European Directorate For The Quality Of Medicines Research Articles

Future of TABST and LABST in the Indian Pharmacopoeia Monographs A Humane Society International/India Workshop Report

Humane Society International India (HSI India) organized and facilitated a workshop on the ‘Future of Target Animal Batch Safety Test (TABST) and Laboratory Animal Batch Safety Test (LABST) in the Indian Pharmacopoeia (IP) Monographs’. The workshop hosted key Indian regulators from the Indian Pharmacopoeia Commission (IPC) and the Central Drugs Standard Control Organization (CDSCO), industry representatives from the Indian Federation of Animal Health Companies (INFAH), Asian Animal Health Association (AAHA), and international experts representing the European Directorate for the Quality of Medicines (EDQM), the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH), and multinational veterinary products manufacturers. The workshop was organized to encourage a bidirectional flow of information and to discuss the deletion of TABST and LABST from the veterinary vaccine monographs in the IP. This workshop was built from the symposium held by Humane Society International on the ‘Global Harmonization of Vaccine Testing Requirements’ held in 2019. This report details the outcomes of the workshop with proposed activities to be taken up as part of the next steps for the elimination or waiving of these tests.

Preparation and Storage of Cryoprecipitate Derived from Amotosalen and UVA-Treated Apheresis Plasma and Assessment of In Vitro Quality Parameters.

Cryoprecipitate is a plasma-derived blood product, enriched for fibrinogen, factor VIII, factor XIII, and von Willebrand factor. Due to infectious risk, the use of cryoprecipitate in Central Europe diminished over the last decades. However, after the introduction of various pathogen-reduction technologies for plasma, cryoprecipitate production in blood centers is a feasible alternative to pharmaceutical fibrinogen concentrate with a high safety profile. In our study, we evaluated the feasibility of the production of twenty-four cryoprecipitate units from pools of two units of apheresis plasma pathogen reduced using amotosalen and ultraviolet light A (UVA) (INTERCEPT® Blood System). The aim was to assess the compliance of the pathogen-reduced cryoprecipitate with the European Directorate for the Quality of Medicines (EDQM) guidelines and the stability of coagulation factors after frozen (≤−25 °C) storage and five-day liquid storage at ambient temperature post-thawing. All pathogen-reduced cryoprecipitate units fulfilled the European requirements for fibrinogen, factor VIII and von Willebrand factor content post-preparation. After five days of liquid storage, content of these factors exceeded the minimum values in the European requirements and the content of other factors was sufficient. Our method of production of cryoprecipitate using pathogen-reduced apheresis plasma in a jumbo bag is feasible and efficient.

European Directorate for the Quality of Medicines: automatic drugs dispensing report

The European Directorate for the Quality of Medicines (EDQM) released automated dose dispensing (ADD) guidelines. Their content was agreed on during an open consultation involving stakeholders, which was held this...

IMPURITY PROFILING IN PHARMACEUTICALS: A REVIEW

Impurities in the drug are the components which are responsible for the change in the quality of drug with respect to the safety and efficacy. Regulatory authorities such as the International Conference on Harmonization (ICH), the United States Food and Drug Administration (FDA), and the European Directorate for the quality of Medicines (EDQM) emphasis on the requirements of the pure drugs and identification of their impurities. There are various sources of impurity in pharmaceutical products such as starting material, reagent, catalyst, intermediate, solvent and degradation product formed during storage of the drug. Impurities are classified into various categories depending upon their origin, composition type, and biological safety. There are different isolation technique of impurities from the drug. The various analytical methods are used to qualify and characterize the impurities. This reveals that there is always needs and the scope for the impurity profiling of drugs in drug development.

Review of quality deficiencies found in active pharmaceutical ingredient master files submitted to the WHO Prequalification of Medicines Programme.

