Pharmaceutical regulatory round up: October 2022

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




Good distribution practice

Good distribution practice (GDP) describes the minimum standards that a wholesale distributor must meet to ensure that the quality and integrity of medicines is maintained throughout the supply chain. One important aspect is with temperature controls.


The United States Pharmacopeia (USP) has issued an interesting stimuli to the revision process, titled ‘The Use of Temperature Mapping for the Qualification of Storage Areas for the Proper Temperature Storage of Drug Products’. This means that the issued text may transition into a pharmacopeial chapter.


The text looks at the use of temperature mapping as a process to qualify storage areas to maintain temperature for the storage of drugs, which is an effective strategy to identify risks as part of a quality management system. The text points out that the extent of physicochemical degradation of drug products depends on factors such as product stability and storage conditions. Hence, storage and handling areas need to maintain labelled temperature ranges to ensure product safety, efficacy, and expiry.


The text forms part of Pharmacopeia Forum 48 (5). See:


RSSL offer comprehensive stability management, in accordance with GMP and ICH guidelines. Discover more here.

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Comparability protocols for FDA submission

The U.S. FDA has issued guidance (October 2022) to assist original applicants and holders of approved new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs) with implementing a chemistry, manufacturing, and controls (CMC) post-approval change through the use of a comparability protocol (CP).


A CP is a comprehensive, prospectively written plan for assessing the effect of a proposed post-approval CMC change(s) on the identity, strength, quality, purity, and potency of a drug product, including a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality).


The update includes the incorporation of the International Council on Harmonisation (ICH) Q12 principles for post-approval changes.


The new guidance is titled “Comparability Protocols for Post-approval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA” and it can be accessed here:




Analytical method transfer

The transfer of analytical methods continues to be a subject that falls foul of regulators or leads to inefficiencies. Regulators are particularly keen to ensure methods are being appropriately and scientifically transferred in. The USP is addressing one variable that seems to cause problems from time to time – precision. Precision is defined by the Royal Society for Chemistry as “as the closeness of agreement between indications or measured quantity values obtained by replicate measurements on the same or similar objects under specified conditions.”


In a s stimuli article, the USP addresses a statistical strategy that has been proposed to compare method precision during the transfer of a validated analytical procedure. Here the situation in the biopharmaceutical industry, where an extensive history of method performance from the "old" laboratory is available, is considered. These data can be used to assess whether precision at the "new" laboratory is comparable to the "old" laboratory. The article includes a practical illustration and outlines a Microsoft Excel formula to assist in correctly concluding precision comparability. The text appears in Pharmacopeia Forum 48 (5).


To support analytical methods, the European Pharmacopeia is proposing a chapter on the design of experiments. The chapter is set to provide an introduction to the use of design of experiments (DoE) for the screening and optimisation of analytical data. The objective is to provide guidance on good practice as well as to set out the regulatory framework and critical aspects that need to be addressed.


Discover how RSSL can support your method development, validation and analytical method transfers here





The European Medicines Agency (EMA) has published an updated assessment report (October 2022) into the CHMP’s Article 5(3) of Regulation (EC) No 726/2004 opinion on nitrosamine impurities in human medicinal products.


Nitrosamines (N-Nitrosamines) are organic compounds and most are carcinogenic (there is a positive association between nitrite and nitrosamine intake and gastric cancer, between meat and processed meat intake and gastric cancer and oesophageal cancer, and between preserved fish, vegetable and smoked food intake and gastric cancer, as per a review article published in the World Journal of Gastroenterology).


The EMA guidance provides provides general guidance and recommendations on mitigating and preventing the presence of nitrosamines in human medicinal products. In this context all MAHs/Applicants of human medicinal products should work with the manufacturers of their Active Pharmaceutical Ingredients (APIs) and finished products (FPs) in order to ensure that the presence of nitrosamine impurities in their medicinal products is mitigated as much as possible and controlled at or below a limit defined based on ICH M7(R1) principles for substances of the “cohort of concern” reflected in this guideline and calculated considering a lifetime daily exposure and kept as low as possible and that appropriate risk mitigating measures are taken.


The revised document can be accessed here:


We offer a bespoke method to identify nitrosamine impurities help you ensure patient and product safety and achieve regulatory compliance. Find out more



The assessment of subvisible particles in liquid products

The USP is providing draft  guidance on ‘Selecting an Appropriate Volume for the Subvisible Particles Per Container Calculation’. The purpose of this text is to provide a more robust framework when it comes to patient safety.


Subvisible particles may lead to occlusions in blood capillaries and certain particle types have potential immunogenicity concerns for biologic drug products (DPs). Therefore, particles are monitored at release and on stability to ensure product quality and patient safety.


To ensure accuracy, it is important to select the correct sample size, especially for small volume therapeutics. A volume multiplier needs to be selected for calculating the particles per container value from the light obscuration analytical testing results of particles per millilitre. The revised text, contained in Pharmacopeia Forum 48 (5), provides some guidance on how to approach this.




Linearity - a line for success?

Linearity is an important characteristic of a quantitative measurement method (analytical, biological, and microbiological). This is something that should be investigated throughout the complete life cycle of the measurement method according to the principles and guidelines of method validation. Linearity refers to the relationship between the final analytical result for a measurement and the concentration of the analyte being measured.


