MONITORING THE COATING PROCESS OF PHARMACEUTICAL PELLETS BY MACHINE VISION

Skrben nadzor nad kakovostjo farmacevtskih izdelkov je ključnega pomena za varnost in zdravje pacientov. Skupaj z nenehnim razvojem novih zdravil in večanjem porabe že obstoječih se povečuje tudi potreba po razvoju na področju farmacevtske procesne tehnologije in napredku pri nadzoru kakovosti zdravil. Izboljšanje proizvodnega procesa v farmacevtski industriji z vidika kakovosti in varnosti izdelkov je bil glavni cilj ameriške Food and Drug Administration (FDA) ob uvedbi smernic za nadzor kakovosti farmacevtskih izdelkov pod skupnim imenom "Process Analytical Technology" (PAT). Posebej je poudarjen razvoj novih inovativnih orodij, ki bi omogočala medprocesni nadzor ključnih parametrov kakovosti materialov in končnih izdelkov v realnem času, kar bi omogočilo identifikacijo in ovrednotenje procesnih spremenljivk, ključnih za kvaliteto izdelka. Obložene farmacevtske pelete, ki se jih da polniti v kapsule ali stisniti v tablete, so vse pogosteje v rabi pri proizvodnji zdravil. Glavni razlogi za to so ugodne lastnosti sproščanja zdravilnih učinkovin in tudi dobre fizikalne lastnosti, ki olajšajo proces proizvodnje. Največja prednost obloženih pelet predstavlja možnost izbire oblagalne snovi in njene količine, ki jo lahko natančno nadziramo z določanjem debeline obloge. S porastom oblaganja pelet v namen izdelave zdravil s prirejenim sproščanjem postajajo poleg povprečne debeline obloge vse bolj pomembne tudi druge lastnosti kakovosti obloge, predvsem enakomernost obloge med peletami in enakomernost obloge na posamezni peleti (morfološka enakomernost). Natančno spremljanje teh lastnosti obloženih pelet je zato ključnega pomena pri zagotavljanju ustreznosti in kakovosti končnega izdelka. Na lastnosti obloženih pelet odločilno vpliva potek procesa oblaganja. Zaradi kompleksnosti postopka, ki ga določa veliko število parametrov, je možnosti za variacije v kakovosti končnega produkta veliko. Neuspešno izveden postopek pomeni veliko količino odpadnih snovi, kar predstavlja veliko obremenitev za okolje. V skladu s smernicami PAT je medprocesni nadzor postopka oblaganja pelet v realnem času pomemben tako za izboljšanje razumevanja in vodenja procesa ter zagotavljanje mustreznosti končnega izdelka kot tudi s stališča učinkovitosti proizvodnje in okoljevarstva. Kakovost procesa oblaganja farmacevtskih pelet se v večini proizvodnih sistemov zagotavlja prek vnaprej določenega poteka, meritve parametrov kakovosti pelet pa se izvedejo šele po koncu procesa oblaganja. Merilne tehnike, ki so v uporabi, večinoma ne omogočajo spremljanja kakovosti procesa v realnem času, so časovno potratne in dokaj nenatančne. V tej doktorski disertaciji predlagamo spremljanje procesa oblaganja farmacevtskih pelet s sistemom strojnega vida, ki – v skladu s smernicami PAT – omogoča samodejno medprocesno, brezkontaktno in časovno učinkovito vrednotenje parametrov kakovosti obloge pelet. Zasnovali in izdelali smo merilni sistem, ki omogoča hiter medprocesni zajem slik visoke kakovosti v obstoječih pogojih vidnosti pelet med oblaganjem v Wursterjevi oblagalni komori. Razvili smo hitre algoritme računalniškega vida za razgradnjo slik in natančno določitev mej pelet na zajetih slikah. Iz določenih mej pelet lahko medprocesno spremljamo rast debeline obloge pelet v realnem času. Izdelani sistem ponuja možnost zajetja velikega števila meritev v kratkem časovnem intervalu, kar omogoča dobre statistične ocene izmerjenih parametrov oblike in velikosti pelet. V doktorski disertaciji predlagamo metode analize podatkov, izmerjenih s sistemom strojnega vida, preko katerih lahko poleg debeline obloge spremljamo tudi druge pomembne parametre kakovosti obloženih pelet, ki jih z dosedanjimi metodami vrednotenja kakovosti obloženih pelet ni bilo mogoče meriti medprocesno in s tolikšno natančnostjo, hitrostjo in kakovostjo statističnih ocen. V disertaciji predlagamo analizo lastnosti oblike izmerjenih pelet, saj te pomembno vplivajo na kakovost več korakov procesa izdelave zdravil. S spremljanjem izbranih parametrov oblike pelet tekom oblaganja lahko ocenimo tudi morfološko enakomernost oblaganja pelet, ki je pomemben parameter kakovosti zlasti pri izdelavi zdravil s prirejenim sproščanjem. Prav