Browsing by Subject "Industrial pharmacy"

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  • Sandström, Saana (Helsingfors universitet, 2015)
    Manufacturing execution systems (MES) are computer systems which are used for controlling and automating manufacturing processes. They are increasingly adapted in pharmaceutical industry. Implementation solutions differ, however, and there is no single solution which would be the optimal one for all facilities. Each manufacturing facility has their unique properties and needs which have to be reflected in the implementation. A successful MES project will bring plenty of benefits such as more efficient use of resources and automated data transfer, but the roll out phase might turn to be problematic if the processes of the organization have not been analysed thoroughly enough at decision making. This creates the need for systematic analysis of possible to-be implementation scenarios which is based on the value-drivers of the organization and considers the decision from multiple viewpoints. This study presents a holistic value driver-based framework with a mathematical weighing method to allow for a systematic and scientifically justified decision for identification of the optimal implementation depth of equipment management (EQM) in MES. A Delphi study method was utilized in this study to create the framework. The framework was developed based on literature and brainstorming sessions with experts and validated by means of a Delphi questionnaire round with expert panel consisting of professionals representing the major stakeholders of MES system in a pharmaceutical manufacturing facility. Classical additive weighing method was applied to create a mathematical basis for valuation and comparison of the scenarios. The robustness of mathematical method was tested by means of a sensitivity analysis. A benchmarking survey was done to obtain information on current implementation solutions and decisions leading to current situation. The presented method not only addresses the costs but also takes into account intangible factors. Intangible factors include aspects such as good manufacturing practice (GMP) quality and user acceptance which are not directly transferable into quantitative units but are crucial both for pharmaceutical industry and the success of the implementation project. The framework describes the decision in the form of a value tree with three main branches, namely GMP, cost and process&organization which cover the main viewpoints important for the decision. The presented method also allows the weighing of different factors according to current needs of the facility and decision in question. Hence, the presented framework leads the decision maker through a systematic and comprehensive analysis of different to-be scenarios for EQM implementation. The benchmarking survey identified three major factors of a successful MES implementation, namely effort in design phase, well-defined processes and close discussion with production. The value drivers valued highest by the expert panelists were related to GMP quality. As a use case, the presented framework was applied in a parenterals clinical manufacturing facility to evaluate six different to-be scenarios and based on the results one of them was selected by the management to be implemented. The results from the use case indicate that the framework is a valuable tool in a decision making process, and encourage the further utilization of the framework in future implementation decisions.
  • Punakivi, Kirsi (Helsingfors universitet, 2019)
    Background: Increased use of internet and the development of different services has led into the growth of ecommerce in many sectors and the e-commerce is growing significantly faster than any other economy in Finland. In addition, the search for different health related information from the internet has increased and this has led into increase in the online purchase of different health-related products and services in many countries. However, buying pharmaceutical preparations from online pharmacies have not become that popular in Finland yet, although there are many online pharmacy service providers. Objective: The aim of this study was to explore the acceptance and use of online pharmacies for the purchase of OTC medicines in Finland. The main purpose was to find out what are drivers and barriers to purchase OTC medicines online and which factors could facilitate to overcome customer perceived barriers. Furthermore, the aim was to investigate online purchase behavior for OTC medicines and to find out the insights required to develop more seamless online customer journey. Materials and methods: This study was conducted as a combination of quantitative survey and qualitative interview. The target group of this study was 18-74 year-old-people people living at the Greater Helsinki area. The data was collected with an online survey (n=262), one focus group discussion (n=5) and one-to-one interview (n=3). Participants of both, the survey and interviews, were chosen by convenience sampling and they were drawn in via social media, mainly by Facebook, and in co-operation with a few pharmacies in the Greater Helsinki area. Quantitative analysis of the survey was made by using version 25.0 of the IBM Statistical Program for Social Sciences (SPSS) and data obtained with open questions and interviews was analyzed by using conventional deductive content analysis. Results: In this study sample, 16.5% had bought medicines online. Independence from time and place, convenience and time saving were the biggest drivers to shop OTC medicines online, while the biggest barriers were lack of additional value, high price of the delivery and long delivery time as well as acute nature of the problem. Cheaper price of the medicine was the strongest factor that could get people consider buying online. Results indicate that the online customer journey follows the general five-stage decision making model while purchasing unfamiliar medicines. Internet turned out to be the primary source of information before purchase and self-diagnosis could be made with the help of information found from the internet. In addition, perceptions and experiences of important others and advice from the pharmacist were considered as useful help in the process of self-diagnosis. Conclusions: Barriers for the purchase are currently dominating over the motivating factors. However, the majority of non-buyers would be ready to consider buying medicines online. Currently,the online pharmacies cannot compete with the prices of the medicines, due to the local regulations, but pricing of other pharmacy products is free and those could work as incentive to buy also medicines online. In addition, it would be worth for online pharmacies to invest on developing quick and reasonably priced delivery services and properly working, real-time chat service as well as further increase awareness of their services. Pharmaceutical companies can improve the customer journey by providing the information consumers usually search at their product pages and already at Google-view as a quick links. In addition, online pharmacies should be provided with sufficient information about their products.