The aim of this work was to determine the number and type of active pharmaceutical ingredient (API) quality deficiencies in API Master Files (APIMFs) as submitted to the World Health Organization (WHO) Prequalification of Medicines Programme (PQP). We conducted a retrospective review of API quality deficiencies identified following the assessment of new APIMFs for non-sterile APIs during a 6-year period from 1 January 2007 to 31 December 2012. All deficiencies were collected, classified and quantified according to the Common Technical Document (CTD) sections and subsections and as groups of commonly raised questions. There were 5446 deficiencies collected from 159 APIMF deficiency letters by CTD section, by selected CTD subsections and by selected CTD subsections and year. More than 50% of the total number of deficiencies related to the manufacturing sections of the CTD, followed by deficiencies concerning the impurities, the API specification and the stability sections of the CTD. A pattern of API deficiencies across the different CTD subsections and over time was identified. The most frequent critical deficiencies were related to how the specific manufacturing process and the key materials used, in particular the API starting material, impact the API impurities content. The number and pattern of APIMF deficiencies did not change over time. The results are compared to the findings in similar studies as reported by the United States Food and Drug Administration (USFDA), the European Directorate for the Quality of Medicines (EDQM) and the European Medicines Agency (EMA) and similarities and differences are discussed. Our findings highlight the need for greater guidance and technical assistance for API manufacturers submitting APIMFs to the PQP.

Finding the most appropriate IR technique for plant species identification

Quality control of herbal medicinal products is of extreme importance. Procedures for identification of plant species, such as biochemical analysis or macroscopic and microscopic examination of morphological and anatomical properties are time consuming and expensive[1]. A good alternative is infrared spectroscopy since it is rapid, easy to use, nondestructive and low-cost. Identification of species from dried whole leaf samples of pharmaceutically important Epilobium and Hypericum genera were investigated. To determine which infrared spectroscopy mode gives most informative spectra for plant species identification different modes of infrared spectroscopy were applied. These were diffuse reflectance, attenuated total reflectance (ATR), direct transmission of whole leaves, and KBr tablet transmission with comminuted leaves. First the informative wavenumbers were chosen by one-way analysis of variance. Afterwards the colinearity was reduced with principal component analysis. At last the species identification was determined with discriminant analysis. Best results were obtained with ATR and KBr tablet transmission. Still there were important differences between genera. ATR proved to be appropriate for discrimination among Epilobium species (accuracy of plant species identification was 98%), Epilobium species differ in distribution and morphology of trichomes on the surface of the leaves[2]. While for Hypericum species KBr tablet transmission proved to give best results (accuracy of plant species identification was 97%). Hypericum species differ in secondary metabolites that are acumulated in the interior of the leaves[3,4]. Results show that morphological properties of plant material should be taken into consideration when developing an infrared spectroscopy based method for identification of plant species.

A case study of development, validation, and acceptance of a non-animal method for assessing human vaccine potency

Hepatitis B vaccine (Engerix B) is a recombinant vaccine containing hepatitis B surface antigen (HBsAg) produced in Saccharomyces cerevisiae. Initially, this vaccine was released using specifications that required an in vivo potency assay in mice. This paper describes the move from the in vivo potency test toward in vitro potency assays: the in vitro Auszyme test (Abbott Laboratories) and the GSK Biologicals in-house test based upon the inhibition enzyme-linked immunosorbent assay (ELISA) principle. The challenges and difficulties during the development and introduction of this in vitro assay are presented from validation studies performed by GSK Biologicals, through regulatory acceptance, to the implementation of the alternative method by the European Directorate for the Quality of Medicines (EDQM) and HealthCare Control Authorities for Official batch release. Based upon our experience introducing an in vitro model for Engerix B potency assay, we offer suggestions to facilitate future introduction of in vitro assays.

Assessment of the Effects of pH, Formulation and Deformulation on the Conformation of Interferon Alpha-2 by NMR

This article reports the results of our investigation of the effects of pH and various formulations on the conformation of interferon (IFN) alpha-2a and IFN alpha-2b using the NMR fingerprinting assay. Samples of (15)N-IFN alpha-2 were produced and their activity was inferred by comparing their NMR spectra with those recorded for the corresponding European Directorate for the Quality of Medicines (EDQM) reference standards. The proteins were then mixed with appropriate excipients to reproduce formulations used in innovator products of Roferon-A and Intron-A and deformulated via cation-exchange chromatography. The conformation of IFN alpha-2 was monitored by two-dimensional (2D)-NMR spectroscopy at various pHs, after formulation and deformulation procedures. Our results show that the process does not alter the conformation of IFN alpha-2 and that the optimal pH for deformulation is 4.0 +/- 0.5. Variation in pH below 3.0 causes the protein to unfold, whereas above pH 4.5, the three-dimensional (3D) fold is maintained, but the NMR spectra indicate a propensity to oligomerize. This behaviour is reversible upon readjusting the pH to 3.5-4.5. Here, we demonstrate the applicability of NMR to assess the structure of protein therapeutics. The proposed method can assist in validating analytical methods that require deformulation of IFN-based products.

