Biowaiver as a Bioequivalence Study Option

Biowaiver is a procedure for establishing the bioequivalence of generic and reference products without in vivo studies. Regulatory requirements for this procedure, as described in a variety of documents, differ in certain features and aspects. These differences need to be analysed.The aim of the study was to compare international and Russian regulatory approaches to the Biopharmaceutics Classification System-based biowaivers, provide recommendations on comparative dissolution testing, and outline opportunities for streamlining the regulatory framework of the Eurasian Economic Union (EAEU).In this article, the authors analyse biowaiver requirements and describe procedures for assessing the permeability and pH-dependent solubility of medicines, comparing dissolution profiles in various media that simulate the gastrointestinal environment, and interpreting test results. This paper shows the role of excipients in the solubility and permeability of an active substance. The authors recommend a methodological approach to the biowaiver procedure for replacing in vivo bioequivalence studies with in vitro tests under the current EAEU regulatory framework and list the characteristics of medicines that limit the applicability of the procedure. In conclusion, this article provides a rationale for harmonising the existing guidelines and requirements

Биовейвер как вид исследования биоэквивалентности

Biowaiver is a procedure for establishing the bioequivalence of generic and reference products without in vivo studies. Regulatory requirements for this procedure, as described in a variety of documents, differ in certain features and aspects. These differences need to be analysed.The aim of the study was to compare international and Russian regulatory approaches to the Biopharmaceutics Classification System-based biowaivers, provide recommendations on comparative dissolution testing, and outline opportunities for streamlining the regulatory framework of the Eurasian Economic Union (EAEU).In this article, the authors analyse biowaiver requirements and describe procedures for assessing the permeability and pH-dependent solubility of medicines, comparing dissolution profiles in various media that simulate the gastrointestinal environment, and interpreting test results. This paper shows the role of excipients in the solubility and permeability of an active substance. The authors recommend a methodological approach to the biowaiver procedure for replacing in vivo bioequivalence studies with in vitro tests under the current EAEU regulatory framework and list the characteristics of medicines that limit the applicability of the procedure. In conclusion, this article provides a rationale for harmonising the existing guidelines and requirements.Биовейвер — это процедура, которая позволяет оценить биоэквивалентность воспроизведенных лекарственных средств без проведения исследований in vivo. Требования к проведению этой процедуры в разных регуляторных документах могут различаться.Цель работы: сравнение подходов международных и российских регуляторных органов к проведению биовейвера, основанного на биофармацевтической классификационной системе (БКС), рекомендации по проведению теста сравнительной кинетики растворения и определение перспектив дальнейшего совершенствования соответствующих нормативных документов Евразийского экономического союза (ЕАЭС).Проанализированы требования к проведению биовейвера, описаны процедуры оценки рН-растворимости и проницаемости лекарственных веществ, выполнения теста сравнительной кинетики растворения в различных средах, моделирующих условия желудочно-кишечного тракта, рассмотрены методики интерпретации полученных результатов. Показана роль вспомогательных веществ, которые оказывают влияние на растворимость и проницаемость действующего вещества. Рекомендован методологический подход к проведению процедуры биовейвера in vitro в качестве замены исследования биоэквивалентности in vivo в соответствии с актуальной нормативной базой ЕАЭС. Перечислены характеристики лекарственных средств, которые являются ограничениями для проведения биовейвера. Обоснована необходимость гармонизации российских и международных требований и руководств

DEVELOPMENT, VALIDATION AND APPLICATION OF ANTI-Xa- AND ANTI-IIa-ENOXAPARINE SODIUM ASSAY

Development, validation and application of in vitro (dosage forms) and in vivo (blood plasma) anti-Xa and anti-IIa enoxaparine sodium assay by UV-spectrophotometer. Assay methods were applied for enoxaparine sodium dosage forms and rabbit plasma samples. It was shown that assay methods are suitable for these analytical purposes including standardization of enoxaparine sodium preparations

Development and Validation of HPLC-MS/MS Method for Busereline Quantitation in Animal Blood Plasma

Introduction. Busereline, being a synthetic gonadotropin-releasing hormone analog, is widely used for hormone-dependent cancer treatment (e.g. prostate cancer and breast cancer). Based on the accumulated scientific data for busereline quantitation in biosamples, the main analytical method that is used for this purpose is high-performance liquid chromatography (HPLC) with fluorescence detection, combined with protein precipitation (TCA 10%) for sample preparation. However, due to several limitations of this method resulting in low sensitivity (at the µg/mL level of concentrations), the HPLC-MS/MS analytical method was chosen for peptide determination in biosamples. The HPLC-MS/MS method is considered to have higher accuracy and specificity. The main sample preparation method for gonadotropin-releasing hormone analogs is solid-phase extraction. In our work, we’ve chosen protein precipitation as an alternative – easier and less laborious biosamples preparation process.Aim. The main objective of this study was the development and validation of HPLC-MS/MS method for busereline quantitation in animal (mini pigs) plasma samples and its further application to pharmacokinetic studies.Materials and methods. Busereline quantitative determination in plasma samples was performed using HPLC-MS/MS method. A protein precipitation procedure (methanol, 1:2, v/v) was used for busereline extraction from pig plasma.Results and discussion. The developed analytical method was validated for selectivity, linearity, matrix effect, accuracy (intra-day, inter-day), precision (intra-day, inter-day), LLOQ, carryover and stability.Conclusion. A new HPLC-MS/MS method for busereline quantitation in blood plasma was developed and successfully validated. The developed method showed linearity over the quantitation range from 1 to 20 ng/mL. The developed method can be successfully applied to busereline pharmacokinetic studies

