Pharmaceutical Regulatory round up: September 2022

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




EU GMP Annex 1

The revised edition of EU GMP Annex 1 has been issued, with a date of implementation of 25th August 2023 (with the exception of one clause – 8.123 – relating to the frequency of sterilising freeze-dryers, which comes into effect on 25th August 2024).


Annex 1 covers the manufacture of sterile products is subject to special requirements to minimise risks of microbiological, particulate and pyrogen contamination of sterile products. The Annex provides guidance as to how sterile products can be protected using the most effective systems and technology.


The guidance includes personnel training, equipment qualification, cleanroom design and environmental monitoring.


The revised guidance emphasizes the importance of embedding Annex 1 principles into the Pharmaceutical Quality System and using Quality Risk Management as a proactive process for addressing contamination hazards.


The link for the revised Annex 1 is:


RSSL will be running a free live webinar on Wednesday 9 November 'EU GMP Annex 1 - The Focus Points', to register and find out more click here




ICH Guideline Q14 Analytical Procedure Development Step2B

ICH is updating its guideline on analytical method development, which complements ICH Q2 Validation of Analytical Procedures. Earlier in 2022 the draft was circulated for comment and a number of comments have been received from professional bodies.


The guidance sets out to direct users to adopt a science and risk-based approach for developing and maintaining analytical procedures suitable for the assessment of the quality of drug substances and drug products.


There is a more detailed connection to both ICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Management. Significant inclusions are consideration of multivariate analytical procedures and for real time release testing (RTRT).


The current draft can be accessed here:




European Pharmacopeia

The 11th edition of the European Pharmacopeia goes live on 1st January 2023. The main changes to the 1st supplement will be:


2.2.27. Thin-layer chromatography

Terminology: updated to reflect current terminology for general chapters.

Procedure: Revised general chapter 2.2.46 no longer restricts the objective of adjustments of chromatographic conditions to cases where the system suitability criteria cannot be met with the original chromatographic conditions. However, these criteria must still be met if an adjustment is made. Since the paragraph applies both to non-quantitative and quantitative procedures, it has been moved under this section.

Visual evaluation, Identification: clarification of the statement regarding performance of the plate and system suitability.


2.2.28. Gas chromatography

Procedure: Revised general chapter 2.2.46 no longer restricts the objective of adjustments of chromatographic conditions to cases where the system suitability criteria cannot be met with the original chromatographic conditions. However, these criteria must still be met if an adjustment is made.


2.2.29. Liquid chromatography

Procedure: Revised general chapter 2.2.46 no longer restricts the objective of adjustments of chromatographic conditions to cases where the system suitability criteria cannot be met with the original chromatographic conditions. However, these criteria must still be met if an adjustment is made.


2.2.30. Size-exclusion chromatography

Procedure: Revised general chapter 2.2.46 no longer restricts the objective of adjustments of chromatographic conditions to cases where the system suitability criteria cannot be met with the original chromatographic conditions. However, these criteria must still be met if an adjustment is made.


2.2.45. Supercritical fluid chromatography

Terminology: updated to reflect current terminology for general chapters.

Procedure: Revised general chapter 2.2.46 no longer refers to supercritical fluid chromatography; hence the paragraph under Procedure is omitted.


2.6.17. Test for anticomplementary activity of immunoglobulin

Deletion of the sentences stating that stabilised sheep blood and antiserum against sheep red blood cells are available from a number of commercial sources: it is acceptable to use assay components prepared in-house or from a commercial source, however, the EDQM cannot recommend commercial reagents or provide information on potential suppliers.


2.7.26. Cell-based assays for potency determination of TNF-alpha antagonists

This general chapter describes in detail the execution of four specific cell-based assay procedures (representative of bioassays commonly used to determine the potency of TNFalpha antagonists) and provides considerations on data analysis, system suitability, assay acceptance criteria and results evaluation. General recommendations on adjustment of assay conditions are also given. It does not exclude the use of alternative procedures that are acceptable to the competent authority. The chapter is the result of extensive experimental work undertaken by a large number of laboratories, to verify the applicability of various bioassays as multi-product procedures suitable to assess the TNF-alpha inhibitory effect. Rationalisation of these cell-based assays will contribute to standardising the different TNFalpha antagonists available and in development.