An international collaborative study to replace the 1st international standard for prekallikrein activator

The aim of this study was to replace the 1st International Standard (IS) for prekallikrein activator (PKA) (code 82/530) with a new IS and European Biological Reference Preparation (BRP). The new standards were freeze dried 20% albumin solution containing PKA, the same solution that is tested using these standards. Aspects of the methodology for PKA determination were also examined as part of this study. A batch of 20% albumin containing approximately 30 IU/ml was donated by a manufacturer of blood products and dispensed into ampoules at the National Institute for Biological Standards and Control (NIBSC) to create the candidate IS (02/168, sample B in the study) and at the European Directorate for the Quality of Medicines (EDQM) to create the candidate BRP (sample C in the study). The concentration of PKA in these preparations was determined in an international collaborative study involving 31 laboratories from 17 countries worldwide in comparison with the 1st IS for PKA (82/530) containing 85 IU of PKA per ampoule. Participants were requested to perform their own in-house method, based on the current Ph. Eur. monograph for determination of PKA in albumin solutions. Participants were provided with sufficient samples to perform two or three assays and were asked to use their local prekallikrein substrate (PKS) and also to use a commercial PKS provided as part of the study, in order to investigate the importance of the source of PKS on the final potency values. Samples B and C emerged with identical PKA concentrations of 29 IU/ml, very close to the expected value. This figure was determined using a variety of statistical methods, with the participants' own calculated values and values calculated centrally at the EDQM using raw data. The value of 29 IU/ml was consistent and independent of the method of calculation, although interlaboratory variability was more sensitive to the statistical analysis method. There was no statistically significant difference in mean potencies when comparing results with the laboratories' own local substrate and the substrate provided for the study. All stability studies indicate that these lyophilized preparations of PKA in 20% albumin are extremely stable. Samples B and C were established as the 2nd IS (code 02/168) and PKA activator in albumin BRP batch 1 (Y0000263), respectively, with a potency of 29 IU per ampoule. Results from this study indicate that testing for PKA in albumin may be less sensitive to the source of PKS than previously feared. The study highlights a number of methodological issues that may need revising in the Ph. Eur. general chapter 2.6.15.

Collaborative study for the establishment of a European Phamacopoeia biological reference preparation for Bordetella pertussis mouse antiserum for serological potency testing of acellular pertussis vaccines

A collaborative study was organised by the European Directorate For the Quality of Medicines (EDQM) to assess the suitability of a candidate mouse antiserum as a European Pharmacopoeia Biological reference preparation (BRP) for acellular pertussis vaccine potency testing. The candidate antiserum was obtained by immunising mice with a five-component acellular pertussis vaccine: pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and Fimbrial 2/Fimbrial 3 (Fim 2&3). The study has been divided into two separate phases. Phase I was a pre-qualification study including three laboratories. This phase was aimed at pre-qualifying the candidate BRP (cBRP) and at documenting the impact of differences in the antibody detection methodology enzyme linked immunosorbent assay (ELISA) procedures on results of pertussis antisera calibration versus the currently used standard US standard pertussis antiserum (mouse) Lot 1 (SPAM-1) (United States Food and Drug Administration (USFDA) reference serum) and the cBRP. As no significant difference between the antibody titres determined by using the different ELISA methodologies was found, a large-scale study enrolling 13 laboratories (Phase II) was carried out, each participant performing its in-house methodology. Its aim was to calibrate the cBRP (in terms of the SPAM-1 reference) and to demonstrate its equivalence or superiority to internal references. The study showed that there was no difference in positive sera titres expressed relative to their corresponding internal reference (homologous situation) or the proposed standard (heterologous situation) reference. The cBRP can, therefore, reliably act as replacement for the in-house reference preparations. Further analysis of the outcome of this study enabled to assign to the cBRP a potency of 39, 138, 34 and 56 ELISA unit per millilitre, respectively, to its anti-PT, anti-FHA, anti-PRN and anti-Fim 2&3 antibody contents. The cBRP has been adopted by the European Pharmacopoeia Commission at its June 2000 session as Bordetella pertussis mouse anti-serum Ph Eur. BRP batch 1.