Control Strategy Considerations for the Continuous Manufacturing of Low-dose Oral Solid Dosage Formulations

Badman C, Cooney CL, Florence A, Konstantinov K, Krumme M, Mascia S, et al. Why we need continuous pharmaceutical manufacturing and how to make it happen. J Pharm Sci. 2019;108(11):3521–3. https://doi.org/10.1016/j.xphs.2019.07.016.

Article  CAS  PubMed  Google Scholar 

Vanhoorne V, Vervaet C. Recent progress in continuous manufacturing of oral solid dosage forms. Int J Pharm. 2020;579:119194. https://doi.org/10.1016/j.ijpharm.2020.119194.

Article  CAS  PubMed  Google Scholar 

Lee SL, O’Connor TF, Yang X, Cruz CN, Chatterjee S, Madurawe RD, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov. 2015;10(3):191–9. https://doi.org/10.1007/s12247-015-9215-8.

Article  Google Scholar 

Williams JC. Continuous mixing of solids. A review. Powder Technol. 1976;15(2):237–43. https://doi.org/10.1016/0032-5910(76)80052-6.

Article  Google Scholar 

Gao Y, Vanarase A, Muzzio F, Ierapetritou M. Characterizing continuous powder mixing using residence time distribution. Chem Eng Sci. 2011;66(3):417–25. https://doi.org/10.1016/j.ces.2010.10.045.

Article  CAS  Google Scholar 

Bautista M, Maurer R, Rolinger L, Gavi E. Piccione PM. Overview and control strategy insights. American Pharmaceutical Review: Mini-batch continuous direct compression; 2022. p. 1–8.

Google Scholar 

Karttunen AP, Poms J, Sacher S, Sparén A, Ruiz Samblás C, Fransson M, et al. Robustness of a continuous direct compression line against disturbances in feeding. Int J Pharm. 2020;574:118882. https://doi.org/10.1016/j.ijpharm.2019.118882.

Article  CAS  PubMed  Google Scholar 

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Continuous manufacturing of drug substances and drug products, Q13. In: ICH harmonised guideline. 2022. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf. Accessed 24 Apr 2026.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical quality system, Q10. In: ICH harmonized tripartite guideline. 2008. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf. Accessed 24 Apr 2026.

Laske S, Paudel A, Scheibelhofer O, Sacher S, Hoermann T, Khinast J, et al. A review of PAT strategies in secondary solid oral dosage manufacturing of small molecules. J Pharm Sci. 2017;106(3):667–712. https://doi.org/10.1016/j.xphs.2016.11.011.

Article  CAS  PubMed  Google Scholar 

Almaya A, De Belder L, Meyer R, Nagapudi K, Lin H-R, Leavesley I, et al. Control strategies for drug product continuous direct compression—state of control, product collection strategies, and startup/shutdown operations for the production of clinical trial materials and commercial products. J Pharm Sci. 2017;106(4):930–43. https://doi.org/10.1016/j.xphs.2016.12.014.

Article  CAS  PubMed  Google Scholar 

Tantuccio ABA. Control strategy development for CM of OSD forms. In: ISPE good practice guide. 2025. https://ispe.org/publications/guidance-documents/good-practice-guide-control-strategy-development-cm-osd-forms. Accessed 24 Apr 2026.

Wang Y. Continuous Manufacturing: Commonly Asked Questions during Manufacturing Assessment. IFPAC Annual Meeting. N. Bethesda, MD, USA2022.

Kashinath KP, Sanjay LR, Ashokbhai MK, Roy S, Sardar MS, Kaity S. Continuous manufacturing based paradigm shift in pharmaceuticals production and current regulatory framework. Chem Eng Res Des. 2025;215:1–22. https://doi.org/10.1016/j.cherd.2025.01.003.

Article  CAS  Google Scholar 

Harms ZD, Shi Z, Kulkarni RA, Myers DP. Characterization of near-infrared and Raman spectroscopy for in-line monitoring of a low-drug load formulation in a continuous manufacturing process. Anal Chem. 2019;91(13):8045–53. https://doi.org/10.1021/acs.analchem.8b05002.

Article  CAS  PubMed  Google Scholar 

Center for Drug Evaluation and Research, Food and Drug Administration. Considerations for complying with 21 CFR 211.110. In: Guidance for industry (draft). 2025. https://www.fda.gov/media/184825/download. Accessed 26 Apr 2026.

Meza CP, Santos MA, Romañach RJ. Quantitation of drug content in a low dosage formulation by transmission near infrared spectroscopy. AAPS PharmSciTech. 2006;7(1):E206–14. https://doi.org/10.1208/pt070129.

Article  PubMed  Google Scholar 

Doddridge GD, Shi Z. Multivariate figures of merit (FOM) investigation on the effect of instrument parameters on a Fourier transform-near infrared spectroscopy (FT-NIRS) based content uniformity method on core tablets. J Pharm Biomed Anal. 2015;102:535–43. https://doi.org/10.1016/j.jpba.2014.10.019.

Article  CAS  PubMed  Google Scholar 

Griffen JA, Owen AW, Matousek P. Quantifying low levels (<0.5% w/w) of warfarin sodium salts in oral solid dose forms using transmission Raman spectroscopy. J Pharm Biomed Anal. 2018;155:276–83. https://doi.org/10.1016/j.jpba.2018.04.008.