tako je pomembna tudi enakomernost obloge med peletamineenakomernost se pojavi predvsem zaradi razlik v velikostih pelet v oblaganju. V disertaciji predlagamo metodo statistične analize porazdelitev pelet po velikosti, izmerjenih s sistemom strojnega vida tekom oblaganja, preko katere lahko ocenimo parametre odvisnosti debeline obloge od velikosti pelet in parametre enakomernosti obloge med peletami. V okviru raziskav doktorske disertacije smo izvedli več poskusov oblaganja v laboratorijskem Wursterjevem sistemu za oblaganje pelet, ki smo jih spremljali s sistemom strojnega vida. Za vsakega izmed izvedenih poskusov predstavimo celovito analizo procesa oblaganja, kot jo omogoča sistem strojnega vida. Rezultati poskusov Izvirni prispevki k znanosti ix kažejo skladno sliko glede na potek posameznega procesa, njihova primerjava z rezultati referenčne metode pa pokaže zelo dobro medsebojno ujemanje. V doktorski disertaciji predstavimo tudi primerjavo in vrednotenje petih drugih analitičnih metod za merjenje parametrov kakovosti obloženih pelet. Z njimi smo izvedli meritve na vzorcih pelet in na podlagi primerjav ovrednotili rezultate sistema strojnega vida. Sistem strojnega vida in predstavljene metode analize podatkov za oceno ključnih parametrov kakovosti omogočajo celovito analizo kakovosti obloge pelet v procesu oblaganja in dajejo nov vpogled v njegove značilnosti. Pridobljeno znanje lahko omogoči bolj poglobljeno razumevanje samega proizvodnega procesa in izboljšave na področju nadzora kakovosti obloženih pelet, kar je v skladu z namenom smernic PAT.Careful control over the quality of pharmaceutical products is vital for the safety and health of patients. With the ongoing process of new drug formulation and the growing use of the existing pharmaceutical products, there is an increasing need for progress in pharmaceutical technology and advances in process quality control with the aim of improving the quality of end products and optimizing production efficiency. Improving the production of pharmaceuticals with respect to their safety and quality is the main goal of the process analytical technology (PAT) guidelines issued by the American Food and Drug Administration (FDA). A special emphasis is placed on developing new tools that would enable real-time and in-line monitoring of critical quality attributes of materials and end products, thus enabling the identification and evaluation of product and process variables that may be critical to product quality. Coated pharmaceutical pellets that can be enclosed in capsules or compressed into tablets are increasingly used in the production of solid dosage forms. Compared to single-unit dosage forms, pellets offer the advantage of more favourable active ingredient release profiles and drug absorption, which improves the therapeutic effects of a medical treatment. In addition, their physical properties and flow characteristics make production processes easier and more efficient. The biggest advantage of pellets is the possibility of applying coatings, offering a high degree of precision and flexibility. The amount of active ingredient included in the coating can be divided into desired dose strengths without formulation or process changes. With the increasing use of pellets as controlled release systems, beside mean coating thickness, the inter-pellet and intra-pellet coating uniformity (morphological coating uniformity) are becoming more and more important quality attributes of coated pellets. Monitoring all of these quality attributes of coated pellets is thus of great importance for assuring the desired end product characteristics. The coating process is the most important production step affecting the critical quality attributes of coated pellets. It is a complex multivariable process allowing many possibilities for end product variability. A failed coating process can result in a discarded batch of pellets, causing a financial and environmental burden. In accordance with PAT guidelines, in-line and real-time monitoring of pellet coating process would bring many benefits, not only in improving the quality of dosage forms of coated pellets, but also for understanding and optimization of coating processes. In most production settings, pre-defined process parameters are