Browsing by study line "Industriell farmaci"

Medical devices play a crucial role in healthcare, yet their importance is underscored by the potential for adverse events that can lead to serious consequences for patients and users. As a result, manufacturers of medical devices are required to actively monitor the safety and performance of their devices after placing them on the market. In response to incidents involving medical devices and their safety, the European Union Medical Device Regulation (MDR) came into force in May 2021, bringing more emphasis to the post-market surveillance (PMS) of medical devices. In this study, the current state of the post-market surveillance system of medical device manufacturers in Finland was investigated by conducting an online questionnaire in 2023. A total of 30 medical device companies participated in the questionnaire for a return rate of 17%. The dataset included manufacturers of different sizes, producing medical devices of all risk classes. To identify differences in the use of post-market surveillance data sources between different types of companies, the two-sided non-parametric Kruskal-Wallis-Test was used. The rest of the data was analysed using descriptive analysis. The post-market surveillance data sources with the highest reported intensity of use included customer complaints and feedback, production monitoring, and regulatory intelligence monitoring, while Post Market Clinical Follow-up and health services research were used significantly less. Significant differences between manufacturers of different device risk classes were identified for three data sources; manufacturers of higher risk class devices were found to utilize these data sources to a higher extent than manufacturers of low-risk devices. The manufacturers of medical devices seem to utilise reactive post-market surveillance data consistently to a high extent. On the other hand, the results suggest that proactive post-market surveillance methods remain underutilised despite the introduction of the MDR. Medical device manufacturers also use post-market surveillance data sources to different extents, in particular with respect to the medical device risk class. Overall, the results indicate that the MDR is bringing more emphasis on post-market surveillance, which in turn has increased the workload of medical device manufacturers.

Background. Critical thinking skills, which are an aspect of generic skills, are related to the success students have in their university studies and working life after graduation. When it is considered whether the current degree programs and education systems support sufficiently the development of the skillset needed in the future working life of a university student, one can focus on examining the development of critical thinking skills of a student. Due to the lack of scientific studies on critical thinking, research should be done on the field of pharmacy to gather information on the critical thinking skills of master of pharmacy students and to determine, if the master’s degree program in pharmacy is generating the kind of professionals needed in the working life. Aim. The main goal is to study the level of critical thinking skills possessed by students in the beginning of their Master of Pharmacy studies. Combining the theoretical background and empirical study is considered in choosing a suitable method for the study. The method chosen for the study has to be applicable to determining a student’s ability to interpret, analyse and evaluate information, based on which a student consciously arrives on a conclusion while taking into consideration the context and different point of views of students. In addition to studying critical thinking skills, the aim is to analyse the students’ quality of argumentation and the use of references in comprising quality arguments. Methods. The studied set of students comprised of 17 students on their first year in the Master of Pharmacy program in University of Helsinki. The study was performed using a constructed-response task which was based on a real-life problem and was composed of three statements the students had to address utilizing the provided materials. When answering an open question, a student has to be able to analyse, evaluate and synthesize information from different sources. Based on this process, the student must demonstrate in their own words the relevance of the processed information and to construct a coherent essay that also utilizes the provided sources appropriately. The critical thinking skills of the students were evaluated from three aspects: the relevance of the content, processing of information and augmentation. A table for evaluation and classification of the data was created based on the literature study on critical thinking. According to the table, the studied material was divided into three categories. Category 1 entailed students with essays showing the lowest level of critical thinking skills while category 3 entailed students with essays showing the highest level of critical thinking skills. Results and conclusions. A deficiency in the level of critical thinking and argumentation skills possessed by the students was found, which has been encountered in previous studies, as well. All in all, only three out of the studied 17 students, showed impressive critical thinking skills. Most of the student (82%) showed defective argumentation, and more than half (65%) had problems with referencing. In addition, all but one student struggled in utilizing the information gathered from the reference materials. Based on the results, it is important to focus on developing the critical thinking skills of the students in the master’s program in pharmacy. To further study the matter, the same study should be performed on students at the end of their master’s studies to determine if the teaching and evaluation methods in the master’s program in pharmacy are sufficient in developing adequate critical thinking skills

