ВВЕДЕНИЕ

biopreparat

БИОпрепараты. Профилактика, диагностика, лечение

Biological Products. Prevention, Diagnosis, Treatment

2221-996X2619-1156

Scientific Centre for Expert Evaluation of Medicinal Products

10.30895/2221-996X-2025-25-3-307-320

biopreparat-674

Research Article

СТАНДАРТИЗАЦИЯ И КОНТРОЛЬ КАЧЕСТВА

QUALITY CONTROL AND STANDARDISATION

Вспомогательные вещества в составе биологических лекарственных препаратов: функциональная классификация, проблемы стабильности, аналитические подходы к определению

Excipients in biological medicinal products: Functional classification, stability issues, and analytical quantitation approaches

https://orcid.org/0000-0003-0026-7365

Минеро

А. С.

Minero

A. S.

Минеро Анастасия Сальвадоровна

Петровский б-р, д. 8, стр. 2, Москва, 127051

Anastasia S. Minero

8/2 Petrovsky Blvd, Moscow 127051

minero@expmed.ru

https://orcid.org/0000-0003-0729-530X

Рунова

О. Б.

Rounova

O. B.

Рунова Ольга Борисовна, канд. хим. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Olga B. Rounova, Cand. Sci. (Chem.)

8/2 Petrovsky Blvd, Moscow 127051

runova@expmed.ru

https://orcid.org/0000-0001-9378-3312

Щербаченко

И. М.

Shcherbachenko

I. M.

Щербаченко Ирина Михайловна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Irina M. Shcherbachenko, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

sherbachenko@expmed.ru

https://orcid.org/0000-0001-5432-1887

Устинникова

О. Б.

Ustinnikova

O. B.

Устинникова Ольга Борисовна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Olga B. Ustinnikova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

ustinnikova@expmed.ru

Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation

2025

29092025

253307320

2025

Минеро А.С., Рунова О.Б., Щербаченко И.М., Устинникова О.Б.

Minero A.S., Rounova O.B., Shcherbachenko I.M., Ustinnikova O.B.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.biopreparations.ru/jour/article/view/674

ВВЕДЕНИЕ

ВВЕДЕНИЕ. Потенциальное нежелательное действие вспомогательных веществ (ВВ) биологических лекарственных препаратов (БЛП) и сложности их аналитического контроля представляют значительную проблему при разработке и экспертизе лекарственных средств. Современные аналитические методы и инновационные подходы к подбору ВВ позволяют минимизировать риски и усовершенствовать контроль качества БЛП.

ЦЕЛЬ

ЦЕЛЬ. Анализ современных методов количественного определения вспомогательных веществ в биологических лекарственных препаратах и оценка перспектив их применения для совершенствования лабораторной экспертизы при регистрации и подтверждения соответствия качества препаратов при вводе в гражданский оборот.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Поиск литературы проводился с использованием баз данных SciFinder, PubMed, eLIBRARY.RU. Представлены данные о функциональной классификации ВВ. Проведен анализ потенциального нежелательного действия ВВ: риск сахарозной нефропатии при применении внутривенных препаратов иммуноглобулинов, содержащих сахарозу; гипогликемия, изменение метаболизма аминокислот, снижение синтеза нуклеиновых кислот и угнетение функциональной активности тромбоцитов вследствие высокой концентрации натрия каприлата в препаратах альбумина. Важным аспектом оценки безопасности использования ВВ является изучение продуктов их деградации. Представлены данные о путях решения проблем, связанных с деградацией ВВ, включая снижение содержания или замену ВВ, как в случае с натрия каприлатом, которые многие производители исключают из состава рецептур БЛП. Рассмотрены инновационные подходы к поиску новых адъювантов (MF59, АS01, АS03, AS04, RC-529), совмещающих функции индукторов иммунного ответа и систем доставки. Представлены данные об использовании математического моделирования при выборе состава композиции ВВ. Проведен анализ современных аналитических методов количественного определения ВВ, включая жидкостную и газожидкостную хроматографию, спектрофотометрические методы для количественной оценки наиболее значимых ВВ в БЛП (аминокислоты, полисорбаты, фенол, феноксиэтанол, бензиловый спирт, натрия каприлат). Рассмотрены перспективные методики, такие как эксклюзионная ВЭЖХ для оценки полисорбата 80, HILIC ВЭЖХ для селективного количественного определения аминокислот в составе композиции, гидрофильная ВЭЖХ с рефрактометрическим детектированием и ионообменная ВЭЖХ с амперометрическим детектированием для анализа стабилизаторов углеводной природы (сорбит, маннит, трегалоза, глюкоза, лактоза, сахароза, мальтоза), а также газожидкостная хроматография для идентификации и количественной оценки 2-феноксиэтанола и м-крезола.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Выбор ВВ для БЛП представляет собой комплексную задачу, требующую разработки стратегии контроля не только установленных норм их содержания, но и возможных продуктов деградации. Разработка унифицированных аналитических методик для количественного определения ВВ является основным направлением для обеспечения качества БЛП на этапах регистрационной экспертизы и ввода в гражданский оборот.

