Науково-методологічні підходи до забезпечення якості мазей аптечного виготовлення

Abstract

У роботі описані науково-методологічні підходи до створення національної фармакопейної концепції якості МВА шляхом теоретичного обґрунтування та проведення ряду експериментальних досліджень. Вперше проведена оцінка ризиків для якості МВА дозволила виділити основні категорії найбільшого впливу на неї, що стало підґрунтям для експериментальних досліджень. Здійснено оцінку стабільності основ МВА та стандартизацію ряду жирних олій, які часто входять до їх складу. За результатами аналізу останніх до ДФУ введені монографії «Соняшникова олія рафінована», «Абрикосова олія рафінована»N та «Персикова олія рафінована»N. Теоретично обґрунтовано використання різних методик кількісного визначення АФІ МВА, проведено їх розробку, валідацію чи верифікацію. За оцінкою технології виготовлення мазей виявлено критичні фактори та надано рекомендації щодо вибору оптимального обладнання. Сформовано підходи до вивчення стабільності МВА експериментальні дослідження якої дозволили збільшити терміни придатності більшості з них. Ґрунтуючись на отриманих результатах запропоновано структуру монографій на різні категорії МВА. Фрагменти дисертаційного дослідження стали підґрунтям для адаптації Настанови PIC/S «Guide to good practices for the preparation of medicinal products in healthcare establishments» та введення до ДФУ монографії «Основні принципи виготовлення нестерильних фармацевтичних препаратів в аптеках».

The thesis describes the scientific and methodological approaches to creating a national pharmacopoeial quality conception for compounded ointments (CO) through theoretical justification and the series of experimental researches. The research design was formed considering foreign experience in the usage of quality assurance system (QAS) principles by compounding pharmacies, and objects for it were selected, based on the CO category. Ointments for stock, ointments with plant components, and ointments that are made on the basis of industrial ointments were selected for the research. To determine the critical factors influencing the quality of the finished CO a risk assessment for it was performed. According to the results of risk identification using brainstorming and the Ishikawa diagram methods, six main risk categories were identified: personnel, APIs and excipients, premises and equipment, manufacturing technology, stability and quality control. The influence factors were defined for each of them and recommendations on the prevention of occurrence of potential defects were formed. The assessment of the categories of consequences, probability of occurrence and possibility of identifying the potential defect (questionnaire 1) and quality, safety and effectiveness (questionnaire 2) were done for the risk’s quantity estimation. According to the results of obtained data processing by the FMEA/FMECA method, it was established that the greatest impact on quality exerted by defects related to the microbiological purity of ointments and their composition/compounding technology. Based on the obtained results, a strategy of experimental research was formed. The standardization of CO auxiliary components was carried out. The period of preservation of the basis components stability during storage in the pharmacy conditions (white soft paraffin and basalis of 2,2 years, wool fat substance of 10,5 months) was defined. The results of determining the number values of fatty oils (sunflower, apricot and peach) showed a correspondence between the value of acid number, increase in peroxide and decrease in iodine value with increasing their shelf life. GC-FID method was used for the standardization of the fatty acid composition of oils using 30 and 100 m columns. The original technique of derivatization was developed during the research. The main fatty acids of all oils in the analysis on both columns were palmitic, stearic, oleic and linoleic. No dependence of fatty acid composition of oils with their shelf life and peroxide value was established. The obtained results became the basis for the creation of monographs «Sunflower oil refined», «Apricot oil refined»N and «Peach oil refined»N which were included to the SPhU. The choice of quality control methods of CO API was substantiated. Methods of titrimetric and spectrophotometric analysis for the API quantitative determination in the studied ointments were verified or validated for using in chemical analysis and validation of preparation technology. A number of chromatographic techniques were developed and validated to determine chemical stability of the studied ointments. Such techniques, in addition to the simultaneous determination of the quantitative content of API, will control the appearance of impurities during the ointment storage. Chromatographic techniques considered to be optimal for use in the analysis of ointments with components of plant origin. Headspace analysis and GC-MS method allow to determine compounds-markers of plant origin, and it is possible to quantify one or more markers for chemical stability estimation by the GC-FID method. The technology of compounding ointments preparation in pharmacies was evaluated. The calculated value of the ingredient’s dosage uncertainty for the 47 ointment prescriptions for an individual patient showed the possibility of using both manual and electronic scales to do it. The main contribution to its value was made by the dosage of ingredients with a mass less than 1.0 g. The increase in the number of components of the ointment didn’t always lead to an increase in the dosage error. Validation of the technological process of Simanovsky and deflagyl ointments preparation allowed to identify critical stages of the process, the main of which is directly the compounding process. The list of researches for studying of CO stability with recommendations on periodicity of their carrying out was offered and substantiated. According to the developed scheme, the study of physical, chemical, microbiological and mechanical stability of ointments was carried out. According to the results of studying the chemical stability by liquid and gas chromatography methods, it considered to be possible to increase the shelf life of Simanovsky ointments up to 2 months, deflagil ointments up to 3 months, metronidazole cream, eucalyptus tincture ointment and ointment with tetracycline hydrochloride up to 6 months. All tested ointments met the requirements for microbiological purity for 6 months, except for ointment with vitamins and oils, as well as ointment with tinctures of calendula and eucalyptus. Studying the change in structural and mechanical properties indicated the preservation of ointments mechanical stability. The possibility of this method using to assess the preservation of quality indicators of industrial ointments after their processing in mortars with the addition of other APIs was substantiated. Based on the results of the research, the structure of monographs for different categories of CO was proposed. Fragments of dissertation research were used in the 44 introduction of the monograph «Basic principles of manufacturing non-sterile pharmaceuticals in pharmacies» to the SPhU. The analysis of foreign requirements for the introduction of QAS in compounding pharmacies and a series of discussions with employees of these pharmacies became the basis for the adaptation of the PIC/S Guideline «Guide to good practices for the preparation of medicinal products in healthcare establishments».

В работе описаны научно-методологические подходы к созданию национальной фармакопейной концепции качества мазей, приготовленных в аптеке (МПА) путем теоретического обоснования и проведения ряда экспериментальных исследований. Впервые проведенная оценка рисков для качества МПА позволила выделить основные категории наибольшего влияния, что стало основой для экспериментальных исследований. Осуществлена оценка стабильности мазевых основ и стандартизация ряда жирных масел, которые часто входят в их состав. По результатам анализа масел в ГФУ введены монографии «Подсолнечное масло рафинированное», «Абрикосовое масло рафинированное»N и «Персиковое масло рафинированное»N. Теоретически обосновано использование разных методик количественного определения АФИ МПА, проведена их разработка, валидация или верификация. По результатам оценки технологии приготовления мазей выделены критические факторы и сформировано рекомендации по выбору оптимального оборудования. Разработаны подходы к изучению стабильности МПА экспериментальные исследования которой позволили увеличить срок годности большинства исследуемых мазей. Основываясь на полученных результатах предложена структура монографий на разные категории МПА. Фрагменты диссертационного исследования стали основой для адаптации Руководства PIC/S «Guide to good practices for the preparation of medicinal products in healthcare establishments» и включения в ГФУ монографии «Основные принципы приготовления нестерильных фармацевтических препаратов в аптеках».