During co-processing, magnesium stearate can induce surface coating on carrier particles in powders which contain at least one other component in addition to magnesium stearate. Magnesium stearate is sometimes added to powder mixtures as it is known to have beneficial effects on powder characteristics, such as physical and chemical stability, and flowability. In order to fully optimize and control the coating/mixing process, it is necessary to be able to characterize the quality of surface coating. Various methods can be used in determining the coating of powder particles. They can roughly be divided into two different categories: direct and indirect methods. For example, spectrophotometric instruments, which are used to visually express the element distribution on particle surface, are considered direct methods. Indirect methods include methods in which coating parameters are inferred using other properties such as water sorption and powder flowability. Principally direct methods have been used in previous studies to determine the quality of coating. Therefore, the area of interest was especially to study indirect methods and compare them to results obtained using direct methods. Having knowledge of the suitability of indirect methods would be interesting as they might have many benefits compared to direct methods, such as quicker analysis speed and cost-efficiency. The aim of the study was to examine the suitability of direct and indirect methods in studying the surface of powders containing magnesium stearate and active pharmaceutical ingredients (APIs) or lactose, more closely how magnesium stearate was placed on carrier particles as well as the uniformity and the thickness of coating layer. The used methods were selected using literature and own consideration while taking the available equipment into account. The powders containing API (d50 < 10 μm) or lactose (d50 > 80 μm) with magnesium stearate had substantially differing characteristics and thus behaved differently. Therefore, there were differences in the suitability of analytical methods in determining surface of powders. Powders containing lactose and magnesium stearate were able to be examined using direct methods (SEM-EDS and ToF-SIMS) and several indirect methods. Samples with API and magnesium stearate were able to be studied with fewer methods. Validation of the suitability of these methods need more research. However, according to the results from this study, it is probable that surface characterization of studied co-particles can be achieved with direct, but also with indirect methods.

Tiivistelmä/Referat – Abstract Background: Biotin is marketed specifically for its hair and nail growth-promoting effects, and its use has become more common in recent years. High doses of 100 mg biotin have also been used to treat MS. There are no high-dose oral products on the Finnish pharmaceutical market. Biotin 100 mg tablets are not available on the global pharmaceutical market either. The University Pharmacy manufactures 100 mg biotin capsules for hospital use. Manual manufacturing of biotin capsules is a resource-intensive process. The physicotechnical properties of biotin such as crystal properties, flowability, hygroscopicity, true density and compressibility properties have not been previously published in the literature. Objectives: The aim of the thesis work was to investigate whether high-dose biotin tablets can be manufactured as an industrial-scale process. To support product development decision-making, the aim of the master's thesis was also to explore the physicotechnical properties of biotin. The main goal was to develop a method for the direct compression of biotin tablets, but also to study the applicability of the wet granulation method. Methods: The crystal form of the raw materials was examined by X-ray powder diffractometer, particle size and particle size distribution by laser velocimeter, and compression behavior by tabletability tests as well as Heckel analysis. The flowability of the raw materials was studied by bulk and tapped density measurements. The production of biotin tablets was studied with six test batches, two of which were high shear wet granulated and four were direct compression processes. The tablets were subjected to European Pharmacopoeia quality tests such as friability, disintegration, and dissolution tests. Results: The particle size distribution of the biotin grade used in the tablets was wide, with an average particle size of 58 μm. Biotin crystals are flaky in shape. Biotin used was the α-crystalline form and its crystalline form did not change as a result of high shear wet granulation. The flow of the biotin grade was extremely poor. Biotin was not found to be particularly hygroscopic. Biotin is brittle, and when compressed, it forms by fragmenting. Pure biotin cannot be compressed into a stable tablet, as even tablets made with high compression forces will form a lid from which the tablet will easily crumble. Biotin sticks to tablet machine’s punches and causes problems in the ejection phase due to high frictional forces. Test batches of the high shear wet granulation process were successful on both eccentric and rotary tablet machine. Two batches of direct compression tests performed on rotary tablet machines had to be stopped after the powder mass got stuck in tablet machine’s hopper. Biotin tablet’s dissolution was slow for all the manufactured batches, with an average of 63-73 % biotin dissolution at 45 min time point. Conclusions: Main property to be optimized for biotin tablet formulations proved to be mass flowability. High shear wet granulation improved significantly flowability. Weight variance of the tablets in the wet granulation batches was also very small. Biotin’s slow dissolution from the tablets was another significant challenge for all the test batches. Further development of biotin tablets should therefore focus on investigating, which measures accelerate biotin tablet’s dissolution. Product development would particularly benefit from the development of a more efficient, ultra-high performance liquid chromatography method for dose analysis of biotin tablets. Wet granulation test batches should be manufactured at different process parameter levels with different excipients and excipient concentrations. Design of experiments statistical approach should be utilized for these further studies so that factor interactions could be detected, and the manufacturing process and drug product could be efficiently optimized.