INTRODUCTION

INTRODUCTION. When developing and evaluating new biological products (BP), potential adverse action and complicated analytical procedure are a specific issue. Innovative analytical methods and selection of excipients allow for risk minimisation and enhanced quality control of biological products.

AIM

AIM. This study aimed to analyse modern quantitative approaches to BP excipients and assess their prospects in improving laboratory expertise during authorisation and quality compliance testing of a biological product that has been launched into the commercial market.

DISCUSSION

DISCUSSION. The literature search was performed using SciFinder, PubMed, and eLIBRARY.RU databases. The authors showed data on functional classification of the excipients. Potential adverse effects were analysed, including sucrose nephropathy when using intravenous immunoglobulin preparations containing sucrose; hypoglycaemia; changes in amino acid metabolism; decreased DNA and RNA synthesis, and inhibition of platelet function caused by elevated sodium caprylate in albumin preparations. Analysed methods are based on excipient degradation. Possible solutions have been described (reduction or replacement with another excipient, such as sodium caprylate excluded from the BPs of many manufacturers). Innovative search approaches were used for new adjuvants (MF59, АS01, АS03, AS04, and RC-529) combining immune response inducers and delivery systems. The described mathematical model was used to select excipient composition. The authors analysed literature covering analytical methods for excipient quantitation, including liquid and gas-liquid chromatography and spectrophotometric quantitation methods of the most significant excipients in BPs (amino acids, polysorbates, phenol, phenoxyethanol, benzyl alcohol, and sodium caprylate). Prospects of different analytical techniques were considered (size-exclusion HPLC for evaluation of polysorbate 80, HILIC HPLC for selective quantitation of amino acid components, hydrophilic HPLC with refractometric detection and ion-exchange HPLC with amperometric detection for selective quantitation of carbohydrate stabilisers (sorbitol, mannitol, trehalose, glucose, lactose, sucrose, maltose), as well as gas-liquid chromatography for 2-phenoxyethanol and m-cresol.

CONCLUSIONS

CONCLUSIONS. Selecting BP excipients is a complex task that requires a control strategy not only for established concentrations, but also for products of possible degradation. Developing unified analytical methods for excipient quantitation is a priority for quality assurance of BPs authorised and launched into the commercial market.

вспомогательные веществабиологические лекарственные препаратыфункциональная классификациястабильностьдеградациявысокоэффективная жидкостная хроматографияВЭЖХконсервантыстабилизаторыадъювантыконтроль качества

excipientsbiological productsfunctional classificationstabilitydegradationhigh performance liquid chromatographyHPLCpreservativesstabilisersadjuvantsquality control

Работа выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00001-25-00 на проведение прикладных научных исследований (номер государственного учета НИР № 124022200103-5)

This study was conducted by the Scientific Centre for Expert Evaluation of Medicinal Products as part of the applied research funded under State Assignment No. 056-00001-25-00 (R&D registry No. 124022200103-5)

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The authors declare that there are no conflicts of interest present.