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

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

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

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

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

DETERMINATION OF CAPECITABINE AND ITS ACTIVE METABOLITE 5-FLUOROURACIL IN BLOOD PLASMA BY HPLC-MS/MS

A method for quantification of capecitabine and 5-fluorouracil in human plasma was developed. The sample preparation was carried out by protein precipitation with methanol. The quantitative determination was performed by HPLC with a triple quadrupole mass-detector. The method was validated in terms of selectivity, calibration curve, accuracy, precision, lower limit of quantification, and stability. The analytical range was 10.0-20000.0 ng/mL for capecitabine and 10.0-400.0 ng/ml for 5-fluorouracil. The developed method may be used for bioequivalence studies of capecitabine drug products

RETROSPECTIVE OF DISSOLUTION TEST OF SOLID DOSAGE FORMS (REVIEW)

The article describes the main historical stages in the development of the science of drug dissolution and the dissolution profile test from the theoretical foundations of dissolution, developed in the first half of the 20th century, and the development of a relationship between dissolution and bioavailability in the 1950s, going to the introduction of biowaiver based on the BCS

VALIDATION OF UV-SPECTROMETRY ASSAY METHOD FOR DISSOLUTION PROFILE TEST FOR LEVOFLOXACINE TABLETS

Validation of UV-spectrometry assay method for dissolution profile test for levofloxacine tablets was carried out. The evaluated validation characteristics were: specificity, linearity, accuracy, precision, analytical range. It was shown than main validation characteristics meet the Russian State Pharmacopoeia requirements

VALIDATION OF UV-SPECTROMETRY ASSAY METHOD FOR DISSOLUTION PROFILE TEST FOR MOXIFLOXACINE TABLETS

Validation of UV-spectrometry assay method for dissolution profile test for levofloxacine tablets was carried out. The evaluated validation characteristics were: specificity, linearity, accuracy, precision, and analytical range. It was shown than main validation characteristics meet the Russian State Pharmacopoeia XIII requirements