  • Mikkonen, Heidi (Helsingfors universitet, 2014)
    One way to improve the solubility of a poorly-water-soluble drug is to make amorphous solid dispersion of it with one or several carrier polymers. However, the amorphous solid dispersions are often unstable. Stability and amorphisation of drug substance depend on e.g. the miscibility of the components in dispersion. Moreover, in the early stage of drug development there is available only limited amount of active substance and time to the analyses. In this study, the primary goal was to develop a method combining the preparing (solvent method) and the analyzing (MTDSC, modulated temperature differential scanning calorimetry) methods. In the method developing part, the possible effect of analyzing parameters of MTDSC to the results was also tested. Amorphous solid dispersions were prepared and analyzed with the invented method. The dispersions were made of poorly-watersoluble itraconazole with hydroxypropylmethylcellulose acetate succinate (HPMC-AS) and/or polyvinylpyrrolidone (PVP K30). X-ray powder diffraction (XRPD) and polarized light microscopy (PLM) were also used to make the interpretation of results easier and more reliable. By analyzing the prepared dispersions the differences in the miscibilities of the used polymers with itraconazole were examined and it was also studied how the miscibility affected to the amorphicity of the prepared dispersion. As a secondary goal, it was tested if combining the two polymers would improve the miscibility and amorphicity of the prepared dispersion. In many cases, with the developed method it was possible to make mixed and amorphous solid dispersion with 10-20 % itraconazole concentration. Used small amount of drug was roughly enough to the detection limit of the used analyzing techniques. The analyzing parameters of MTDSC were not seen to affect to the results in this study which makes the use of this method easier. The results of used analyses were in some part contradictory and that is why it is recommended to use several analyzing techniques or methods that combine different kinds of techniques. In the study, it was seen that in the most part of the prepared dispersions there was more HPMC-AS than PVP K30. This was speculated to be caused by the ionic bonds between the basic itraconazole molecules and acidic succinyl groups in HPMC-ASs and also because of more hygroscopic nature of PVP K30 which increases mobility which in turn increases probability of collision of itraconazole molecules. The use of two polymers in the same time was useful especially in the case of 90/10 HPMC-AS/PVP K30 polymer ratio. This was speculated to be caused by different vaporization rates of the used solvents (DCM and methanol) and too slow evaporation phase. To explain and examine this observation more thoroughly, nuclear magnetic resonance (NMR) -measurements were done. When analyzing the prepared dispersions and itraconazole alone, it was observed that with used amorphisation method (solvent method) itraconazole was in a form that differs from the original polymorph. This form of itraconazole was probably some kind of liquid crystal and was examined further by heating the sample and analyzing it by XRPD. Although there are some other studies to support this hypothesis, this interpretation needs some confirmatory analyses with other methods: with high temperature SAXS (small angle X-ray scattering) and NMR.
  • Lindevall, Mari (Helsingin yliopisto, 2021)
    The purpose of this systematic review is to investigate the usage of artificial intelligence in the pharmaceutical industry in the fields of pharmaceutical manufacturing, product development, and quality control. Today, developing and getting a new drug on the market is time-consuming, ineffective, and expensive. Artificial intelligence is seen as one possible solution to the problems of the pharmaceutical industry. From 734 articles 77 academic study articles were included. Included articles showed artificial neural networks to be the most used artificial intelligence method between 1991 and 2021. The search was conducted from three databases with the following inclusion criteria: studies using AI in either pharmaceutical manufacturing, product development or quality control, English as the language, and Western medicine-based pharmacy as a branch of science. This systematic literature review has three main limitations: the possibility of an important search word missing from the search algorithm, the selection of articles according to one person's assessment, and the possible narrow picture of the used artificial intelligence methods in the pharmaceutical industry, as pharmaceutical companies also research the subject. The use of artificial intelligence in product development has been studied the most, while its use in quality control has been studied the least. In the studies, tablets were a popular drug form, while biological drugs were underrepresented. In total, the number of studies published increased over three decades. However, most of the articles were published in 2020. Nearly half of the articles had some connection to a pharmaceutical company, indicating the interest of both the academy and pharmaceutical companies in the use of artificial intelligence in manufacturing, product development, and quality control. In the future, the efficacy of artificial intelligence, as well as its limitations as a method, should be investigated to conclude its potential to play a key role in reforming the pharmaceutical industry. The results of the study show that a wave of artificial intelligence has arrived in the pharmaceutical industry, however, its real benefits will only be seen with future research.
  • Sainio, Janne (Helsingfors universitet, 2011)
    Lactose is probably the most used tablet excipient in the field of pharmacy. Although lactose is thoroughly characterized and available in many different forms there is a need to find a replacer for lactose as a filler/binder in tablet formulations because it has some downsides. Melibiose is a relatively unknown disaccharide that has not been thoroughly characterized and not previously used as an excipient in tablets. Structurally melibiose is close to lactose as it is also formed from the same two monosaccharides, glucose and galactose. Aim of this research is to characterize and to study physicochemical properties of melibiose. Also the potential of melibiose to be used as pharmaceutical tablet excipient, even as a substitute for lactose is evaluated. Current knowledge about fundamentals of tableting and methods for determinating of deformation behavior and tabletability are reviewed. In this research Raman spectroscopy, X-ray powder diffraction (XRPD), near-infrared spectroscopy (NIR) and Fourier-transform infrared spectroscopy (FT-IR) were used to study differences between two melibiose batches purchased from two suppliers. In NIR and FT-IR measurements no difference between materials could be observed. XPRD and Raman however found differences between the two melibiose batches. Also the effects of moisture content and heating to material properties were studied and moisture content of materials seems to cause some differences. Thermal analytical methods, differential scanning calorimetry (DSC) and thermogravimetry (TG) were used to study thermal behaviour of melibiose and difference between materials was found. Other melibiose batch contains residual water which evaporates at higher temperatures causing the differences in thermal behaviour. Scanning electron microscopy images were used to evaluate particle size, particle shape and morphology. Bulk, tapped and true densities and flow properties of melibiose was measured. Particle size of the melibiose batches are quite different resulting causing differences in the flowability. Instrumented tableting machine and compression simulator were used to evaluate tableting properties of melbiose compared to α-lactose monohydrate. Heckel analysis and strain-rate sensitivity index were used to determine deformation mechanism of melibiose monohydrate in relation to α-lactose monohydrate during compaction. Melibiose seems to have similar deformation behaviour than α-lactose monohydrate. Melibiose is most likely fragmenting material. Melibiose has better compactibility than α - lactose monohydrate as it produces tablets with higher tensile strength with similar compression pressures. More compression studies are however needed to confirm these results because limitations of this study.