2.8.2. Foreign matter

The requirements for other foreign elements like moulds, insects and other animal contamination have been further specified.


2.9.5. Uniformity of mass of single-dose preparations

Table 2.9.5.-1 expanded to include additional dosage forms that refer to this general chapter.


2.9.38. Particle-size distribution estimation by analytical sieving

This minor revision corresponds to Revision 1, Correction 1 (based on PDG working procedure) within the Pharmacopoeial harmonisation process ( Ph. Eur., JP, USP). The coordinating pharmacopoeia is the JP.

This minor revision to the diameters of the test sieves takes into account the standard diameters described in international guidelines (e.g. ISO, ASTM, JIS). The general chapter now includes test sieve diameters of 200 mm and 203 mm (8 inches) as well as 75 mm and 76 mm (3 inches).


3.2.9. Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders

The general revision of the general chapter included changes to the following:


  • Definition and scope: use of natural rubber latex not permitted but dry natural rubber may be used.
  • Identification: IR, which may in itself be selective, maintained as the main and basic technique for rubber identification; status of the Total ash test changed from always necessary to only possibly needed and complementary; other potential techniques listed.
  • Acidity or alkalinity: guidance on how to choose titrant added.
  • Absorbance: filtration only needed for turbid or hazy solutions.
  • Extractable heavy metals: deleted to align with ICH Q3D and Ph. Eur. policy on elemental impurities.
  • Functional tests: introduction expanded to clarify cases in which the tests for penetrability, fragmentation and self-sealing may have to be adapted or can be omitted.
  • Fragmentation: specific testing procedure for closures used for dry preparations removed. Allowing the sample to stand for 16 h at room temperature proved unnecessary and this requirement has therefore been deleted from the procedure.




Radiopharmaceutical preparations (0125)

This general monograph on Radiopharmaceutical preparations has undergone a global revision and update, including editorial modifications and the following:


Definitions: clarification with respect to the monograph’s scope including how to deal with radionuclide precursors used in continuous processes and which are therefore unavailable for testing.


Paragraphs on Radionuclidic purity, Radiochemical purity and Chemical purity have been merged with the respective sections under “Tests”. Outdated and irrelevant terminology has been deleted (“carrier-free preparation”, “no carrier added preparation”). The term “molar radioactivity” has been added, as well as an explanation of the statement “maximum recommended dose in millilitres (V)”.


  • Production section: updated to reflect current state-of-the-art radionuclide production
  • methods and to include information on chemical precursors and excipients. General textbook information has been deleted.
  • Identification: clarification that a radionuclide is identified by its half-life or nature and energy of its radiation or both.
  • pH, Elemental impurities and Particulate contamination: introduction of sections.
  • Non-radioactive substances and related substances: expansion of the section explaining how potential impurities are to be considered.
  • Sterility: the section has been grouped with the other tests not involving radioactivity
  • measurement and has been expanded to allow omission of a pre-filtration filter integrity test and to include the requirements for radionuclide precursors.
  • Physiological distribution: the section has been grouped with the other tests not involving radioactivity measurement. The part on the performance of the test has been removed as, inline with the 3R principles, the test should no longer be used. However, it had been accepted that certain monographs for radiopharmaceutical preparations still prescribed the test. Due to the small numbers of these preparations used in practice, cross-validation of alternative tests would consume more animals than the continuation of the test for many years. These monographs contain test details.
  • Bacterial endotoxins: changes to the section to indicate that limits for radionuclide precursors must allow for contributions from other sources in the production of radiopharmaceuticals.
  • Radionuclidic purity: removal of the half-life test and inclusion of an approximate half-life test as a contributor to the Identification of positron-emitting radionuclides.
  • Clarification that preparations made from radionuclide precursors must comply with the precursor’s radionuclidic purity requirements throughout the shelf life of the final preparation.
  • Radioactivity: section added to explain that in case no Ph. Eur. monograph exists, limits are to be defined and justified.
  • Labelling: additions have been made to the section.