Pharmaceutical industry is in a process of adopting new technologies due to the growing interest towards the continuous manufacturing approach. However, while the continuous wet granulation process with twin-screw granulator (TSG) has been studied widely, there has been less focus on subsequent continuous granule drying process. As a result, truly continuous granule drying device has not been available for a long time. However, L.B. Bohle has introduced a horizontal truly continuous fluid bed dryer (CFBD) in form of a perforated belt. In such system the wet granules are transported via vibration along the bed without actual fluidization while the hot air dries the granules. Accordingly, Bohle QbCon-25 fully integrated powder-to-tablet system facilitates the combination of a TSG and CFBD. However, the combination is relatively new and only few studies using these methods are available. Aim of this study was to experimentally evaluate the novel Bohle’s CFBD and elucidate the effect of formulation and process parameters of TSG and CFBD on granule residual water content. Additionally, the granules were characterized by their size distribution and bulk and tapped densities. Granule temperature and residence time in the dryer was determined with CubiSens mini sensors. In total 84 wet granulation trials in design of experiments setup were performed and multiple linear regression (MLR) model was used to investigate the effects of different process parameters on granule loss-on-drying (LoD) response. As a result, formulation microcrystalline cellulose (MCC) amount and all studied process parameters of TSG and CFBD showed significant effect on drying result indicating a robust manufacturing process. The increase in the amount of MCC in the formulation as well as the increase in L/S ratio and line rate in the wet granulation was reflected in a higher residual water content in dried granules. However, with increased drying time, airflow rate and inlet air temperature the granule residual water content decreased. The most influential process parameter affecting the granule residual water content was the used L/S ratio. In contrast, the material acceleration which corresponds to the granule drying time was the most significant process parameter of the CFBD affecting the granule residual water. However, the material acceleration did not only correspond to the material residence time in the dryer, but also to the thickness of the granule bed in the dryer. This indicated that the material acceleration is a critical process parameter of the CFBD. However, the thickness of the granule bed could not be measured in real time in this study. Additionally, at intense drying conditions granules showed a very dry outcome and further studies are required to elucidate the operational limit of the CFBD device. Furthermore, the vibration during the drying phase did not have an effect on granule size or the bulk and tapped densities. Material behavior in system was plug-flow like and mean material residence time in the CFBD was only 40 seconds with the middle material acceleration setting. Moreover, the temperature of the granules rose close to the process air temperature, but only for a very short time. Additionally, the used process settings in wet granulation affected the granule temperature, however, the most influential factor on the granule temperature was the used inlet air temperature. Overall, Bohle QbCon25 manufacturing system with TSG and CFBD showed high suitability to wet granulate and dry the produced granules with a uniform residual water content up to 20 kg/h throughput rate without process instability issues.

Oxygen has been used as a medicine since the 18th century and is widely used as prescription and over-the-counter (OTC) medicine. Especially with global COVID-19 pandemic, which started in 2020, the demand for medicinal oxygen has increased significantly and the quality of medicinal oxygen has become increasingly important. Only few studies have been published on the critical process and quality parameters of gases and their impact on product quality. Because oxygen is classified as a medical product, it must be manufactured in accordance with good manufacturing practices regulations (GMP). One part of EU and other GMP guidelines is mandatory annual product quality review (PQR) which must assess the critical quality and process parameters as well as their trends. The aim of the study was to define the critical process and quality parameters for the medicinal oxygen filling process and to analyze the process control, stability, and capability for annual PQR using process data. Process stability and the state of control of processes were assessed using statistical quality and process management tools, such as the Shewhart control diagram and process capability index. Studied process parameters included vacuum level and pressure measured by the filling equipment. Evaluated quality parameters included analysis pressure, O2 and H2O contents. The results of the study showed that the process is not stable and there was a lot of variation between the parameters. Most variation was detected between different cylinder volumes and filling and analysis ramps in all parameters and between different weekdays in H2O content. However, all parameters remained within the specification limits and the Cpk values of all critical parameters were good. By analyzing the data, many variables that can affect the parameters and add variation to the process data can be identified. Based on the results, the necessary measures to improve and optimize the process and quality was identified. In order to stabilize processes and improve performance, the demonstrable variation in process data should be reduced, for example by harmonizing operating methods. According to the study, it was also possible to assess the revalidations required for the process.