  • Hussein, Zahra (Helsingfors universitet, 2018)
    Drug shortages have become a global issue and reasons for drug shortages are several and multifactorial. Definition of drug shortages is not unambiguous. However, in literature are numerous different suggestions to determine the phenomenon of drug shortages. This study provides more focused information on drug shortages and the reasons behind them. The study was performed in cooperation with Orion Corporation. The aim of this study was to explore the in-depth reasons behind medicine shortages from the perspective of one European pharmaceutical company with special focus on Finland, Germany, the United Kingdom and Sweden. Interviews of the company employees were used to achieve this aim and build a few case studies. Further the aim was to investigate in-depth reasons for drug shortages using data from case studies. Case studies were provided by Orion since this enabled use of unpublished information compare the case studies with relevant legal and regulatory measures in the European pharmaceutical framework which influence drug shortages. Reviewing available data from literature and from EUDRA GMDP database for drug shortages and investigate if the data is detailed enough to understand in-depth reasons for drug shortages. Based on the interview results the most common reasons behind drug shortages in Europe are mainly pharmaceutical market structure 38%. It contains many different factors, such as small stock size, local and foreign manufacturing issues, logistics and distribution issues, changes in demand and regulatory issues. However, the manufacturing (33%) or regulatory (29%) reasons are almost as numerous as pharmaceutical market structure issues. Pharmaceutical market structure issues include most common reasons which are categorized in supply-related and demand-related reasons. According to this study supply-related reasons are more common (73%) than demand-related reasons (27%). Some reasons behind drug shortages overlap and often cause a domino effect, whilst other are unique or stand alone, like reasons resulting from natural disasters. The results of this study seem generalizable because the EUDRA GDMP database shows same results and case studies illustrative same reasons behind drug shortages. This study provides more focused information on drug shortages and the reasons behind them from the perspective of pharmaceutical company and authorities.
  • Ahtola, Martti (Helsingfors universitet, 2015)
    The goal of the thesis was to optimize a dry powder layering process that would produce a swelling polymer layer that could work as a base layer for another layer. The GPCG 1 (Glatt) fluidized bed granulator was equipped with a rotor. Such hydrophilic polymers were used for coating that would not be sensible timewise for wet coating methods because of long process time. For design of experiments Definitive Screening was chosen because it works in situations where time is limited and there is high number of parameters. There were six parameters, four related to the equipment settings and two related to the formulation, that were tested on three levels. The results were used to get optimized parameters using a model in MODDE software. The quality of the coating was analyzed by measuring the friability (strain test with fluidized bed granulator), particle size (dynamic image analyzer), density (helium pycnometer and mercurity porosimeter), erosion (size exclusion chromatography), loss on drying (halogen moisture analyzer) and coating efficiency (weighing and loss on drying). Coating was also analyzed also with scanning electron microscopy. The process was robust with regards to sphericity of the coated pellets. In SEM pictures none of the coatings showed complete film formation. Friability method did not show significant differences between batches. Coating efficiency was high for all batches. Correlations between product characteristics were analyzed and some correlations were observed between including correlations between LOD/CE and densities. No correlation between the densities measured with two different methods were seen. Some of the settings in the DOE were too extreme and produced batches that were very difficult to analyze. Two more batches were produced with adjusted settings. This affected somewhat the ability to develop a reliable model. Model development were also affected by insufficient results from erosion tests and because coating efficiency results with water was used. Some stability problems were noticed during design of experiments and chosen equipment limited the scale of settings. Coating material adhered to the surface of the pellets and process could be adjusted by changing the parameters of the DOE. Some correlations were noticed between formulation, equipment settings and coating properties.
  • Kinnunen, Roosa (Helsingfors universitet, 2017)
    Increasing number of companion animals and market for companion animal drug products will bring about new challenges to the companion animal drug product marketing. Thus animal health companies have to rethink determinants of companion animal drug launch success so that their products could differ from other similar products. The aim of this study was to examine if the dominant approach of the new product launch (product-centered-, traditional sales and marketing- and strategic orientations approach) also more popular than relationship approach in the animal drug product marketing. The approach was chosen because big differences exist between the animal- and the human drug marketing. In addition it was researched how the recent changes of the animal health field has been effected to animal drug product marketing. The study was addressed to animal health marketing experts in Finland, the United Kingdom, Germany, France, Spain and Italy by electronic questionnaire. A previously generated questionnaire was employed. It was used after slight modifications and repiloting. According to the study it was found that there is dominating the same procedures as generally in industries in the launch of veterinary drug products. However, relationship approach, which emphasizes the importance of customer relationships, is quite important in the launch of a new veterinary drug product. Based on the results, relationship approach complements dominant approach in the launch of veterinary drug product. Based on answers given to the open-ended questions, veterinary drug companies consider current chances positive and aim to take advantage of the changes. Based on this study at least the senior management of veterinary drug companies seems to be aware the importance of relationship activities. From the results it can be seen that the relationship activities have not been utilized in the launches as much as it would be potential. Veterinary drug companies lean too much on that the company's products will be succeed with very low relationship activities because veterinary drug market is small and they have much less competitors than the human drug companies has. In addition there is working primarily high experienced people in the veterinary pharmaceutical industry, which has an impact that marketing practices are not updated easily.
