Suppression of the Test for Abnormal Toxicity from the European Pharmacopoeia

During its 159th plenary session, the European Pharmacopoeia Commission endorsed the complete suppression of the test for abnormal toxicity from the European Pharmacopoeia (Ph. Eur.).

As part of this exercise, 49 monographs revised to remove the test for abnormal toxicity were adopted by the Commission; notably, these included 36 monographs on vaccines for human use. In addition, as the general chapter Abnormal Toxicity (2.6.9) will no longer be referenced in any monograph, it will subsequently be rendered obsolete and will also be deleted from the Ph. Eur.

The Ph. Eur. Commission remains fully committed to the reduction of animal use wherever possible in pharmacopoeial testing, in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes. The decision to suppress the test for abnormal toxicity at the 159th session of the Ph. Eur. Commission is a strong illustration of this commitment.

See: abnormal toxicity

Posted by Dr. Tim Sandle

First Ph. Eur. monograph on a monoclonal antibody

The European Pharmacopoeia Commission has achieved an important milestone in the field of biotherapeutic products with the adoption of the monograph for Infliximab concentrated solution (2928).

The Ph. Eur. Commission embarked upon the setting of public standards for therapeutic monoclonal antibodies (mAbs) in 2014 with a pilot phase and following extensive consultation with its stakeholders.

See: https://www.edqm.eu/en/node/16070

Posted by Dr. Tim Sandle

59th Session of the European Pharmacopeia Commission

The European Pharmacopoeia (Ph. Eur.) Commission adopted 11 new monographs at its 159th Session, which took place in Strasbourg on 21-22 November 2017:

A monograph elaborated under the P4 procedure, Rotigotine (3014). This procedure applies to substances still under patent protection.

The first monograph on a multisource monoclonal antibody, Infliximab concentrated solution (2928); a dedicated press release will be published soon.

Monographs on Phenoxymethylpenicillin, benzathine (2636), Zoledronic acid monohydrate (2743), Imidacloprid for veterinary use (2924), Podophyllotoxin (2750), Sulfobutylbetadex sodium (2804), Concentrated solutions for haemofiltration and haemodiafiltration (2770), Digitalis purpurea for homoeopathic preparations (2705), Lightyellow sophora root (2440), Gastrodia rhizome (2721) and Phytomenadione, racemic (3011).

See: EDQM

Posted by Dr. Tim Sandle

PHARMACOPEIAL FORUM VOL. 43 No.2

News from the USP Pharmacopeial Forum:

Chapter 1231 “Water for Pharmaceutical Purposes” (Revision proposal target, USP41-NF36 1st Supplement)

Proposed revisions are as follows:

• Add information to the section on Sampling for microbial and chemical considerations intended to provide more clarification and guidance on sample hold times.
• Include some modifications to terminology in the Microbial Evaluations section.
• Provide clarification under Chemical Evaluations regarding compliance with elemental impurities requirements.

Posted by Dr. Tim Sandle

European Pharmacopoeia 9th Edition (Supplement 9.1)

The 1^st supplement to the 9^th edition of the European Pharmacopeia became effective on 1^st April 2017.

Of interest to readers:

Water for injections (0169)

Production: revision to include purification processes equivalent to distillation (such as reverse osmosis coupled with appropriate techniques) for producing water for injections (WFI), in addition to distillation; use of non-distillation technologies for the production of WFI requires that notice is given to the supervisory authority of the manufacturer before implementation.

A requirement for regular monitoring of total organic carbon has been added to further emphasize the specific test controls required in the Production section.



Posted by Dr. Tim Sandle

Pharmeuropa 29.1

Pharmeuropa is a free online EDQM publication. Draft monographs are published in Pharmeuropa for public enquiry, which lasts for three months.

Draft Monographs and General Texts for Comment.

2.3.2    Identification of fatty oils by thin-layer chromatography

Method A: chromatogram of hydrogenated arachis oil added.

2.2.32  Loss on drying

Due to its toxicity, the replacement of diphosphorus pentoxide with a molecular sieve is proposed.  The introduction of a standardised amount of desiccant to be used will also help to alleviate to a certain extent that variability.

The conditions of ‘high vacuum’, which were reported to be difficult to achieve with available instruments, are proposed for deletion; this would trigger a revision of the concerned monographs in due time.  Additional clarifications are proposed throughout the general chapter.

 

Posted by Dr. Tim Sandle

Ph. Eur. Commission aimed to reduce animal testing

The recent adoption at its 156th session of the following texts demonstrates the Commission’s commitment to the replacement, reduction and refinement of animal tests in the quality control of medicines.

