34.2 (requires registration).




Sterility testing


The European Pharmacopeia is revising the general chapter for the sterility test. This is to allow the use of alternative methods according to general chapter 5.1.6. “Alternative methods for control of microbiological quality”.


In terms of the main proposed changes: 


  • In the precautions against microbial contamination section, requirements about the environment and location in which the sterility test has to be performed have been simplified because this type of information is usually not defined in the Ph. Eur.
  • The line stating that the sterility test is the only analytical method available to the authorities has been removed.
  • Sampling plan considerations have been completed in order to also provide recommendations for terminally sterilised products and lyophilised products.
  • Recommendations for sterility test invalidation are no longer limited to condition (d) of general chapter 2.6.1. Sterility.
  • Editorial changes have been made throughout the text for greater clarity.


The general chapter has been amended and republished for public consultation with the modifications to the text published in Pharmeuropa 34.2 (requires registration).





Inhalation products


The European Pharmacopeia is proposing a new chapter on inhalation products. The procedures for testing the uniformity of delivered doses intra- and inter-container have been transferred to a new general chapter entitled “Uniformity of delivered dose of inhalation and nasal preparations” (2.9.54) as it is applicable to both nasal preparations and preparations for inhalation. Therefore, these have been deleted from this text. With the exception of some editorial changes, the acceptance criteria for the uniformity of delivered dose are unchanged from the previous version and are still included in this monograph.


The proposed general chapter 2.9.54 is the outcome of bilateral harmonisation with the Japanese Pharmacopeia (JP). For preparations for inhalation, the acceptance criteria for the uniformity of delivered dose are also harmonised. The main changes are:


  • Leak rate: as this test is generally applicable for all preparations that are supplied in pressurised containers, it has been transferred to the monograph Pressurised Pharmaceutical Preparations (0523). The requirement to comply with the test is kept unchanged through the existing cross-reference to the monograph 0523 in the definition section.
  • The procedures for testing the uniformity of delivered dose for some preparations for inhalation and nasal preparations have been transferred to this general chapter from the monographs on Preparations for Inhalation (0671) and Nasal Preparations (0676). The acceptance criteria (partially harmonised for the various preparations) have been kept in the corresponding general monographs. Changes in these texts are published for public consultation in Pharmeuropa and the revisions should be looked at together.


The following differences between the JP and Ph. Eur. versions of the general chapter remain:


  • For pressurised and non-pressurised preparations for inhalation and for device-metered powder inhalers, the JP also allows the delivered dose as stated on the label to be used as the reference value for the limits of acceptance.
  • For pressurised and non-pressurised metered-dose preparations for inhalation, in justified and authorised cases, the JP allows an extension of the ranges, but no value may be less than 50% or more than 150% of the reference value.
  • For nasal preparations, the JP indicates that the tolerance ranges are product specified. 


The draft chapter is accessible via Pharmeuropa (requires registration). 




Test For Extractable Volume Of Parenteral Preparations


The European Pharmacopeia is revising chapter 2.9.17 “Test For Extractable Volume Of Parenteral Preparations”. The draft corresponds to Revision 2 Stage 2 ver.1 (based on the Pharmacopoeial Discussion Group (PDG) working procedure) within the pharmacopoeial harmonisation process. The co-ordinating pharmacopoeia is the European Pharmacopoeia. The original text submitted to the PDG is published in the Pharmacopoeial Harmonisation section.


Compared to the monograph published in the 11th Edition of the Ph. Eur., the following changes are proposed:


  • The testing procedure has been updated, eliminating the requirement for a specific number of test samples to conduct the test. Due to different tolerances regarding the fill volume during production and the performance of the filling equipment, the number of containers to be tested is to be determined using a suitable statistical approach.
  • The requirement for the use of a specific syringe and needle has been removed. The size of the syringe and needle to be used is to be read from the product label to better mimic clinical practice.
  • Two sentences have also been deleted from the single-dose containers section, with the effect that: 
    • pooling of volumes is no longer allowed when measuring the extracted volume from small containers, since it is important that each container fulfils this requirement.
    • direct emptying is no longer described for small-volume parenterals in single-dose containers with a capacity of 10 mL or more to better mimic clinical practice.


The draft chapter is accessible via Pharmeuropa (requires registration). 


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