  • Hautaniemi, Mikaela (Helsingfors universitet, 2012)
    In pharmaceuticals amorphous state can be obtained either intentionally or unintentionally. Intentional production is used, for example, to improve the dissolution of poorly soluble compounds, to stabilize the structure of proteins, or to improve the mechanical properties of excipients (e.g., lactose). Unintentional introduction of amorphous phases can result from general manufacturing procedures of pharmaceuticals, such as coating, granulation, drying, milling, and compression. The presence of amorphous regions, even in small quantities, can exhibit a significant influence on the physical and chemical stability of pharmaceutical products. Molecular mobility in formulation with amorphous content is believed to be the key factor of their stability. Therefore, evaluating of molecular mobility is an important step in pharmaceutical product development. The aim of this study was to estimate molecular motions in amorphous disaccharides using calorimetric approach at temperatures below the glass transition temperature (Tg), where relaxation process is very slow as compared to the time of experiment. When temperature is low enough, the initial relaxation time parameter (τi) can be used as an estimate for relaxation process on the timescale of pharmaceutical product shelf life. The results of the present study revealed similar trend in stability of amorphous forms for the disaccharides (sucrose experiencing the fastest structural relaxation), which can be assumed on the basis of Tg alone, where higher Tg would result in more stable glassy state (Tg of sucrose is the lowest). Storage temperature of Tg - 55oC or lower would suffice for amorphous trehalose, melibiose and cellobiose to achieve at least 2 year's relaxation time, while for sucrose the temperature is Tg - 70oC. Fragility has been used as a helpful mean for classifying amorphous materials. All the compounds can be classified as fragile. Fragility ranking in the present study contains some degree of uncertainty, while 3 different approaches revealed somewhat different results for ranking the disaccharides. The variation in the results can be attributed to the overall sensitivity of DSC. The method described in the present study is quite difficult to apply without supportive information from other techniques. The results, obtained with the method, are very dependent on the slope in plotting ln q vs. 1/Tg, and even small fluctuations in the estimation can lead to different fragility values and consequently to different relaxation times. However, the final results reveal values for relaxation times well below Tg, which are in reasonable agreement with modern theoretical understanding of glassy state dynamics.
  • Korventausta, Susanna (Helsingin yliopisto, 2022)
    Etätyö yleistyi maaliskuussa 2020 äkillisesti COVID-19 pandemian seurauksena maailman terveysjärjestö WHO:n suosituksesta. Etätyö on ollut ennen koronapandemiaa harvinaista lääketeollisuudessa, joten etätyötä lääketeollisuudessa on tutkittu hyvin vähän. Etätyön on arvioitu jäävän pysyväksi ratkaisuksi, joten on ajankohtaista tutkia etätyön soveltuvuutta ja tehokkuutta lääketeollisuudessa. Etätyöntekijöiden tuottavuus kasvaa yleensä huomattavasti. Työpaikalla koetaan jatkuvasti keskeytyksiä, melua ja muita häiriötekijöitä, joiden lisäksi työmatkat kuormittavat työntekijöitä. Etätyöntekijät säästyvät suurimmalta osalta näistä ongelmista, jolloin suurempi osa heidän työpäivästään kuluu varsinaiseen työntekoon. Valtaosa etätyöntekijöistä tekee etätyötä osan työajastaan. Tutkimuksen tavoitteena oli selvittää kokemuksia etätyöstä, etätyön soveltuvuutta ja etätyön tehokkuuteen vaikuttavia tekijöitä lääketeollisuudessa. Tutkimus on toteutettu Orion Oyj:n Suomen toimipisteissä. Tutkimuksen toteuttamistapa oli kvantitatiivisen ja kvalitatiivisen kyselytutkimuksen yhdistelmä. Yhdistämällä kvantitatiivisia ja kvalitatiivisia kysymyksiä pyrittiin saamaan tarkempia tietoja kuin pelkällä kvantitatiivisella tutkimuksella voitaisiin saada. Kysely oli avoinna 15.11.–26.11.2021. Vastausprosentiksi saatiin 34,9 %. Etätyön merkittävimmiksi hyödyiksi havaittiin työ- ja vapaa-ajan joustavampi yhteensovittaminen ja se, että etätyössä keskittyminen on parempaa. Kommunikaation koetaan onnistuvan hyvin etätyössä, mutta kasvokkain tapahtuvaa kommunikaatiota pidetään myös tärkeänä. Esimerkiksi kehitys- ja ideointipalaverit olisi hyvä järjestää mahdollisuuksien mukaan kasvokkain. Lisäksi hiljaisen tiedon siirtyminen on vähäisempää etätyössä. Etätyö soveltuu hyvin tutkimus- ja tuotekehitystyöhön, eikä sen koeta heikentävän merkittävästi kykyä innovoida. Tulosten perusteella etätyötä haluttaisiin tehdä enemmän kuin 40 % työajasta ja etätyötä pidetään tehokkaana työskentelytapana. Kyselyssä ei selvitetty, minkälaisia etätyömääriä vastaajat ovat tehneet vahvan etätyösuosituksen aikana. Osa vastaajista on saattanut olla muita enemmän lähitöissä, mikä voi vaikuttaa tuloksiin. Saadut tulokset olivat kuitenkin samansuuntaisia kuin aikaisemmissa tutkimuksissa. Suurin osa tähän kyselyyn osallistuneista oli erittäin kokeneita ja työnsä hyvin osaavia työntekijöitä, mikä voi lisätä etätyömyönteisyyttä tuloksissa.