• Ph. Eur. General Chapter Adopted: Substitution of in vivo methods by in vitro methods for the quality control of vaccines (5.2.14)
• Revisions of the general texts on Tests for extraneous agents in viral vaccines for human use (2.6.16) and Cell substrates for the production of vaccines for human use (5.2.3)

See the Press Release for full details

More information about the Ph. Eur. Commission achievements for 3Rs 

 
More about the Ph. Eur. work programme

Visit our KNOWLEDGE database to find more information on Ph. Eur. texts



Posted by Dr. Tim Sandle

European Pharmacopoeia 9th Edition

A new edition of the European Pharmacopeia is effective from 1st Jan 2017. The following changes have been made:

Test for heavy metals have been deleted from the monographs concerned.

‘Anhydrous’ has been deleted from the title of the monographs concerned.

           

Monographs

As a first step of the Ph. Eur. strategy of implementation of the ICH Q3D guideline

for elemental impurities and according to the decision taken at the 151st session of the European Pharmacopoeia Commission (March 2015), the test for heavy metals (2.4.8 and equivalent) will be deleted from all individual monographs on substances for pharmaceutical use (except substances for veterinary use only). Impacted monographs are listed in the table below. These deletions will be implemented for the 9th Edition and will therefore come into force on 1 January 2017.

            Acetic Acid Glacial (0590)

            Alanine (0752)

            Arginine hydrochloride (0805)

            Calcium chloride dihydrate (0015)

            Caprylic acid (1401) - Octanoic acid

            Citric acid monohydrate (0456)

            Disodium edetate (0232)

            Disodium phosphate dihydrate (0602)

            Glycine (0614)

            Heparin sodium (0333)

            Hydrochloric acid, concentrated (0002)

            Lysine hydrochloride (0930)

            Octoxinol 10 (1553) – Triton X 100

            Polysorbate 20 (0426)

            Polysorbate 80 (0428)

            Sodium acetate trihydrate (0411)

            Sodium chloride (0193)

            Sodium citrate (0412)

            Sodium dihydrogen phosphate dihydrate (0194)

            Sodium hydrogen carbonate (0195)

Assay: use of the colour indicator has been replaced by a potentiometric end-point determination.

Sodium hydroxide (0677)

Trehalose dihydrate (2297)

Tri-n-butyl phosphate (1682)

Trometamol (1053)

Tryptophan (1272)

Corrected Texts

The following texts have been corrected. The corrections are to be taken into account not later than 31 Aug 16

2.2.27  Thin layer chromatography

Posted by Dr. Tim Sandle

Pharmeuropa 28.4

A chapter of interest has been published in Pharmeuropa, and it is out for public comment. Draft monographs are published in Pharmeuropa for public enquiry, which lasts for three months. If no further revision is required the draft monograph is proposed to the European Pharmacopoeia Commission if adopted an implementation date is given and this is about one year after the adoption of the monograph. The monograph is then published in the European Pharmacopoeia (or supplement).

Draft Monographs and General Texts for Comment

3.2.1    Glass containers for pharmaceutical use

Hydrolytic resistance: additional details concerning the autoclaving process, with respect to equipment and handling, have been included; the procedure for cleaning the containers to be tested has been revised in order to result in better reproducibility.

Filling and heating: instructions have been added in order to cope with small containers in which the water is not sufficiently retained.

Posted by Dr. Tim Sandle

Pharmacopeial Forum 42 (5)

A new edition of the Pharmacopeial Forum Vol. 42, No.5, has been issued. Items of interest include:

Chapter197  Spectrophotometric Identification Tests

Proposed revisions:

1.         A title change is proposed.

2.         A new section, Introduction and Scope is proposed.

3.         A new section, Identification Methodology, is proposed.

4.         A section heading change from Infrared Absorption to Infrared Spectroscopy is proposed.

5.         Technical and editorial revisions for Infrared Spectroscopy are proposed. The main technical revision for this section allows the comparison of the spectrum of the test specimen to the spectrum of the USP Reference Standard previously recorded.

6.         A new section, Near-Infrared and Raman Spectroscopy, is proposed.

7.         A section heading change from Ultraviolet Absorption to Ultraviolet-Visible Spectroscopy is proposed.

8.         A new section, X-ray Powder Diffraction Spectroscopy, is proposed.

9.         A new section, Equivalent/Alternative Tests, is proposed.

Chapter 1210 Statistical Tools for Procedure Validation [NEW]

Proposed revision details:

This chapter is proposed as a companion to Validation of Compendial Procedures 〈1225〉 with the purpose of providing statistical methods that can be used in the validation of analytical procedures. Specifically, this revision clarifies the accuracy and precision calculations while removing specific linearity requirements. Linearity may be inferred from accuracy or other statistical methods as deemed appropriate. This chapter discusses all of the following analytical performance characteristics from a statistical perspective: accuracy, precision, range, detection limit, quantitation limit, and linearity. Additional related topics that are discussed in this proposed chapter include statistical power, two one-sided test of statistical equivalence, tolerance intervals, and prediction intervals.

