Application of artificial neural networks in the optimization of lyophilization process in the production of esomeprazole powder for solution for injections/infusions

Abstract

Cilj ovog istraživanja bio je definisanje kritičnih parametara proizvodnje i optimizacija procesa proizvodnje esomeprazol praška za rastvor za injekciju/infuziju, 40 mg postupkom liofilizacije, kako bi se obezbedio odgovarajući kvalitet uvećane serije leka tokom roka upotrebe. Istraživanje se sastojalo iz tri dela. U prvom delu istraživanja ispitana je kinetika degradacije lekovite supstance esomeprazol-natrijum u farmaceutskom obliku prašak za rastvor za injekciju/infuziju, izvršena je identifikacija nečistoća koje su posledica degradacije lekovite supstance i ispitana je stabilnost rekonstituisanog proizvoda. U ovom delu istraživanja je utvrđen uticaj faktora formulacije, kritičnih proizvodnih koraka i kritičnih delova opreme/sistema na mogućnost dobijanja stabilnog gotovog proizvoda uvećanih serija (scale-up sa 17.000 na 33.000 bočica). Detaljno su ispitane fizičko-hemijske karakteristike i mikrobiološki kvalitet uvećanih serija kod kojih je varirana temperatura kojoj su izložene napunjene bočice pre početka programa liofilizacije od 20 ℃, -5 ℃, -15 ℃, -30 ℃ (korak pre-zamrzavanja). Ispitano je i maksimalno vreme koje delimično zatvorene napunjene bočice rastvorom esomeprazola mogu da provedu od trenutka punjenja do momenta početka liofilizacije na navedenim temperaturama. Utvrđeno je da punjenje liofilizatora na temperaturi polica od -30 ℃ u poređenju sa temperaturom od 20 ℃, značajno produžava vreme za koje rastvor esomeprazola ostaje stabilan i bez promena njegovih fizičko-hemijskih i mikrobioloških karakteristika. Pre-zamrzavanje na temperaturi od -30 ℃ je dovoljno da obezbedi direktno zamrzavanje rastvora u svim bočicama, pri čemu rastvor postaje inertan i na taj način sprečava da dođe do snižavanja pH vrednosti usled izlaganja rastvora kiseoniku. Dobijeni rezultati su potvrdili da definisani parametri procesa i ispitivanje u toku procesa, zajedno sa korakom pre-zamrzavanja, obezbeđuju pouzdanu i ponovljivu proizvodnju esomeprazol praška za rastvor za injekciju/infuziju, ispunjavajući sve unapred definisane atribute kvaliteta i specifikacije za finalni proizvod. U drugoj fazi, na osnovu dobijenih podataka o proizvodu i procesu proizvodnje iz prve faze istraživanja, primenom Quality by design (QbD) koncepta, u okviru FMEA (engl. Failure Mode and Effects Analysis - Analiza efekata u slučaju neizvršenja (FMEA)) analize rizika, definisani su svi CQA (engl. Critical Quality Attributes - kritični atributi kvaliteta (CQA)) sa najvećim RPN skorom (engl. Risk Priority Number – prioritetni broj rizika (RPN)). Na osnovu CQA, najkritičnijih za postizanje željenog kvaliteta esomeprazol praška za rastvor za injekciju/infuziju, procenjene su sve varijable formulacije i proizvodnog procesa koje potencijalno mogu uticati na dobijanje rezultata izvan specifikacije. One promenljive formulacije i procesa za koje je pokazano da je obezbeđen odgovarajući kvalitet proizvoda su izostavljene iz daljeg razmatranja. Sa druge strane, temperatura (sobna temperatura, temperatura polica, temperatura zamrzavanja) kojoj je proizvod izložen, kao i vremensko trajanje ove izloženosti (vreme zadržavanja), koje su korelirane kao kritični parametri procesa sa promenama pH vrednosti rastvora kao CQA, uz sadržaj esomeprazola i srodnih supstanci, su dalje razmatrani i korišćeni su kao ulazni podaci za definisanje design space-a (prostor za dizajniranje kvaliteta). Za treniranje veštačke neuronske mreže tipa višeslojnog perceptrona (engl. Multi Layer Perceptron - MLP) korišćenjeni su rezultati 32 eksperimentalne probe iz prve faze. Mreža koja najbolje opisuje uticaj navedenih ulaznih promenljivih na pH vrednost rastvora je odabrana, a na osnovu dobijenih rezultata definisan je design space za liofilizaciju uvećanih serija koji opisuju granice temperature polica (-10 ℃ do -30 ℃) i vreme koje delimično zatvorene bočice mogu da provedu izložene vazduhu (5 – 26 h), a da pH vrednost rastvora ostane u granicama specifikacije (pH 10,8-11,8)...The