  • Ritamäki, Kaisu (Helsingfors universitet, 2019)
    Pharmaceutical companies are required to comply with fair market guidelines and regulations. However, definition of fair market value (FMV) in clinical trial is not unambiguous. In literature are some suggestions how to determine the phenomenon of FMV in clinical trial. Understanding the FMV and how it should be applied into practice when conducting clinical research is challenging. This study provides more focused information on FMV in clinical trials and its determination. FMV should be determined for research-related activities in clinical drug research. FMV of research related activities can be consistent if similar sites are performing similarly conducted studies for similar sponsors. Therapeutic area and geographical location of the trial site can also influence for the FMV. This study was performed in co-operation with Roche. The aim of the study was create a consistent and transparent method to assist in the determination of FMV in medical drug research in relation to the payments paid by the sponsor to the sites. Clinical trial agreements (CTA) and associated agreements were analysed to investigate FMV of research-related activities by study site, study type, therapeutic area and geographical area. Average price and price range of each research-related activity from previous CTAs and associated agreements of Roche Finland was calculated. Based on available data from literature and study results research-related activities and factors affecting to the FMV of clinical trials were discussed to create comprehensive understanding of FMV in clinical drug research. Based on this study average price of the specific research-related activities can be different by therapy area, site, study type and geographical area. All these factors are relevant when assessing FMV of specific research-related activity. Studied therapy area and site seems to have the most important impact when evaluating FMV. For some research-related activities such as national coordinator investigator (NCI) fee price ranges could be very big whereas in other research-related activities such as pharmacy fees prices could be quite similar. Some research-related activities were very study specific which affected evaluation of those activities. CTAs and associated agreements are valid documents to gather information assessing FMV of research-related activities in medical drug research. Average price and price range of the research related activity can be used when assessing FMV in medical drug research. However, price of the specific research-related activity need to be evaluated considering the studied therapy area, site, study type and geographical area.
  • Häggman, Verner (Helsingfors universitet, 2019)
    If pharmaceutical quality system fails it causes a hazard to the patient’s health, but also to the manufacturer’s economy. For this reason, the manufacturer’s must make sure their products comply with the quality requirements placed by authorities. To ensure the compliance, the authorities perform inspections at the manufacturing sites. If the site does not comply with the quality requirements, the authority will take necessary measures. The goal of this study was to find what type of quality issues FDA and the authorities within EU have observed while inspecting manufacturing facilities, which of these issues are most common, in which countries the sites companies with issues have been located. The results were assessed from European pharmaceutical company’s point of view. The data for the study was collected from Eudra GMDP database and from FDA Warning letters sent by FDA headquarters from years 2015-2017. Qualitative analysis of content was chosen as the method of analysis. The collected data was classified into main classes and subclasses based on reoccurring topics. The classes were transferred in tables to compare how which of the classes were most common. Most often the facilities with quality issues were located in China and India. The authorities also perform a lot of quality inspections in these countries, but that alone doesn’t explain the large number of quality issues in these countries. The number of sites with quality issues per inspection was also high. Both the authorities of EU countries and FDA had mainly observed similar issues. Often quality issues were related to data integrity. Other common themes were quality management system, cleaning of equipment and facilities and analytical methods. There were also some differences in the observed issues. E.g. FDA had rarely observed issues related to personnel while EU authorities had observed such issues frequently. Quality issues which had led to measures by authorities were often related to larger problems with the quality management or to very basic quality actions. If company doesn’t have well-functioning quality organization, the quality system is often inadequate also in other ways. By comparing their own activities with the issues observed at other companies, it is easier for a company to improve their quality and avoid major quality issuer before they occur.
  • Salminen, Veera (Helsingin yliopisto, 2021)
    Continuous monitoring of the safety profile of medicinal products is essential also after marketing authorisation approval to ensure the patient safety. Spontaneous reporting of adverse drug reactions is one of the most important methods to collect post-approval safety data of medicinal products. The advantages of spontaneous reporting system include reaching large population throughout a long period of time for many medicinal products, however, it also has some limitations. One commonly recognized problem of the system in many countries is under-reporting of adverse drug reactions. The national reporting scheme in different countries slightly vary, even between Nordic countries. The main aim of this study was to find out what improvements should be done to the current reporting scheme in Finland so that it would better encourage healthcare professionals to report in relevant situations, which respond to the purpose of the spontaneous reporting system. Physicians (n=20), pharmacists (B.Sc.) (n=78), pharmacists (M.Sc.) (n=21) and nurses (n=13) responded to the anonymous open voluntary online questionnaire. Close-ended questions were analyzed and results summarized in graphs and tables. Statistical analysis was done using chi-squared test. Content analysis was performed for open-ended questions by utilizing both, inductive and deductive approach. In the study, we found some differences in healthcare professionals’ opinions what kind of adverse drug reactions should be reported. Some of the healthcare professionals were also aware that they had not reported all suspected adverse drug reactions that came into their knowledge and several reasons were recognized for this. Seriousness of the reaction was considered the most motivating factor for healthcare professionals to report about suspected adverse drug reactions. The results of this study suggest that in healthcare professionals’ opinion, the most important factors that should be considered to improve reporting in Finland are training for healthcare professionals and simplifying the reporting as much as possible. Some differences were noticed between the occupational groups regarding preferences in the reporting route and especially physicians seemed to prefer formation of the report from the information system as a reporting method more than open web-based reporting form. Mobile application for reporting was not preferred that much among Finnish healthcare professionals. The results of this study support the hypothesis that under-reporting of suspected adverse drug reactions is also present in Finland. The reporting instructions should be clarified, training availability should be considered and reporting should be simplified as much as possible to improve the reporting.