used to ensure the repeatability of end product characteristics. The endpoint of a coating process is determined by in-process sample acquisition and an off-line analytical method is used to determine the quality of coating. The quality of coated pellets is thus tested at the end of the process, not allowing for timely adjustments of process parameters to modify the end product quality. In addition, the analytical techniques are often time consuming and imprecise due to small number of pellets analysed. In this dissertation, we propose a machine vision system as a PAT tool for monitoring the coating process allowing for automatic contactless in-line assessment of critical quality attributes of coated pellets in real-time. We designed a measuring system that enables fast in-line acquisition of high-quality images of pellets in the existing visibility conditions of a Wurster coating apparatus. We developed fast computer vision algorithms for image analysis and accurate determination of pellet borders on the acquired images. These results enable the monitoring of coating thickness of pellets in real-time, during the coating process. The advantage of an automatic machine vision system is that large number of measurements can be obtained in a relatively short time, yielding good statistical estimations of pellet shape and size properties and their distributions throughout the coating process. In this dissertation, we propose methods for analysing measurements, obtained by the machine vision system, that allow the evaluation of additional quality parameters that cannot be determined with currently used methods for assessing quality of coated pellets, at least not with this level of accuracy, time efficiency and quality of statistical estimations. We propose an analysis of the pellets’ shape parameters obtained from the pellet borders measurements, which is a valuable information as pellets’ shape properties affect the quality of several steps of pharmaceutical production process. Monitoring the specific shape parameters of pellets through the course of the coating process enables the evaluation of morphological coating uniformity, which is an important quality parameter of coated pellets, especially with controlled release systems. Equally as important is the inter-pellet coating uniformity that occurs mainly due to differences in size of pellets in the coating process. In the dissertation, we propose a method of statistical analysis of pellet size distributions, obtained with the machine vision system throughout the coating process, that enables evaluation of the dependence of coating thickness on pellet size, evaluation of coating thickness distribution, and inter-pellet coating uniformity parameters. We conducted several pellet coating experiments in a laboratory-size Wurster coating apparatus that we monitored with the machine vision system. In the dissertation, a wholesome analysis of each experimental coating process is presented, as enabled by the in-line measurements of machine vision system. The in-line results show consistency with the course of each process. We also found a very good agreement with the results of a reference method. Many different analytical methods and procedures are in use for the off-line evaluation of quality parameters of coated pharmaceutical pellets. Pellet samples, collected during the experimental coating processes, were analysed with five additional analytical methods. As part of the dissertation, a quantitative comparison of the results for pellet coating quality parameters measurements is presented together with a qualitative assessment of the methodological features of the methods that affect their adequacy for quality control of coated pharmaceutical pellets. The machine vision system, together with the newly presented methods for analysis of in-line data for the evaluation of the key quality parameters of coated pellets, enables a comprehensive assessment of quality of coated pellets, giving new insight into the coating process. Information obtained through the presented coating analysis could lead to a deeper understanding of the coating process and thus improve the quality control of coated pharmaceutical pellets, which is in accordance with the goals of the PAT guidelines