The problem facing laboratory analysts is that linearity has been defined in different ways in literature and guidelines (such as being proportional and as straight line) and it has been described for different purposes (such as for calibration and accuracy studies).


A new USP stimuli article provides a generic definition of linearity designed to support both method calibration and accuracy studies, making it possible to discuss linearity for quantal bioassays, and support the life cycle of the method.


The text appears in Pharmacopeia Forum 48 (5):





Excipients may be used in pharmaceutical formulations; while they have a variety of functions, excipients have limited (if any) pharmacological activity. A key quality consideration is with how they relate to compendial specifications, performance-related properties (PRPs), critical material attributes (CMAs), critical quality attributes (CQAs) of the drug product, and quality by design (QbD) principles that aid in their selection and control.


The USP currently has a chapter on excipients, designed to ensure robust drug products with consistent quality. The chapter is <1059> and it is currently undergoing review.


The update expands on the use of excipients in a formulation and the CQAs of the drug product - the physical, chemical, biological, or microbiological properties or characteristics of the drug product that should be within an appropriate limit, range, or distribution to ensure the desired product quality.


Earlier in the year, the USP signalled that it was updating the chapter titled ‘〈1078〉 Good Manufacturing Practices for Bulk Pharmaceutical Excipients’. There is a line of symmetry between these two areas of the USP; hence, 2023 could see some key changes in the excipients release and testing space. Notably, the use of risk assessments under a quality risk management (QRM) programme by the excipient manufacturer is recommended. This is to identify those aspects of the raw materials and manufacturing process that require the implementation of GMP controls to minimize the risks to excipient quality and patient safety while maintaining regulatory compliance.



Microbial control strategies for cell therapy products

A draft chapter has been proposed for the USP titled ‘Microbial Control Strategies for Cell Therapy Products’ (USP <1114>). Cell therapy products are aseptically manufactured biological products that are composed of autologous, allogenic, or xenogeneic cells that may undergo substantial manipulations outside the body before being re-administered to the patient. Therefore, microbiological control is very important.


The draft text considers the associated microbial contamination risks and challenges, detection of microbial contamination. The text also provides practical guidance specific to microbial control strategies for cell therapy products.


Within Europe, an equivalent chapter is also undergoing update. This is 2.6.27. Microbiological Examination of Cell-based Preparations.’


Here, the approaches to microbiological examination of cell-based preparations are designed to take into account the characteristics and limitations of these preparations, in particular their shelf-life, which may not always allow for completion of conventional microbiological examination tests before administration to the patient, as well as the amounts available for testing and sampling-related issues.


The main changes are in relation to the growth promotion test where harmonisation of the incubation time with general chapter 2.6.1. Sterility is proposed. The incubation time of the growth promotion test has been changed to “not more than 3 days in the case of bacteria and not more than 5 days in the case of fungi” because: This changes has occurred because collaborative studies and data from the literature indicate that Bacillus fragilis grows within 3 days.


Discover how we can support your analytical cell and gene therapy requirements here



Microbial glossary

It is likely that a new chapter will appear in the USP that takes the form of a glossary of commonly used microbiological terms. If agreed, this will become chapter <1117.1>. The draft chapter aligns with ‘International Organization for Standardization. ISO 11139:2018: Sterilization of health care products—Vocabulary of terms used in sterilization and related equipment and process standards. 2018’ and ‘ASTM International. ASTM F838-20 Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration’.





Cytometry as a microbial control method

In a new USP chapter of interest, cytometry as a microbiological method is addressed. This is a draft new USP chapter ‘〈74〉 Solid Phase Cytometry-Based Rapid Microbial Methods for the Detection of Contamination in Short Shelf-Life Products’.


The detection and enumeration of vital stained microbial cells captured on a membrane forms the basis of solid phase cytometry. With solid phase cytometry, large volumes of filterable products can be processed and an image of the entire membrane can be captured or scanned to detect viable microorganisms, so that the technology is suitable for contamination testing.


The draft chapter provides a risk-based test method for the detection of microbial contamination.



India Pharmacopeia

Two changes are taking place for the Indian Pharmacopeia relating to chemistry. These are current available for comment:


  • Amendments Proposed - Chemical Monographs/General Chapters: 2.4.22. Optical Rotation and Specific Optical Rotation
  • Amendments Proposed - Chemical Monographs/General Chapters: 2.4.26. Solubility




Computer systems

The U.S. FDA has issued a draft guidance on computer software assurance for computers and automated data processing systems used as part of medical device production or the quality system. This draft guidance is intended to:


  • Describe "computer software assurance" as a risk-based approach to establish confidence in the automation used for production or quality systems, and identify where additional rigor may be appropriate; and
  • Describe various methods and testing activities that may be applied to establish computer software assurance and provide objective evidence to fulfil regulatory requirements, such as computer software validation requirements in 21 CFR part 820 (Part 820).






Tablets and capsules are widely manufactured and prescribed and may provide a number of advantages over other dosage forms, including ease of storage, portability, ease of administration, and accuracy in dosing.


However, variations can creep into the process. For this reason, the FDA has issued a new guidance document titled “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules.”


In particular the FDA are concerned with differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors.



Our multidisciplinary team of experts can support you with physical characterisation of your drug product, discover more here.



Annex 1 webinar series: Dr Tim Sandle has collaborated with RSSL on an insightful series covering key Annex 1 focus areas. To learn more and view the series please click here.

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