Chapter 121 >            Sterilization and Sterility Assurance of Compendial Articles

There were two main objectives in updating this chapter. One was to make sure current information was accurate. The other objective was to develop a new format for the information, with improved organization of specific topics. It was decided to accomplish the update in two phases. The two-stage revision started in the last USP cycle (2010–2015). The initial focus of the revision was on the sterilization aspects of the chapter, to be followed by revision of content relevant to sterility assurance. In considering how to update 〈1211〉, which has its origins in the late 1980s, it was decided to split the chapter, separating out the sterilization content by moving it to a new chapter family, Sterilization of Compendial Articles 〈1229〉. The content on sterility assurance is remaining in 〈1211〉, and the chapter is being renamed Sterility Assurance 〈1211〉. With the development of the 〈1229〉 family of chapters, focused on the various sterilization processes, now nearly complete, the focus of the future 〈1211〉 will be limited to sterility assurance. This draft proposal, which is a major revision to the existing 〈1211〉, is a short-term fix while a complete rewrite is under development.

Additionally, minor editorial changes have been made to update this chapter to current USP style.

The following Briefing list includes monographs and/or chapters that both reference the General Chapter under revision and require revision to keep references to the General Chapter accurate. Other monographs and/or chapters may also be listed, even where the reference to the General Chapter remains unchanged, as additional notice to stakeholders where there is believed to be potential for the change in the general chapter itself to affect pass-fail determinations for particular monograph articles

Chapter 1229.14 Sterilization Cycle Development [NEW]

This new chapter is an addition to the Sterilization of Compendial Articles 〈1229〉 family of chapters. Sterilization is not only a means to eliminate microorganisms, but is also a process that may alter materials and thereby impact usefulness, safety, or both. The correct development and implementation of a sterilization process involves a number of important steps. This chapter provides an overview of those steps and the general principles involved in the development of a sterilization cycle.

Chapter 1229.15 Sterilizing Filtration of Gases [NEW]

This new chapter is an addition to the Sterilization of Compendial Articles 〈1229〉 family of chapters. Sterilization processes are broadly divided into two categories: destruction of microorganisms and physical removal of those microorganisms from the material being sterilized. Autoclaving is an example of the former, and sterilizing filtration is an example of the latter. The sterilization of gases that contact sterile components, container and closures, and product contact surfaces of processing equipment is typically accomplished by passing the gas through one or more sterilizing-grade membrane filters. This proposed chapter provides an overview of the general principles involved in the sterilizing filtration of gases, including the types of filters used, the retention mechanisms, and the validation of the filtration process.



Posted by Dr. Tim Sandle

Pharmacopeial Forum 42 (4)

A new edition of the Pharmacopeial Forum Vol. 42, No.4, has been issued. Items of interest include:

Chapter 785 Osmolality and Osmolarity

Proposed revision details:

• Add clarity to the text in the Introduction.
• Add examples of how to convert from osmolality to osmolarity.
• Add information about the shelf life of Standard Solutions in Measurement of Osmolality, Standard Solutions.
• Add tolerances for the amounts of sodium chloride (NaCl) in Measurement of Osmolality, Standard Solutions and how they should be prepared.
• Update instructions on how to evaluate repeatability in the osmometer calibration.
• Include information about possible suppliers of commercially available standard solutions used in the osmometer calibration.

Additionally, minor editorial changes have been made to update the chapter to current USP style.

Chapter 857 Ultraviolet-Visible Spectroscopy

Proposed revision details:

• Introduction: Clarification on the type of equipment covered and not covered by this chapter.
• Control of Wavelengths: Inclusion of possible procedures and clarification of the acceptance criteria.
• Control of Absorbance: Inclusion of the procedures and acceptance criteria for the regions of 0–1 A and 1–3 A; update of the National Institute of Standards and Technology (NIST) documents referenced; and inclusion of tabulated values of absorptivity for potassium dichromate solutions. Clarification of the acceptance criteria for neutral-density glass filters.
• Limit of Stray Light: Inclusion of two procedures for measuring stray light.
• Resolution: Inclusion of a more detailed procedure to evaluate this parameter.
• Validation, Quantitation Limit: Update of the ASTM document referenced.
• Validation, Linearity: Replacement of correlation coefficient R with r2.
• Validation, Robustness: Inclusion of the statement that this parameter is evaluated during method development

Chapter 1079.1 Storage and Transportation of Investigational Drug Products [NEW]

Chapter 1857  Ultraviolet-Visible Spectroscopy – Theory and Practice

Changes include: 

• Analytical Considerations, Instrumental Factors, Spectral Bandwidth, inclusion of the use of the atomic deuterium line to confirm the spectral bandwidth.
• Analytical Considerations, Instrumental Factors, Stray Light, inclusion of additional information and discussion on the effects of stray light.
• Analytical Considerations, Sampling Factors, Cell Corrections, changing the title of this subsection to “Cell Matching Corrections.