  • Kyynäräinen, Kerttu (Helsingfors universitet, 2013)
    In vivo dissolution of drug molecules depends on the conditions in the gastrointestinal tract, like pH, composition of the fluids and hydrodynamics. Weakly basic compounds dissolve rapidly in low pH in stomach but in intestinal conditions forming of supersaturated solution may occur. This unstable state is the driving force either for rapid absorption from small intestine or for possible precipitation of drug. Difference in precipitation and thus in bioavailability between fasted and fed states can be significant. In this study behaviour of three weakly basic drugs, dipyridamole, ketoconazole and compound A, were studied with aid of two-phase microdissolution method. Three clinically relevant doses were used in the studies. In the study both fasted and fed states were tested as well as the effect of different pH in stomach phase and significance of biorelevant solutions over general buffer solutions. Dissolution of the drugs were examined in the media that simulate gastric fluids (SGF pH 1,2, SGF pH 4,0, FaSSGF pH 1,6 and acetate buffer pH 5,0). When biorelevant simulated intestinal fluid (FaSSIF or FeSSIF) was added to the solution to simulate the drug transfer out of stomach into small intestine, precipitation of different doses were analysed. Also the level of supersaturation compared to solubility results was examined. In addition the effects of various mixing speeds (300 rpm and 150 rpm) and scales (USP I and minidissolution) on precipitation were studied. Concentrations were measured directly from dissolution vessels with fibre optic probes. Re-dissolution of the drugs in small intestine and influence of physical properties on dissolution rate were evaluated with flow through dissolution method. In the fed state simulated microdissolution tests even the high doses of the drugs did not precipitate. Instead, in the tests simulating fasted state the effect of dose was clear and the relative part of dissolved drug were the smaller the higher was the dose. The high doses precipitated fast while the small doses remained much supersaturated. When FaSSGF was used the solutions staid longer in supersaturated state. Higher pH in stomach phase had remarkable impairing effect on the dissolved part of the drug in the small intestine phase and no supersaturated solutions were formed. In the microdissolution smaller mixing speed seemed to cause more precipitation and ranges of the results were larger. Different hydrodynamics in different scale dissolution methods as well caused divergent results. The effect of physical properties of precipitate to re-dissolution could be observed with the flow through dissolution tests. According to this study, two-phased dissolution method fit for few milligrams of API and it can be used to evaluate the precipitation potential of basic drugs in fasted and fed states. Also the effect of higher pH in the stomach on dissolved portion of API can be analysed. The method can be used as a risk assessment method for example when you want to know when the dose raises the risk to precipitation or as a tool to be used in early formulation development. As such dissolution tests can be used to get qualitative data of precipitation phenomenon when comparing basic drug compounds. The dissolution, precipitation and re-dissolution parameters will in future be utilised in pharmacokinetic model to evaluate the effect and significance of these phases on the drug absorption in vivo.
  • Hietala, Tarja (Helsingfors universitet, 2017)
    Twin screw granulation (TSG) has gained considerable interest as a continuous wet granulation method in the pharmaceutical industry and has been studied the most. However, there is still lack of understanding how continuous granulation affects the material compaction behavior even though it has been noticed in several dry and batch wet granulation studies that the granulation process has an influence on the final tablet strength. Thus, studies on the material compactability and tabletability after continuous wet granulation are relevant for the overall understanding of twin screw granulation process and its effect on material behavior in tableting. Hence, the main objective of this study was to investigate the influence of continuous twin screw granulation on the compactability and tabletability of commonly used excipients. Additionally, the impact of binder on the compaction behavior of materials was examined. Furthermore, the suitability of two "loss in compressibility" models i.e. the Unified Compaction Curve (UCC) model and a porosity model to predict the loss in tablet strength after twin screw granulation and for the materials used was assessed. Earlier, the models have been applied to dry and batch wet granulations only. Full factorial design of three variables (binder type, binder addition method and the number of kneading elements) with two levels was conducted for the ConsiGma1 twin screw granulation of formulations containing microcrystalline cellulose (MCC), mannitol or anhydrous dicalcium phosphate (DCPA) as the main excipient and polyvinylpyrrolidone (PVP) or hydroxypropyl cellulose (HPC) as binder. Magnesium stearate was added as lubricant after granulation prior to tableting. In addition to the full factorial design, granulation with PVP, dry binder addition and four kneading elements was repeated for each main excipient. In total this made 27 experiments. The granules were dried and milled after granulation and all the batches were tableted. Additionally, all the formulations were direct compressed in order to be able to detect the change in compactability and tabletability after granulation. Torque of the granulation was determined as well as bulk density and particle size distribution of the granules. Additionally, the tensile strength and porosity of the tablets were analysed. Tabletability and compactability were determined based on the compaction pressure and the obtained tensile strength and porosity values of the tablets. Furthermore, parameters (PWG, TWG and εWG) describing the loss in compressibility models were calculated. MCC experienced loss in compactability and tabletability after twin screw granulation due to hornification effect. On the other hand, the compaction behavior of mannitol improved due to the formation of porous granules. The compactability of DCPA decreased and the tabletability increased. However, the change was only moderate presumably due to brittle nature of DCPA. Additionally, the binder type had an effect of the compaction behavior of the materials, PVP producing stronger tablets compared with the less hydrophilic HPC. However, the binder addition method played only a small role in modifying the compaction behavior. The UCC model was applicable to MCC as loss in tabletability was detected. Thus, the model can be used to predict tablet tensile strength when MCC is granulated with twin screw granulator. Additionally, the UCC model can be used to design the granulation process to achieve a target tensile strength based on small scale preliminary studies thus reducing the resources needed for case-studies. However, the UCC model was not feasible to mannitol and DCPA because they experienced improvement in tabletability after twin screw granulation. The porosity model was applicable to MCC and DCPA but not to mannitol as it showed improvement in compactability. The porosity model described the loss in compactability of MCC only moderately due to lack of tensile strength data points and the linearity of the tensile strength-porosity relationship. However, the model described well the loss in compactability of DCPA at tablet porosities achieved with compaction pressures used in industry. As a conclusion, the results demonstrate that twin screw granulation can have a significant impact on the final tablet strength and that the compaction behavior of the formulation can change either way depending on the used materials. Furthermore, the small influence of the binder addition method on the tablet strength indicates that the time consuming binder dissolving process step can be excluded from the tablet production chain enabling continuous manufacturing with twin screw granulation.
