Ph. Eur. Monograph 0008

[Ronna Bordelon]

Forpurified water and water for injections, specifications in line with the corresponding Ph. Eur. monographs 0008 and 0169 are expected. If the specification does not meet these requirements, the quality is reported as potable water on the CEP 2.0.

There have been tremendous changes in the pharmacopeias regarding heavy metals analysis. In December 2014, the final ICH Q3D Guideline came out to harmonize approval requirements under various regulatory regimes. Also, the visual limit value test required under USP is now being replaced by an element-selective and quantitative instrumental measurement technique in accordance with USP and USP . The Ph. Eur. has also recently released new regulations in chapters 5.20 and 2.4.20. Since January 1, 2017, the testing parameters outlined in chapter 2.4.8 (heavy metals) are no longer included in all monographs. Only monograph 0008 (Water purified, Aqua purificata) is excepted from this new regulation. Thus in cases where the current monographs have to be followed, conducting heavy metals analyses is no longer standard procedure.

Due to the large number of analytes and the low determination limits to be achieved, the use of ICP/MS for element determination has vastly gained importance in pharmaceuticals. Eurofins BioPharma Product Testing has been a reliable industry partner in this field for many years.

The final version of the ICH Q3D Guideline (Elemental Impurities) came out in December 2014. Threshold values were established for 24 different elements based on toxicological data for various exposure paths. In a risk assessment of the production process the manufacturer has to identify known and potential sources of impurities and test for these versus the limit values.

The purpose of the Guideline is to harmonize differing regulatory requirements under various regional regulatory regimes. However, there are considerable implementation differences between the USP and EP regulations regarding both the selection of elements and the setting of limit values.

The non-selective and interference-susceptible visual heavy metals testing procedure per USP (Heavy Metals) is now outdated, being over 100 years old. For all new approvals in the US, the new chapters USP (Elemental Impurities Limits) and USP (Elemental Impurities Procedures) are already in place. This testing will become mandatory in January 2018 for release studies of existing approvals and for all monographed active and inactive substances.

In these chapters, limit values are set for 15 elements in pharmaceutical products and examination by means of ICP/MS and ICP/OES established as a standard method. The scope of testing is determined in a risk assessment of the elements that could be naturally found in, added to or unknowingly end up in the final product. Therefore, analysis of all 15 elements is not necessarily required.

EP 5.20 (Metal catalysts or metal reagent residues) establishes limit values for 14 elements from metallic catalysts or reagents. Determination method requirements are regulated in EP 2.4.20 (Determination of metal catalysts or metal reagent residues).

A helpful risk assessment tool for the manufacturing process that gives you a quick overview of the presence or absence of many elements at low cost. This allows identification of elements of interest that can then be quantified as required.

Highly effective for obtaining an initial overview of content levels of specific elements. In the risk assessment process, for example, elements subject to control can be monitored to ensure they remain below a warning limit.

Both EP and USP require matrix validation to be performed to establish that the analysis method is specifically usable for the respective matrix. In the respective monographs there are precise specifications regarding the parameters to be conformed with. We would be glad to advise you in this area and send you a testing proposal.

All incoming packages are immediately registered before they are unpacked. Samples are first checked for integrity and storage conditions, then registered in our lab system. From this time, each sample container is uniquely marked with a barcode. Every procedural step is subject to four-eyes-principle.

On the ECA Academy website you have all the important information for your daily work in the GMP/GDP environment directly at hand: current news, suitable online training, eLearning offers, conferences, seminars and courses, a comprehensive guideline database and many other services. Should you not find what you need, just contact us by phone at +49 (0)6221 / 84 44 0 or send an e-mail to in...@gmp-compliance.org.

At the beginning of July, the FDA published a Warning Letter due to a lack of chemical and microbiological controls in the manufacture of a product for dermal application and inadequate testing of the ingredients used.

The EDQM has revised the monographs Water for Injection (0169), Purified Water (0008) and TOC Level in Pharmaceutical Water (2.2.44) and has now published them for comment. Learn more about the EDQM water monographs.