goal of this research was to define critical production parameters and optimize the lyophilization process in the production of esomeprazole 40 mg powder for solution for injection/infusion, which will ensure the quality of the drug of the enlarged batches during the declared shelf life. The research consisted of three parts. In the first part of the research, the kinetics of the degradation of the active pharmaceutical ingredient (API) esomeprazole sodium in the pharmaceutical form of lyophilisate for injections was examined, where the impurities resulting from the degradation of the API were identified and the stability of the reconstituted product was examined. In this part of the research, the influence of formulation factors, critical production steps and critical parts of the equipment/system on the possibility of obtaining a stable finished product of an enlarged batches (scale-up from 17,000 to 33,000 vials) was also determined. The physico-chemical and microbiological results obtained for the scale-up batches, where the temperature to which the filled vials were exposed after filling and before the start of the lyophilization program was varied from 20℃, -5℃, -15℃, -30℃ (pre-freezing step), were examined. The maximum time that partially closed vials filled with esomeprazole solution can spend from the moment of filling, to the moment of lyophilization, at the given temperatures, was also tested. It was found that filling the lyophilizer at a shelf temperature of -30℃, compared to a temperature of 20℃, significantly increases the time for which the esomeprazole solution remains stable and without changes in its physicochemical and microbiological characteristics. Pre-freezing at a temperature corresponding to that of the first step of the lyophilization program (freezing step - at a temperature of -30℃), is sufficient to ensure direct freezing of the solution in all vials, whereby the solution becomes inert and prevents pH decrease due to exposure to oxygen. The results obtained in this way confirmed that the defined process parameters and in-process testing, together with the pre-freezing step, ensure reliable and reproducible production of esomeprazole lyophilisate for solution for injection/infusion, meeting all predefined quality attributes and specifications for the final product. In the second phase, based on the knowledge about the product and the production process from the first phase of research, applying the Quality by design (QbD) concept, within the FMEA (Failure Mode and Effects Analysis) risk analysis, all CQAs (Critical Quality Attributes) with the highest RPN score (risk priority number) are defined. Based on CQA, the most critical for achieving the desired quality of esomeprazole powder for solution for injection/infusion, all formulation and manufacturing process variables that could potentially affect obtaining results outside the specification were evaluated. Those formulations and process variables for which there is a proven assurance of good control and a positive experience in ensuring adequate product quality, are omitted from further consideration. On the other hand, the temperature (room temperature, shelf temperature, freezing temperature) to which the product is exposed, as well as the duration of this exposure (holding time), which were correlated as critical process parameters with changes in the pH value of the solution as CQA, and also with assay of esomeprazole and related substances, were further considered and used as input data to define the design space. An artificial neural network with multi-layer perceptron (MLP) was trained using the results of 32 experimental trials from the first phase. The network that best describes the influence of these input variables on the pH value of the solution was selected, and based on the obtained results, a design space was defined for the lyophilization of scale-up batches that describe the shelf temperature limits (-10℃ to -30℃) and the time that partially closed vials can spent exposed to air (5-26h), while the pH value of the solution remains within the specification limits (10.8-11.8)..