  • Myllymäki, Pilvi (Helsingfors universitet, 2018)
    The majority of potential new chemical entities reaching drug development phase belong to Class II the Biopharmaceutics Classification System (BCS) which complicates formulation of orally administered drugs. Therefore, there is a need to develop methods to increase the solubility and dissolution rate. Transformation of a crystalline drug into its amorphous form can be used to enhance these properties of poorly water-soluble drugs. However, amorphous drugs are thermodynamically unstable and tend to recrystallize back to the crystalline form. Coamorphous forms are a new and promising method to stabilize amorphous form. A relatively new approach is to combine the active drug compound with an amino acid to form a coamorphous system. In this study, co-amorphous systems were prepared from gamma, alpha or amorphous form of indomethacin (IND) and tryptophan (TRP) by ball milling. The solid-state changes during milling were investigated to obtain information about the co-amorphization process. The main objective was to investigate the effects of initial solid state of indomethacin on the formation pathways. In addition, different analytical methods were compared with respect to observed endpoints of the formation process. Raman spectroscopy has not been used in previous studies regarding solid state changes in co-amorphous forms. The presence of fluorescence in amorphous systems may have limited use of the method. A time-gated Raman setup together with X-ray powder diffraction and differential scanning calorimetry (DSC) was used to investigate this kind of potentially fluorescent system. Principal component analysis of spectral data revealed that the three different binary systems had individual and direct pathways towards the same end points during milling. This indicates that the co-amorphous form formed after 60 minutes of ball milling is not dependent on the initial solid-state form of IND. Straight pathways also indicated direct transformation to the coamorphous form. DSC was found to be the most sensitive method to detect changes for the longest period during co-amorphization. Conventional Raman spectroscopy was found to be suitable for investigation of the co-amorphization process. However, time-gated Raman spectroscopy did not show significant advantages compared to conventional Raman data. This study revealed that the most stable form of IND could be used for production of co-amorphous form together with TRP. Raman spectroscopy could potentially be used for investigating coamorphization also as an in-process analytical method.
  • von Schantz, Sofia (Helsingfors universitet, 2015)
    This study aims to address how easily an individual with no prior inhaler experience can learn to use a dry powder inhaler (DPI) through video education. This is a comparative study of four DPIs (Diskus, Easyhaler, Ellipta and Turbuhaler). Different properties affecting ease of use, patient preference as well as educational videos as a method of providing inhaler instructions were investigated. The study used a triangular methodology. The sample consisted of 31 individuals (24-35 years). All participants were considered inhaler naïve. After watching the video education material for a particular inhaler the participants' demonstrated the use of it. Educational videos for all four inhalers were watched and use of all placebo inhalers was demonstrated in a random order. These demonstrations were videotaped. The demonstrations were thereafter checked against a predefined checklist and all mistakes were recorded. Only 33 % of inhaler demonstrations were completed without the participants making any mistakes that could compromise the efficacy of the inhaled medication in a real-life situation. The frequency of error varied greatly between different types of inhalers. Ellipta proved to be most often used correctly with 55 % demonstrating use without making any mistakes. This was closely followed by Diskus for which 48 % demonstrated correct use. The difference between the average error frequency for Ellipta and Diskus was statistically insignificant. With Easyhaler 19 % percent of participants were able to demonstrate correct use, the corresponding percentage for Turbuhaler was 16 %. When comparing participants' demonstrations for Easyhaler and Turbuhaler, the difference in average error frequency between the devices were not statistically significant. The average frequency of error was lower when using Ellipta in comparison to Easyhaler and Turbuhaler (statistically significant). The same indications were found when comparing average frequency of error for Diskus, to those for Easyhaler and Turbuhaler. Comparing the participants self-reported correct use against the actual numbers it is clear that participants often thought they were using the inhaler correctly when they in fact were not. When asked to rank the inhalers from most preferred to least preferred, Ellipta emerged as a favorite. Turbuhaler received the second highest scores, Diskus the third and Easyhaler was least preferred. However, only the difference between preference scores for Ellipta and Easyhaler was deemed statistically significant. The high frequency of error suggests that even though participants generally considered the inhalers intuitive and easy to use, they would have required more comprehensive inhaler education in order to achieve correct inhaler technique. Further, the results indicate that video demonstrations are not ideal for providing inhaler education for first time inhalers users. The most prominent problem with video education is that it provides no feedback to the user regarding their inhaler technique. This may present real problems as the results of this study show that participants tended to overestimate their own inhaler technique. Patient education plays a central role in asthma care and needs to be given proper attention even though the inhalers might be considered intuitive and easy to operate. Interesting areas for future research include investigating interactive learning videos as a way of improving video education on inhaler technique.