Water for injections (0169)

Deletion of tests for inorganic substances in the section on sterilised water for injections (SWFI). This section previously included tests for Acidity or alkalinity, Chlorides, Nitrates, Sulfates, Aluminium, Ammonium, and Calcium and magnesium. It also described (and still describes) a Conductivity test, with specific acceptance criteria, depending on the size of the container.


Based on well-known chemical and physical properties of water, and ions in water, it is possible to determine the minimum conductivity that these inorganic impurities would produce when present at the highest allowable concentration for each of the species according to the chemical tests.


Consequently, if the sample passed the conductivity test, it would necessarily pass each of the original chemical tests. In view of the above, the chemical tests Acidity or alcalinity, Chlorides, Nitrates, Sulfates, Ammonium, and Calcium and magnesium have been deleted in favour of a single, instrument-based, quantitative test.


The test for Aluminium, however, has been maintained, since it is a requirement for SWFI used in the manufacture of dialysis solutions.





ISPE has issued a second edition to GAMP 5, during 2022. GAMP refers to Good Automated Manufacturing Practice. This is the system for producing quality equipment using the concept of prospective validation following a life cycle model. The document is specifically designed to aid suppliers and users in the pharmaceutical industry.





Out of specification

The U.S. FDA has updated its out of specification guidance. This guidance for industry provides the current thinking on how to evaluate out-of- specification (OOS) test results. OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications.

The main changes relate to averaging and with interpreting outlier test results.

The guidance can be accessed here:




USP revises ‘Microbiology Laboratory Best Practices’ chapter

The USP microbiology committee has undertaken a review and revision of the ‘Microbiology Laboratory Best Practices’ chapter USP <1117>. The new chapter came into effect on 1st August 2022. There are a number of changes within the chapter, for which the biggest update relates to the manufacture and use of culture media. Other sections of importance include the necessity to assess samples for low endotoxin recovery where endotoxin testing is required.

The DOI for the chapter is:




USP introduces validation of alternative methods to antibiotic assays

Microbiological assay methods have traditionally been used to quantify the potency, or antimicrobial activity, of antibiotics. Microbial assays provide a direct measure of the effectiveness of the antibiotic against a reference microorganism.


A new general USP chapter <1223.1> provides points to consider for manufacturers who want to use physicochemical alternatives instead of the microbial assay methods.


Given the widespread use of high-performance liquid chromatography (HPLC) as an alternative to microbial assay methods, the chapter focuses on HPLC methods. However, the principles set forth in this chapter are applicable to any alternative physicochemical procedure.




Sterilisation principles

The USP has introduced a general chapter on sterilisation principles. The new general information chapter <1229> provides an overview of the concepts and principles involved in sterilization (by various modes) of compendial articles that must be sterile. It includes information about supportive sterilization processes utilized in their preparation.


The chapter is based around:


  • Sterilization process development that includes evaluation of the stability and compatibility of materials, container integrity, expected presterilization bioburden, equipment method control parameters, etc.
  • Identification of sterilization process parameters that preserve the inherent properties of the materials yet inactivate or remove microorganisms.
  • Demonstration that the sterilization process and equipment are capable of operating within the prescribed parameters and corresponding to independent measurements of the critical parameters.
  • Performance of replicate studies that represent the operational range of the equipment and employ actual or simulated product. The use of biological indicators for correlation between the measured physical parameters, and the expected lethality is recommended wherever possible.
  • Maintenance and monitoring of the validated process during routine operation.
  • Assurance that the bioburden (number and type) of the materials is acceptable and is maintained within predetermined limits during routine operation.




Viral clearance

A new USP chapter on viral clarence has been produced, chapter <1229.18>. There are varied means of virus removal and clearance. The most widely used methods are filtration, chromatography, thermal, chemical (solvent/detergent combinations), and radiation treatments, and the chapter explores each of these.