The FDA rarely goes into great detail about expected measures in its Warning Letters, especially not when it comes to instructions on the desired procedure. This is now different in a Warning Letter that was published in July. It describes in considerable detail what the FDA considers to be appropriate CAPA measures in a specific case.

Water intended for the preparation of Herbal drug extracts (0765) complies with the sections Purified water in bulk or Purified water in containers in the monograph Purified water (0008), or is water intended for human consumption of a quality equivalent to that defined in Directive 98/83/EC which is monitored according to the Production section described below.

When water intended for human consumption is used as water for preparation of extracts it is a clear, colourless liquid. It is stored (where necessary) and distributed under conditions designed to prevent growth of micro-organisms and to avoid other contamination.

Reference solution Dissolve 0.163 g of potassium nitrate R and 0.149 g of potassium bromide R in water R and dilute to 100.0 mL with the same solvent. Dilute 5.0 mL of the solution to 100.0 mL with water R.

Under normal conditions, an appropriate action level is a microbial count of 100 CFU/mL, determined by filtration through a membrane with a nominal pore size not greater than 0.45 m, using casein soya bean digest agar and incubating at 30-35 C for not less than 5 days.

The Innovative Devices Access Pathway (IDAP) pilot was launched on the 19th of September 2023 by the Department of Health and Social Care (DHSC), Health Technology Wales (HTW), the Medicines and Healthcare products Regulatory Agency (MHRA), the National Health Service England (NHSE), the National Institute for Health and Care Excellence (NICE), the Office for Life Sciences (OLS), and the Scottish Health Technologies Group (SHTG). The aim of this new pathway is to support the rapid development of innovative technologies that can be introduced into the National Health Service (NHS) to address unmet clinical needs for patients and healthcare professionals at the earliest opportunity, without compromising on standards of safety, quality, and effectiveness. Please find further information here.

The MHRA has issued a detailed guidance on the new International Recognition Procedure (IRP) for medicines manufacturers, including how to use the scheme to apply for a medicine licence in the UK, following approval by trusted regulatory partners in Australia, Canada, the European Union, Japan, Switzerland, Singapore, and the United States.

As the UK exited the EU, the MHRA introduced a mechanism that allowed the agency to rely on European Commission (EC) decisions when considering application for a UK marketing authorisation to authorise medicinal products. This procedure, known as the European Commission Decision Reliance Procedure (ECDRP), is due to come to an end December 31, and the IRP will come into effect on 1 January 2024.

The MHRA publishes routine updates to performance data for the assessment of clinical trials and established medicines to help improve the predictability of decision making in applications for clinical trials, marketing authorisations and variations to existing approvals. Please find the latest performance update here.

The German Central Authority of the Lnder for Health Protection with regard to Medicinal Products and Medical Devices (Zentralstelle der Lnder fr Gesundheitsschutz bei Arzneimitteln und Medizinprodukten, ZLG) has published a newly prepared document (in german only) entitled "Inspektion der Eignung von Transportprozessen" (Inspection of the Suitability of Transport Processes). The document, which is applicable to GMP and GDP areas, consists of a catalogue of standards, questions and recommendations, which serves to harmonise the preparation, execution and follow-up of an inspection.

As the transport of medicinal products, veterinary medicinal products and active pharmaceutical ingredients (APIs) are considered, the contents are of interest not only to inspectors but to pharmaceutical manufacturers and wholesalers as well.

Revised versions of the monographs, Water for injections (0169) and Purified water (0008), will be published in Supplement 11.4 of the European Pharmacopoeia (Ph. Eur.) in October 2023 with the implementation date of 1 April 2024. Adopted by the Ph. Eur. Commission at its 175th session in March 2023, these two texts now allow the use of recombinant factor C (rFC) to test for bacterial endotoxins in pharmaceutical waters. The revision was carried out following the issuing of a new general chapter, Test for bacterial endotoxins using recombinant factor C (2.6.32), describing a bacterial endotoxin test (BET) that can be used as an alternative to the classic limulus amoebocyte lysate (LAL)-based methods. The use of rFC is a step towards alleviating the need for animal resources as it is a synthetic reagent which does not rely on lysate derived from species of horseshoe crab. Please find further information here.

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