The level of anti-D antibodies in human immunoglobulin products for intravenous administration (IVIG) is controlled by the direct haemagglutination method prescribed by the European Pharmacopoeia (Ph. Eur.) that requires 2 control reference reagents. The World Health Organization (WHO) positive control International Reference Reagent (IRR; 02/228) with a nominal titre of 8 defines the highest acceptable titre, while the negative control preparation (02/226) has a nominal titre of <2. Working reference preparations (04/132 and 04/140) were subsequently established as Biological Reference Preparations (BRPs) for the Ph. Eur., and for distribution by the United States Food and Drug Administration (US FDA) and the National Institute for Biological Standards and Control (NIBSC). Due to diminishing stocks of these working reference preparations across the 3 institutions, a joint international study was organised to establish harmonised replacement batches. Sixteen laboratories contributed data to the study to evaluate positive and negative candidate replacement batches (13/148 and 12/300, respectively) against the WHO positive and negative control IRRs and the current working reference preparations (BRPs). The results show that the candidate reference preparations (13/148 and 12/300) are indistinguishable from the corresponding IRRs and current BRPs. The candidate preparations 13/148 and 12/300 were adopted by the Ph. Eur. Commission as Immunoglobulin (anti-D antibodies test) BRP batch 2 and Immunoglobulin (anti-D antibodies test negative control) BRP batch 2 with nominal haemagglutination titres of 8 and <2, respectively. The same materials were also adopted as NIBSC and US FDA reference preparations, thus ensuring full harmonisation.

The control of somatropin products according to the monographs of the European Pharmacopoeia (Ph. Eur.) requires a system suitability preparation for the test for related proteins by liquid chromatography. A preparation consisting in a mixture of somatropin and desamidosomatropin, such as the Ph. Eur. Somatropin/desamidosomatropin resolution mixture Chemical Reference Substance (CRS), is to be used to ascertain adequate resolution of the chromatographic setup. Due to low stocks, the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union ran a study to establish a new batch of this system suitability CRS. A freeze-dried candidate batch (cCRS2) was produced and tested at the European Directorate for the Quality of Medicines and HealthCare (EDQM, Council of Europe). The resolution between the peaks due to somatropin and desamidosomatropin was 1.7 and the symmetry factor for the somatropin peak was 1.2. The mean percentage area of the desamidosomatropin peak was 14.6 %. These results showed that cCRS2 is suitable for its intended purpose. Based on these data, in May 2020 the Ph. Eur. Commission established the candidate batch as Ph. Eur. Soma-tropin/desamidosomatropin resolution mixture CRS batch 2.

European Pharmacopoeia (Ph. Eur.) monograph 0828 prescribes two in vitro assays to evaluate the biological activity of low-molecular-mass heparin products. These assess the capacity of low-molecular-mass heparins to accelerate the inhibition of factor Xa and factor IIa by antithrombin. A reference standard calibrated in International Units (IU) such as the Heparin low-molecular-mass for assay Biological Reference Preparation (BRP), is required to express results. Due to low stocks, the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union launched an international collaborative study to establish a replacement batch for the current Heparin low-molecular-mass BRP (BRP10). Thirteen Official Medicines Control Laboratories and manufacturers contributed data to calibrate a candidate batch against the World Health Organization (WHO) 3rd International Standard for Heparin, low molecular weight (11/176; 3rd IS) using chromogenic assays. The overall anti-Xa and IIa activities of the candidate BRP against the 3rd IS based on the participants\' calculations and on central calculation at the European Directorate for the Quality of Medicines & HealthCare (EDQM) were very close. The inter-laboratory variation for both assays was between 2.8 % and 7.5 %. The study data confirmed the assigned activities of BRP10. Based on the results of this collaborative study, in December 2019 the Ph. Eur. Commission adopted the candidate BRP as Heparin low-molecular-mass for assay BRP batch 11 with assigned anti-Xa activity of 110 IU/mL and anti-IIa activity of 37 IU/mL.

An international collaborative study was organised under the aegis of the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union to calibrate a replacement batch for the European Pharmacopoeia (Ph. Eur.) Heparin sodium Biological Reference Preparation (BRP). Seventeen laboratories contributed data to value assign a candidate batch (cBRP4) in International Units (IU) against the WHO 6th International Standard for Unfractionated Heparin using chromogenic and sheep plasma clotting assays according to Ph. Eur. texts 2.7.5. on unfractionated heparin and 0878 on human antithrombin III. The continuity of consecutive batches of BRP was evaluated by including BRP3 in the set of test samples. The central analysis of the study data showed good precision and reproducibility of both chromo-genic and clotting assays among laboratories. Based on the study data, the Ph. Eur. Commission adopted cBRP4 as Ph. Eur. Heparin sodium BRP4 with assigned activities of 985 IU/mL for anti-IIa assays, 995 IU/mL for anti-Xa assays and 1035 IU/mL for sheep clotting assays.