Biological indicators

The USP chapter for biological indicators has undergone a revision, and this comes into effect on 1st August 2022 (Chapter <1229.5>).


A biological indicator (BI) is a well-characterized preparation of a specific microorganism that has known resistance to a specific sterilization process. BIs are used to demonstrate the effectiveness of processes that render a product sterile in its final package or container, as well as the effectiveness of the sterilization of equipment, product contact materials, and packaging components as required.


BIs are also be used to monitor established sterilization cycles and are used for periodic reassessment of sterilization process effectiveness. BIs are process aids and can support the correlation of physical parameters to microbiological destruction.


Microorganisms recognized as suitable for BIs are spore-forming bacteria; the spores of these microorganisms are significantly more resistant than the vegetative cells that comprise the majority of bioburden in or on materials.


The main change in the chapter is with “The BI manufacturer should include survival and kill times for the BI in their documentation and this should be verified by the end user. The resistance of the BI should be determined by the manufacturer under defined conditions.” (changes in italics).




Moist heat sterilisation of aqueous liquids

A new USP chapter has been issued about the sterilisation of liquids – chapter <1229.2>. 


Steam sterilization of aqueous liquids (including both suspensions and emulsions with mixing), also known as sterilization of nonporous loads, is the method of choice for aqueous parenteral products, in-process aqueous liquids, laboratory media, and biological waste materials. This type of sterilization is accomplished primarily in closed containers. During steam sterilization by direct contact (also called steam sterilization of parts, hard goods, or porous items) the steam in the chamber directly contacts the surface of load items to effect sterilization (see Steam Sterilization by Direct Contact 〈1229.1〉). In contrast, sterilization of liquids in containers is accomplished by application of heat to the container, heating of the container wall, and ultimately heating of the internal liquid volume. This can be accomplished using steam, superheated water, and air in various combinations. Some aqueous liquids are susceptible to over-processing that could render them unfit for their intended use. Manufacturers should consider the influence of these differences when they establish a suitable process.




Bioburden monitoring

The USP has introduced a chapter for monitoring of bioburden in relation to pharmaceutical terminal sterilisation practices.  This is chapter <1229.3>.


Monitoring of in-process bioburden of pharmaceutical components and products is an essential element of the overall contamination-control program for appropriate sterilization process control. Bioburden monitoring should be designed for the recovery of a broad range of microorganisms that are likely to be present in the material being processed. Sterilization processes are implemented in order to eliminate bioburden in materials and the products, ensuring both adequate process control and end-user safety.




EMA guidance supports development of new antibiotics

As part of its efforts to support a global approach to the development of new antimicrobial medicines, EMA has published the final revised guideline on the evaluation of human medicines for the treatment of bacterial infections.


Antimicrobial resistance (AMR), which is the ability of microorganisms to resist antimicrobial treatments, especially antibiotics, has a direct impact on the health of people and animals and carries a heavy economic burden worldwide. In the European Union (EU) alone, it is responsible for an estimated 33,000 deaths per year. It is also estimated that AMR costs the EU €1.5 billion per year in healthcare costs and productivity losses.


EMA plays an important role in the fight against AMR by guiding and supporting the development of new medicines and treatment approaches, especially for patients with infections caused by multidrug-resistant bacteria, who currently have very few therapeutic options.


As AMR is a global threat, regulators in the EU, the United States and Japan have agreed to align as much as possible their respective data requirements so that medicine developers can design clinical trials that meet the evidence needs of multiple regulatory agencies. The revised document reflects the outcome of these discussions, and also includes:


  • clarifications on recommended clinical development programmes for antimicrobials intended to address an unmet need;
  • guidance on clinical trials to support treatment of uncomplicated urinary tract infections and uncomplicated gonorrhoea;
  • updated guidance on displaying microbiological and clinical efficacy data in the summary of product characteristics.


The revised guideline is published together with an addendum aiming to steer clinical development programmes required to support the authorisation of medicines for treatment of bacterial infections in children.



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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