  • Böhling, Linda (Helsingin yliopisto, 2021)
    Tablet is the most common pharmaceutical dosage form due to ease of administration, chemical and physical stability, and relatively low manufacturing cost. Direct compression is the preferred method for tablet production. Direct compression formulations typically contain a considerable amount of excipients. Therefore, excipients can have a significant effect on the tableting properties of formulations. More research is needed for better comprehension of the compression behaviour of different materials. The objective of this work was to investigate tableting properties of different excipients and their binary mixtures with two different laboratory scale tableting devices; the Gamlen® D1000 Powder Compaction Analyzer and the FlexiTab®. The excipients used were microcrystalline cellulose (MCC), lactose, mannitol, starch, and dicalcium phosphate (DCP). Different compression pressures were used to survey the compression behaviour of the excipients at a wide pressure range. In addition, potential effects of compression speed, dwell time, and lubrication method were considered. The excipients and their binary mixtures were characterised based on compressibility (solid fraction vs. compression pressure) and tabletability (tensile strength vs. compression pressure). The results obtained with the devices were compared to enhance process understanding. Based on the compressibility curves, it appeared that plastic deformation was the main compression mechanism of MCC and starch and fragmentation the main compression mechanism of lactose, mannitol, and DCP. The tabletability of MCC was excellent, and also the tabletability of mannitol was good. The tabletability of DCP was intermediate, whereas lactose and starch had inferior tabletabilities. In general, the tabletabilities and compressibilities of the binary mixtures were more or less what was expected based on the results of the individual materials. The results obtained with the different speed parameters and lubrication methods were mainly in line with the perceptions of the compression mechanisms of different materials. In overall, the results obtained in the Gamlen and FlexiTab experiments were quite similar. However, tensile strengths appeared generally slightly lower in the FlexiTab experiments. Probable explanations are the higher compression speed of the FlexiTab and differences in hardness measurements. This study indicated that the FlexiTab and Gamlen devices have different benefits. The Gamlen device is clearly very suitable for investigating tableting properties during formulation development, but the FlexiTab device has the advantages of higher compression speed and automatic powder feeding mechanism. Tabletability results were slightly better with the Gamlen, but more experiments are needed for solving the reasons (e.g. compression speed and hardness measurements). More information of the compression behaviour of different materials could be obtained by analyzing punch displacement data and by using different compression equations.
  • Nikkilä, Tiiu (Helsingfors universitet, 2019)
    Background: Continuous manufacturing has been utilized for decades in many industries since it has many advantages compared to batch manufacturing. Therefore the interest towards continuous processes has arisen also in the pharmaceutical industry. Also, the strict regulations characteristic of pharma industry have started to change more favorable towards continuous manufacturing when the possibilities of continuous processes to produce higher quality products faster and more efficiently, have been proven in many researches. Objectives: Objectives of this thesis were to clarify the effect of the material characteristics on material flowability from continuous feeders and to study how different toolings, like feeding screws, affect the feeding of materials with different characteristics. Based on these results, a possibility to model the feeding results of a material based on only some measured material characteristics was also under investigation. The aim was to develop a clear and systematic procedure which would simplify the determination of the most suitable equipment when starting to feed a new material. Methods: The similarity of flowability of various pharmaceutical powders from continuous feeders was studied. First material characteristics affecting material flowability from a feeder based on literature was determined from 26 pharmaceutical powders. Following this, six materials were chosen to be studied with gravimetric powder feeders using different kinds of research frames. The six materials formed three material pairs, in which two materials had clear similarities in the flowability characteristics. The reason for this was that the flowability from feeders with similar materials could be compared. The feeding of materials was determined investigating the feed rate capacity and accuracy of feed rate of material. Also, the effect of feeder screws and the speed of the screws on the feeding capability of a material was investigated. A model to predict the feeding result based on material characteristics was built using PLSand MLR-methods. Results: The prediction of material feeding was not possible with PLS- and MLR-modeling methods. The feeding of similar materials was wound to be alike. Poor flow characteristics correlated with poor feeding results. PCA- and cluster analysis were found suitable to define the similarity of materials. Conclusions: The success of feeding of pharmaceutical powders is clearly affected by the material flowability properties. The feeding screws and screw speed affect the feeding accuracy, too. The prediction of feeding results of specific material, would need much more data to produce valid and trustworthy models. However, it seems highly possible to be able to build a model with more materials.