Article  CAS  PubMed  Google Scholar 

De Leersnyder F, Peeters E, Djalabi H, Vanhoorne V, Van Snick B, Hong K, et al. Development and validation of an in-line NIR spectroscopic method for continuous blend potency determination in the feed frame of a tablet press. J Pharm Biomed Anal. 2018;151:274–83. https://doi.org/10.1016/j.jpba.2018.01.032.

Article  CAS  PubMed  Google Scholar 

De Leersnyder F, Vanhoorne V, Kumar A, Vervaet C, De Beer T. Evaluation of an in-line NIR spectroscopic method for the determination of the residence time in a tablet press. Int J Pharm. 2019;565:358–66. https://doi.org/10.1016/j.ijpharm.2019.05.006.

Article  CAS  PubMed  Google Scholar 

Sierra-Vega NO, Martínez-Cartagena PA, Alvarado-Hernández BB, Romañach RJ, Méndez R. In-line monitoring of low drug concentration of flowing powders in a new sampler device. Int J Pharm. 2020;583:119358. https://doi.org/10.1016/j.ijpharm.2020.119358.

Article  CAS  PubMed  Google Scholar 

Ortega-Zúñiga C, la Rosa C-D, Román-Ospino AD, Serrano-Vargas A, Romañach RJ, Méndez R. Development of near infrared spectroscopic calibration models for in-line determination of low drug concentration, bulk density, and relative specific void volume within a feed frame. J Pharm Biomed Anal. 2019;164:211–22. https://doi.org/10.1016/j.jpba.2018.10.046.

Article  CAS  PubMed  Google Scholar 

Velez-Silva NL, Drennen JK 3rd, Anderson CA. Continuous manufacturing of pharmaceutical products: a density-insensitive near infrared method for the in-line monitoring of continuous powder streams. Int J Pharm. 2024;650:123699. https://doi.org/10.1016/j.ijpharm.2023.123699.

Sierra-Vega NO, Sánchez-Paternina A, Maldonado N, Cárdenas V, Romañach RJ, Méndez R. In line monitoring of the powder flow behavior and drug content in a Fette 3090 feed frame at different operating conditions using near infrared spectroscopy. J Pharm Biomed Anal. 2018;154:384–96. https://doi.org/10.1016/j.jpba.2018.03.017.

Article  CAS  PubMed  Google Scholar 

Sierra-Vega NO, Romañach RJ, Méndez R. Real-time quantification of low-dose cohesive formulations within a sampling interface for flowing powders. Int J Pharm. 2020. https://doi.org/10.1016/j.ijpharm.2020.119726.

Article  PubMed  Google Scholar 

Rangel-Gil RS, Sierra-Vega NO, Romañach RJ, Méndez R. Assessment of blend uniformity in a stream sampler device using Raman spectroscopy. Int J Pharm. 2023;639:122934. https://doi.org/10.1016/j.ijpharm.2023.122934.

Article  CAS  PubMed  Google Scholar 

Rangel-Gil RS, Nasrala-Álvarez JM, Romañach RJ, Méndez R. Blend uniformity monitoring in a continuous manufacturing mixing process for a low-dosage formulation using a stream sampler and near infrared spectroscopy. Int J Pharm. 2024;661:124478. https://doi.org/10.1016/j.ijpharm.2024.124478.

Article  CAS  PubMed  Google Scholar 

Román-Ospino AD, Baranwal Y, Li J, Vargas J, Igne B, Bate S, et al. Sampling optimization for blend monitoring of a low dose formulation in a tablet press feed frame using spatially resolved near-infrared spectroscopy. Int J Pharm. 2021;602:120594. https://doi.org/10.1016/j.ijpharm.2021.120594.

Article  CAS  PubMed  Google Scholar 

Mateo-Ortiz D, Colon Y, Romañach RJ, Méndez R. Analysis of powder phenomena inside a Fette 3090 feed frame using in-line NIR spectroscopy. J Pharm Biomed Anal. 2014;100:40–9. https://doi.org/10.1016/j.jpba.2014.07.014.

Article  CAS  PubMed  Google Scholar 

Ortega-Zúñiga CA, Román-Ospino AD, Gupta S, Omar T, Baranwal Y, Sanchez-Paternina A, et al. Real-time monitoring of small changes in powder blends and ejected tablets in a low-dose formulation with 1 %w/w of active pharmaceutical ingredient using Raman and near-infrared spatially resolved spectroscopy within a tablet press. Int J Pharm. 2025;670:125165. https://doi.org/10.1016/j.ijpharm.2025.125165.

Article  CAS  PubMed  Google Scholar 

De Man A, De Souter L, Shi Z, Mao C, De Beer T. Evaluating the improvement of blend potency measurements in the feed frame of a rotary tablet press using combined NIR and Raman spectroscopy. Anal Chem. 2024;96(26):10586–93. https://doi.org/10.1021/acs.analchem.4c01134.

Article  CAS  PubMed  Google Scholar 

Galata DL, Domokos A, Démuth B, Záhonyi P, Fülöp G, Nagy ZK, et al. In-line indirect concentration measurement of ultralow dose API during twin-screw wet granulation based on NIR and Raman spectroscopy. Int J Pharm. 2024;664:124650. https://doi.org/10.1016/j.ijpharm.2024.124650.

Comments (0)

No login
gif