Posted by Dr. Tim Sandle

Pharmeuropa 28.3

A new edition of Pharmeuropa has been issued (28.3). Pharmeuropa is an EDQM publication. Draft monographs are published in Pharmeuropa for public enquiry, which lasts for three months.

Items of interest are:

3.2.3    Sterile plastic containers for human blood and blood components

Tests: the use of water for injections R has been replaced by water R (the use of sterilised water for injection is not considered suitable for testing purposes); this change is in accordance with general chapter 3.1.1.1. Materials based on plasticised poly(vinylchloride) for containers for human blood and blood components.

Pyrogens: to avoid animal testing, in accordance with EU Directive 2010/63/EU and the policy of the European Pharmacopoeia Commission, the test for pyrogens has been replaced by the test for bacterial endotoxins.

Packaging, Labelling: the requirements have been revised.

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

The scope of this general chapter has been expanded to include coated closures, bi-layer seals and lubricated closures to reflect better the range of closures on the market. More details are provided in the Identification section for greater clarity.

Identification A (IR): the amount of rubber required is described as ‘an appropriate amount’ to allow more flexibility.

Identification B (total ash): an indication has been added to explain how to proceed with samples that are not subjected to steam sterilisation; an indication has been added to allow compliance with the limit for a specific rubber type, when available.

Solution S: the washing step performed before the preparation of solution S has been deleted; the procedure for the measurement of the temperature during autoclaving has been clarified.

Appearance of solution S: limits for nephelometric measurements have been included.

Acidity or alkalinity: clarification has been added on when to perform the titration.

Extractable zinc: the description of the test solution preparation has been revised to be more specific.

Self-sealing test: a requirement to use a vial that fits with the closure has been added

0008    Water, Purified

In line with the Ph. Eur. implementation strategy of the ICH Q3D Guideline on Elemental impurities, the test for heavy metals (2.4.8) is deleted.

However, to retain the aspect of control for elemental impurities, the ‘Purified water in bulk’ section of the monograph is revised to address the situation where purified water in bulk does not comply with the requirements for conductivity prescribed in Water for injections (0169) in bulk.

Posted by Dr. Tim Sandle

Pharmeuropa reviews

Pharmeuropa 28.1 contains two draft monographs of interest:

2.2.2    Degree of coloration of liquids

This draft corresponds to Stage 4 within the Pharmacopoeial harmonisation process (Ph. Eur., JP, and USP). The coordinating pharmacopoeia is the USP.

0333                Heparin Sodium

Related substances: the proposal is to introduce a disregard limit to the related substances test, in line with the principles of general chapter 2.2.46 Chromatographic separation techniques. The current text does not specify a quantitative limit for ‘any other impurity’ and compliance with the acceptance criterion depends on the sensitivity of the method.

Pharmeuropa 28.2 contains two further draft monographs of interest:

1473    Soya-bean oil, refined

Identification: reference to the test for composition of fatty acids has been added since it is more specific than that for identification of fatty oils by TLC; the latter has been maintained as second identification.

Composition of fatty acids: the term ‘and isomer’ has been included in the limit for oleic acid since baseline separation of oleic acid and its more abundant positional isomer, cis-vaccenic acid, is not achieved with the current method

2034                Substances for Pharmaceutical Use

In line with the implementation strategy of the ICH Q3D guideline, a new paragraph on elemental impurities has been added to this general monograph. Its aim is to clarify requirements for substances for pharmaceutical use used for the production of medicinal products that are outside of the scope of general chapter 5.20 (which will be aligned with the ICH Q3D guideline). For medicinal products within the scope of general chapter 5.20, the limits for elemental impurities apply to the medicinal product.

In addition, a sentence has been added to the production section to highlight the need during risk assessment, to take any necessary account of potential elemental impurities derived from intentionally added catalysts and reagents.

Pharmeuropa is an online EDQM publication. Draft monographs are published in Pharmeuropa for public enquiry, which lasts for three months. Comments received are processed by EDQM, at this stage the draft can be amended and republished. If no further revision is required the draft monograph is proposed to the European Pharmacopoeia Commission if adopted an implementation date is given and this is about one year after the adoption of the monograph.

Posted by Dr. Tim Sandle