CERTIFICATION OF QUALITY MANAGEMENT SYSTEM OF LLC «CENTER OF PHARMACEUTICAL ANALYTICS» ACCORDING TO THE REQUIREMENTS OF ISO 9001:2015 (GOST R ISO 9001-2015) (REVIEW)

Introduction. In 2018 «Center of Pharmaceutical Analytics» LLC successfully passed the certification of quality management system for compliance with the requirements of ISO 9001: 2015 and GOST R ISO 9001-2015 «Quality Management System. Requirements».Text. Certification was conducted by the Certification Association «Russian Register» – a Russian company, which is an accredited body for certification of management systems of organizations. This article describes the program of certification audit of the «Russian Register», which includes: certification, consisting of two stages, inspection checks during the first and second year and re-certification audit during the third year before the expiration of the certificate. The structure of works on confirmation of the certificate of conformity of «Russian Register» includes field audits designed to assess the degree of compliance of the organization with the established requirements of the standard for compliance with which certification was carried out [1]. The objectives of the certification audit were: verification of compliance of the management system with the requirements of ISO 9001: 2015 (GOST R ISO 9001-2015), verification of established processes and documentation of the management system of the organization; assessment of the ability of the management system to ensure compliance with applicable legislative, regulatory and contractual requirements; assessment of the effectiveness of the management system to ensure that the goals can be achieved; identification of areas for possible improvement of the management system. The audit was conducted over two days on processes and units related to the activities of the organization. The audit confirmed the scope of certification in respect of: research work, bioanalytical studies, pharmacokinetic studies, STCR (comparative text of dissolution kinetics). The scope of the audit included verification of adequacy, compliance of activities and elements of the management system, including: production, management and support processes; policies; goals; organizational structure of management; documentation of management system, analysis of measures taken by the organization to eliminate the problem areas identified at the 1st stage of certification [2]. Conclusion. In September 2018, the analytical center was issued certificates of compliance with the requirements of GOST R ISO 9001:2015 in the certification Association «Russian Register» with the accreditation of the Federal service for accreditation of the Russian Federation (Rosaccreditation); international standard ISO 9001: 2015 in the Certification system of the Russian Register, a member of the international forum on accreditation IAF; certificate of conformity

AN EXPERIENCE OF IMPLEMENTING LIMS SYSTEM IN THE BIOANALYTICAL LABORATORY (PART 1)

Center of Pharmaceutical Analytics purchased and installed LabWare LIMS laboratory information system, LabWare ELN electronic laboratory journals from LabWare company. At the moment, the system is integrating into the work of the laboratory, templates for research work are created and employees are trained. The article opens a series of articles of the integration of the LIMS system into the work of the analytical center. LabWare has received universal recognition, is a leader in the global market of global Laboratory information systems (LIMS) and has a wide range of loyal users

MODERN APPROACHES OF DISSOLUTION PROFILE TEST (REVIEW)

Modern approaches of dissolution profile test were reviewed in terms of documents, research design, principles of choice of test conditions, selection and validation of assay methods, results evaluation and technique of the carrying out of experiment directly. The article reflects both Russian and foreign perspectives on dissolution profile test

EVALUATION OF THE AUTOMATION INFLUENCE ON THE DISSOLUTION VARIABILITY RESULTS FOR BETASERC TABLETS

The article describes the dissolution test results for the Betaserc (betahistine) IR tablets using the equipment with manual sampling and automatic sampling. The results were compared using F-test and Student's t-test and considered to be comparable for manual and automatic dissolution equipment

EXPERIENCE OF CERTIFICATION BIOANALYTICAL LABORATORY ACCORDING TO REQUIREMENTS OF GOST 33044-2014 «PRINCIPLES OF GOOD LABORATORY PRACTICE» (GLP)

Certificate of compliance to GOST 33044-2014 "Principles of Good Laboratory Practice" issued by an internationally recognized, competent and independent certification body serves, is one of the criteria for the selection of the contractor and the guarantee of the quality of services provided to many customers, as one of the mandatory conditions and exit organization development at the global, national or sectoral markets. This paper describes the first experience of GLP-certification for Russian bioanalytical laboratory