The European Pharmacopoeia (Ph. Eur.), includes both individual monographs on essential oils and a general monograph that covers all essential oils for pharmaceutical use, whether covered by an individual monograph or not. The individual monographs generally describe gas chromatography as a first identification test, while thin-layer chromatography (TLC) and high-performance thin-layer chromatography (HPTLC) methods are included in the second identification series. To comply with Ph. Eur. general chapter 2.8.25. High-performance thin-layer chromatography of herbal drugs and herbal drug preparations, HPTLC parameters must be standardised. Currently, 18 of the 32 monographs on essential oils feature the same TLC/HPTLC method, but differ in terms of the other conditions described. A single, standardised chromatographic system with a system suitability test (SST) and intensity markers for all 32 essential oils covered by individual monographs would be desirable, particularly for pharmacies and other users that cannot perform gas chromatography for financial reasons. To this end, this paper describes the development of a general HPTLC method for the identification of essential oils in compliance with general chapter 2.8.25. The method proposes the use of ethyl acetate, toluene (5:95 V/V) as mobile phase, isoeugenol/isoeugenyl acetate for the SST, and a combination of one alcohol (either borneol or linalool) and one ester (either linalyl acetate or bornyl acetate) as intensity markers.

Content tolerance limits should respect the acceptable variation in the content of the active substance or excipient from its production and the variability of the results of the analytical procedure prescribed to determine the content by the appropriate pharmacopoeia. This usually prevails in the active substances and excipients. They should be derived statistically based on the precision of the prescribed analytical method determined by the interlaboratory test. Calculations from published precision characteristics show that some tolerance intervals for the active substance content are probably too narrow in Ph. Eur. This can lead to erroneous decisions about their quality.

Indication of the equivalence point for the titration of primary aromatic amines (sulphonamides, etc.) with sodium nitrite solution according to Ph. Eur. (2.5.8) is performed electrometrically or using a prescribed indicator, the electrometric method not being specified. Better reproducibility of the assay results would add to Ph. Eur. the electrometric method to be used for the indication and suitable electrodes for it. The authors of the paper propose a potentiometric indication, which is in Ph. Eur. widely used. Further, they propose to consider whether in Article 2.5.8. Ph. Eur. indications using an indicator as an alternative to the instrumental indication required. The titration in the presence of hydrochloric acid favourably affects the addition of potassium bromide, cooling the solution prior to the titration prescribed by Ph. Eur. is not needed.

Recent reports of severe haemolytic reactions upon high dose treatment with new generation intravenous immunoglobulins (IVIGs) prompted us to examine the anti-A and anti-B haemagglutinin content of these therapeutics. We compared four different test methods, namely the indirect and direct haemagglutination test as described in the European Pharmacopoiea (Ph. Eur.) and two commercial gelcard systems with the aim to define the most reliable method for a large-scale comparison of different IVIG products. Absolute titres varied when the same samples were analyzed by the four methods, while the relative ranking of six different IVIG preparations representing different manufacturing classes was identical. New generation IVIGs showed 1-2 titre steps higher anti-A titres than the older products. Haemagglutinin titres of all 48 IVIG batches analyzed were within the current Ph. Eur. specification of ≤1:64 when tested by the official pharmacopoeial method. Based on efficiency, reliability and lower costs, the direct gelcard method could be a valid alternative to the official Ph. Eur. method to serve as a limit test. However, due to the highest intermediate precision, the official Ph. Eur. method seems to be most suitable to compare haemagglutinin titres of different IVIG products.

Neutral Methacrylate Copolymer is a fully polymerised copolymer used in the pharmaceutical industry to permit pH-independent delayed release of active ingredients from oral dosage forms. This function has potential use with food supplements and this article describes available information on the safety of the substance. Oral administration of radiolabelled copolymer to rats resulted in the detection of chemically unchanged copolymer in the faeces, with negligible absorption. Safety studies revealed no adverse toxicity following repeated administration at doses of up to 2000 mg/kg bw/d in a sub-chronic study in rats or 250 mg/kg bw/d in a sub-chronic study in dogs. No reproductive toxicity occurred at up to 2000 mg/kg bw/d in rats or rabbits. The substance shows no evidence of genotoxicity, has low acute toxicity and no irritation or sensitisation potential. An ADI value of 20 mg/kg bw was concluded from two alternative approaches. Daily exposure from use in dietary supplements is estimated as up to 10.0 mg/kg bw in adults and 13.3 mg/kg bw in children. There would therefore appear to be no safety concerns under the intended conditions of use. The information provided is intended to support an evaluation that the substance may be \"generally recognized as safe\" (GRAS).