| Abstract | Cilj istraživanja
Cilj ovog specijalističkog rada je dati uvid u aktualna glavna razmatranja o kritičnim procesnim
parametrima, prikazati alate procesne analitičke tehnologije za praćenje procesa proizvodnje u
stvarnom vremenu i osiguranja kritičnih atributa kvalitete gotovog lijeka te kao takav biti
koristan alat za usmjeravanje u daljnje proučavanje literature i primjenu procesne analitičke
tehnologije u proizvodnom procesu. Radom će se posebno osvijestiti važnost kontinuirane
kontrole procesa proizvodnje u svrhu izrade djelotvornih, sigurnih i kvalitetnih lijekova.
Materijali i metode
Istraživanja u okviru specijalističkog rada teorijskog su karaktera. Pretraživanjem odgovarajuće
stručne i znanstvene literature, regulatornih smjernica, zakona i pravilnika, prikupljeni su
podaci o zahtjevima kontrola procesa proizvodnje čvrstih farmaceutskih oblika. Okosnicu
regulatornih zahtjeva čine smjernice dobre proizvođačke prakse (GMP prema engl. Good
Manufacturing Practice), nacionalna legislativa Zakon o lijekovima i popratni pravilnici,
Europska farmakopeja i ICH smjernice (ICH prema engl. International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). Bibliografske
baze podataka kao što su PubMed, Science Direct, ResearchGate, National Library of Medicine,
Scopus, Web of Science korištene su za prikupljanje podataka o kritičnim procesnim
parametrima, kritičnim atributima kvalitete, kontrolnoj strategija proizvoda, procesnoj
analitičkoj tehnologiji (PAT) i primjeni iste u farmaceutskoj proizvodnji, kontroli procesa
proizvodnje, NIR spektrometriji, Ramanovoj spektrometriji, kontinuiranoj farmaceutskoj
proizvodnji tableta.
Rezultati
Rezultati su prikazani kroz regulatorne zahtjeve za validacijom proizvodnog procesa,
kontinuiranu proizvodnju i primjenu PAT alata u farmaceutskoj proizvodnji čvrstih oblika.
Regulatorni aspekt prikazuje zahtjev dobre proizvođačke prakse za pristupom validaciji procesa
i kontinuiranoj procesnoj verifikaciji. Također prikazuje zahtjeve kontinuirane farmaceutske
proizvodnje, osiguranje kvalitete gotovog proizvoda, praćenjem i kontrolom proizvodnog
procesa. Prikazani su najčešći kritični procesni parametri te njihov utjecaj na kritične atribute
kvalitete u proizvodnji čvrstih farmaceutskih oblika. Jednako tako opisana je kontrolna
strategija proizvoda i primjene PAT alata, te vrste PAT alata koji se mogu primijeniti u izradi
tableta i filmom obloženih tableta, kao i način regulacije proizvodnog procesa upotrebom
podataka u realnom vremenu.
Zaključak
Za postizanje visoke kvalitete lijeka, ključno je u razvojnoj fazi proučiti kritične atribute
materijala, definirati kritične atribute kvalitete i procesne parametre. Regulativne smjernice
potiču znanstveni pristup razvoju farmaceutskog proizvoda primjenom načela kvalitete
ugrađene dizajnom (engl. Quality by Design, QbD). Validacija procesa ili kontinuirana
procesna verifikacija (engl. Continued process verification, CPV) su neophodni prije puštanja
lijeka na tržište. Hibridni pristup validacije kombinira tradicionalni i kontinuirani pristup.
Korištenje naprednih alata poput PAT-a, uključujući in-line i on-line tehnologije, podržava
praćenje kvalitete u stvarnom vremenu. Kontinuirana farmaceutska proizvodnja se smatra
optimalnim izborom za visoko opasne lijekove, ali zahtijeva posebnu opremu. Pravilna
strategija praćenja procesa i daljnji razvoj tehnologije, uključujući umjetnu inteligenciju, čine
ključne faktore prema Pharma 4.0. temeljenom na QbD. |
| Abstract (english) | Objectives
The aim of this reasrch is to provide an insight into the current key considerations of critical
process parameters, to present the tools of process analytics to monitor the production process
in real time and to ensure the critical attributes of the quality of the finished drug product, and
thus to be a useful tool for further literature studies and the application of process analytical
technologies in the production process. Most importantly, the work will raise awareness of the
importance of continuous control of the production process for the manufacture of effective,
safe and high quality medicinal products.
Materials and Methods
The research in the context of the technical paper is of a theoretical nature. By searching the
relevant technical and scientific literature, regulatory guidelines, laws and regulations, data was
collected on the control requirements for the production process of solid pharmaceutical forms.
The backbone of the regulatory requirements is formed by the Good Manufacturing Practise
(GMP) guidelines, national legislation, the Medicinal Products Act and associated regulations,
the European Pharmacopoeia and the ICH guidelines (ICH stands for International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). Bibliographic
databases such as PubMed, Science Direct, ResearchGate, National Library of Medicine,
Scopus, Web of Science were used to collect data on critical process parameters, critical quality
attributes, product control strategies, process analytical technology (PAT) and its application in
pharmaceutical production, production process control, NIR spectrometry, Raman
spectrometry, continuous pharmaceutical production of tablets.
Results
The results are presented on the basis of the regulatory requirements for validation of the
production process, continuous production and the application of PAT tools in pharmaceutical
production of solid forms. The regulatory aspect shows the requirements of good manufacturing
practise for access to process validation and continuous process verification. It also shows the
requirements for continuous pharmaceutical production, ensuring the quality of the final
product, monitoring and control of the production process. The most common critical process
parameters and their impact on critical quality characteristics in the production of solid
pharmaceutical forms are presented. The product control strategy and the application of PAT
tools and the types of PAT tools that can be used in the production of tablets and film-coated
tablets are described, as well as the regulation of the production process using real-time data.
Conclusion
To achieve high quality of the finished drug product, it is crucial to analyse the critical
properties of the material and define the critical quality characteristics and process parameters
in the development phase. Regulatory guidelines promote a scientific approach to development
of pharmaceutical product using quality by design approach (QbD). Process validation or
continuous process verification (CPV) is necessary before a drug is commercialised. A hybrid
approach to validation combines traditional and continuous approaches. The use of advanced
tools such as PAT, including in-line and on-line technologies, supports real-time quality
monitoring. Continuous pharmaceutical production is considered the optimal choice for highly
hazardous drugs but requires specialised equipment. An appropriate process monitoring
strategy and the further development of technology, including artificial intelligence, are key
factors on the road to Pharma 4.0. based on QbD. |
