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DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Five new General Chapters in the European Pharmacopoeia on Genotoxic Impurities in Pharmaceutical APIs

 regulatory  Comments Off on Five new General Chapters in the European Pharmacopoeia on Genotoxic Impurities in Pharmaceutical APIs
Apr 292016
 

During the manufacture of APIs as sulfonate salts, esters of sulfonic acid may develop in undesired chemical side reactions. Recently, five new General Monographs have been included in the European Pharmacopoeia which describe how to cope with these impurities. Read more about these genotoxic impurities and the possibility to control them thanks to risk assessments.

http://www.gmp-compliance.org/enews_05313_Five-new-General-Chapters-in-the-European-Pharmacopoeia-on-Genotoxic-Impurities-in-Pharmaceutical-APIs_15499,S-AYL_n.html

Sulfonic acids are often used for the manufacture of pharmaceutical APIs. They serve as counterions in crystallisation processes, as protective groups or acid catalysts in API syntheses. Here, if short-chain alcohols such as methanol, ethanol or isopropanol are present, the formation of esters of these sulfonic acids can occur, which may have a genotoxic potential (alkylation of DNA).

The Mesilate Working Party which has been appointed in 2008 by the European Pharmacopoeia Commission has elaborated five General Chapters on different sulfonates which have been published in the European Pharmacopoeia Supplement 8.7 that came into force on 1 April 2016. The General Chapters are as follows:

  • 2.5.37 Methyl, ethyl and isopropyl methanesulfonate in methanesulfonic acid
  • 2.5.38 Methyl, ethyl and isopropyl methanesulfonate in active substances
  • 2.5.39 Methanesulfonyl chloride in methanesulfonic acid
  • 2.5.40 Methyl, ethyl and isopropyl toluenesulfonate in active substances
  • 2.5.41 Methyl, ethyl and isopropyl benzenesulfonate in active substances

As reported in a press release from the EDQM dated 25 February 2016 the completion of Chapter 2.5.41 marks the end of the Mesilate Working Party, as decided by the Ph. Eur. Commission. Simultaneously, the Commission had also decided to revise  the section “Production” in APIs-Sulfonates monographs and replace it by an additional standard text according to which the principles of risk management have to be used in the manufacture of APIs with regard to the genotoxic impurities. The text is as follows:

“It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers.”

Basically, the General Chapters of the European Pharmacopoeia will only be binding when they are referred to in a monograph; the only exception is when the reference made has only a recommendation character. This applies to all these five General Chapters. The purpose of the new text segment in the “Production” sections is to alert the applicant of a marketing authorisation of the risk related to such sulfonates impurities. He / she is not obliged to perform the analytical testing described in the general monographs; it is rather sufficient  to strongly justify the absence of these impurities by means of a risk assessment in the application. The ultimate decision whether this justification is suffiicient lies with the assessor of the competent authority.

 

/////Five new General Chapters, European Pharmacopoeia, Genotoxic Impurities, Pharmaceutical APIs

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ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities

 regulatory  Comments Off on ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities
Apr 072016
 

 

ICH Q3D implemented in the European Pharmacopoeia: Revision of Two General Monographs with Regard to Elemental Impurities

Two general monographs of the European Pharmacopoeia have been revised and published for comment in the newest “Pharmeuropa” edition. Read more about what you will have to consider in future with regard to the control of elemental impurities in pharmaceutical preparations, APIs and excipients.

see

http://www.gmp-compliance.org/enews_05296_ICH-Q3D-implemented-in-the-European-Pharmacopoeia-Revision-of-Two-General-Monographs-with-Regard-to-Elemental-Impurities_15499,15332,S-AYL_n.html

In a press release dated 30 November 2015, the EDQM announced the revision of two general pharmacopoeial monographs: “Substances for pharmaceutical use” (2034) and “Pharmaceutical preparations” (2619). The decision was taken during the 153rd session of the European Pharmacopoeia Commission; the Commission follows its strategy for implementing the ICH Guideline Q3D “Guideline for Elemental Impurities” in the European Pharmacopoeia. A section “Elemental Impurities” has been added to both monographs which emphasizes that the provisions laid down in General Chapter 5.20 of the Pharmacopoeia (identical in wording with ICH Q3D) apply to the limits of metallic impurities and to their control. For pharmaceutical preparations and substances for pharmaceutical use outside the scope of Chapter 5.20 (e.g. unlicensed patient-specific preparations, herbal products, radiopharmaceuticals, etc.), the manufacturer is obliged to perform a risk assessment with regard to the limits of those impurities and – if necessary – to use validated analytical procedures for their determination. The principles to be applied for such a risk assessment arise from a press release from the EDQM dated 7 August 2015: it is expected that the provisions defined on the Guidelines ICH Q3D or ICH Q9 are followed. Lastly, according to this press release, the control strategy of elemental impurities as well as the substantial demonstration of suitability of the analytical methods used in the marketing authorisation dossier remains in the responsibility of the manufacturer.

The definition of “Substances for pharmaceutical use” in the monograph 2034 states: “Substances for pharmaceutical use are any organic or inorganic substances or excipients for the production of medicinal products for human or veterinary use. … Substances for pharmaceutical use may be used as such or as starting materials for subsequent formulation to prepare medicinal products. Depending on the formulation, certain substances may be used either as active substances or as excipients.”

The drafts of the two revised general monographs are accessible for free in the Journal “Pharmeuropa“, Edition 28/2. You only need to register and log in with your password. The comment deadline for both monograph drafts ends on 30 June 2016.

 

 

 

 

 

 

 

 

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Other reading

https://www.thermoscientific.com/content/dam/tfs/ATG/CMD/cmd-documents/ref/third/USP-Primer-eBook.pdf

https://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/Regional_Discussion_Groups/Southern_California_Pharmaceutical/SCPDG%20Impurities_Olsen%20Jan%20event.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_IWG_Final_Concept_Paper_ October_21_2014.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_IWG_Final_Business_Plan_ October_21_2014.pdf

///////ICH Q3D,  implemented,  European Pharmacopoeia, Revision, Two General Monographs,  Elemental Impurities

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