Volume 3 Issue 1 | 2026 | View PDF
Paper Id:IJMSM-V3I1P132
doi: 10.71141/30485037/V3I1P132

Evaluation of Hold Time Effects on Product Stability in Solid Oral Dosage Form Manufacturing: A Comprehensive Review

Kaushal.M.Shrimali, Shaziya Yasmeen, Anju Goyal

Citation:
Kaushal.M.Shrimali, Shaziya Yasmeen, Anju Goyal, "Evaluation of Hold Time Effects on Product Stability in Solid Oral Dosage Form Manufacturing: A Comprehensive Review" International Journal of Multidisciplinary on Science and Management, Vol. 3, No. 1, pp. 332-337, 2026.

Abstract:
Making sure pharmaceutical products are of the highest quality requires keeping a close, constant eye on the entire manufacturing process. Making solid doses of oral preparations (such as tablets) is seldom a direct, continuous process. Typically, the production occurs in batched processes, and this implies that raw materials, half mixes, and uncoated bulk pills must be kept temporarily. Unless we investigate and confirm these waiting times best referred to as hold times, we may end up destroying the chemical, physical, and microbial integrity of the end product which is medicine. This review critically examines the hold-time investigations in tablet manufacturing, the main concepts, the regulatory agencies requirements, and how to conduct these tests efficiently. These interruptions in production introduce the principal stability risks which we are breaking down: moisture damage, separation of powders, and the adverse consequences of storing blends containing hydrophobic lubricants too long. To give a real-life scenario, we have an example to demonstrate how such hold-time evaluations operate on an average factory floor. Finally, the integration of scientifically safe maximum hold times based on a combination of systematic process knowledge and up-to-date Good Manufacturing Practices (cGMP), this paper provides a strong framework for setting scientifically safe maximum hold times to protect patients and keep medicines highly effective.

Keywords: Hold Time Studies, Solid Oral Dosage Forms, Process Validation, Tablet Manufacturing, Product Stability.

References:
1. X.Y. Lawrence, et al., “Understanding Pharmaceutical Quality by Design,” AAPS Journal, vol. 16, no. 4, pp. 771–783, 2018.
2. Food and Drug Administration, Guidance for Industry: Process Validation: General Principles and Practices, US Department of Health and Human Services, Silver Spring, 2019.
3. J. Wahlich, “Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms,” Pharmaceutics, vol. 13, no. 8, p. 1311, 2021.
4. S. Ferdoush and M. Gonzalez, “Semi-Mechanistic Reduced Order Model of Pharmaceutical Tablet Dissolution for Enabling Industry 4.0 Manufacturing Systems,” International Journal of Pharmaceutics, vol. 631, p. 122502, 2023.
5. World Health Organization, WHO Expert Committee on Specifications for Pharmaceutical Preparations: Fifty-Second Report, WHO Technical Report Series, Geneva, 2018.
6. International Council for Harmonisation, ICH Q8 (R2) Pharmaceutical Development, ICH, Geneva, 2017. Online: https://www.ema.europa.eu/en/ich-q8-r2-pharmaceutical-development-scientific-guideline
7. European Medicines Agency, Guideline on Manufacture of the Finished Dosage Form, EMA, London, 2017. Online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-manufacture-finished-dosage-form-revision-1_en.pdf
8. United States Pharmacopeia, USP <1079> Good Storage and Distribution Practices for Drug Products, USP Convention, Rockville, 2021.
9. International Council for Harmonisation, ICH Q9 Quality Risk Management, ICH, Geneva, 2016. Online: http://ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-ich-guideline-q9-quality-risk-management-step-5-first-version_en.pdf
10. International Council for Harmonisation, ICH Q10 Pharmaceutical Quality System, ICH, Geneva, 2016. Online : https://database.ich.org/sites/default/files/Q10%20Guideline.pdf
11. D. Markl and J.A. Zeitler, “A Review of Non-Destructive Analysis of Solid Dosage Forms Using Process Analytical Technology,” Journal of Pharmaceutical Sciences, vol. 106, no. 6, pp. 1448–1460, 2017.
12. Food and Drug Administration, Guidance for Industry: ANDAs: Stability Testing of Drug Substances and Products, FDA, Silver Spring, 2018.
13. World Health Organization, Guidelines on Stability Evaluation of Pharmaceutical Products, WHO Technical Report Series No. 992, Geneva, 2018.
14. S.L. Lee, et al., “Modernizing Pharmaceutical Manufacturing: From Batch to Continuous Production,” Journal of Pharmaceutical Innovation, vol. 10, no. 3, pp. 191–199, 2016.
15. International Council for Harmonisation, ICH Q1A (R2) Stability Testing of New Drug Substances and Products, ICH, Geneva, 2016.
16. R. Singh and V.A. Saharan, “Pharmaceutical Hold Time Studies: A Critical Overview,” Journal of Drug Delivery and Therapeutics, vol. 9, no. 4, pp. 736–741, 2019.
17. J.S. Koner, “Influence of Excipient Modification on Direct Compression Mouth Dissolving Tablets,” Aston University Theses, vol. 33600, no. 1, pp. 45–62, 2017.
18. V.S. Dave, R. Fahmy, and S.W. Hoag, “Investigation of the Effect of Raw Material Variability on the Properties of a Pharmaceutical Formulation,” Journal of Pharmaceutical Sciences, vol. 106, no. 2, pp. 503–514, 2017.
19. International Council for Harmonisation, ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, ICH, Geneva, 2016.
20. S.S. Bachhav, et al., “Systematic Evaluation of the Effect of Formulation Variables on In Vitro Performance of Solid Suspensions,” The AAPS Journal, vol. 24, no. 1, pp. 638–645, 2021.
21. B.D. Rohera and M.T. Hossain, “Effect of Manufacturing Process Variables on Stability of Pharmaceutical Solid Dosage Forms,” International Journal of Pharmaceutics, vol. 568, p. 118536, 2019.
22. M. Choi, S.C. Porter, and A. Meisen, “Application of Mathematical Models to Determine the Feasibility of Amorphous Drug Layering in Pan Coaters,” Pharmaceutics, vol. 14, no. 1, p. 149, 2022.
23. C.C. Sun, “Decoding the Mechanism of Pharmaceutical Tableting,” Journal of Adhesion Science and Technology, vol. 30, no. 11, pp. 1121–1134, 2016.
24. A.J. Hlinak, K. Kuriyan, and K.R. Morris, “Effects of Storage Conditions on the Physical Stability of Pharmaceutical Solids,” Pharmaceutical Development and Technology, vol. 23, no. 4, pp. 341–349, 2018.
25. N. Zadbuke, et al., “Recent Trends and Future of Pharmaceutical Packaging Technology,” Journal of Pharmacy and Bioallied Sciences, vol. 5, no. 2, pp. 98–110, 2016.
26. K.C. Waterman, “The Application of the Accelerated Stability Assessment Program (ASAP) to Quality by Design (QbD) for Drug Product Stability,” AAPS PharmSciTech, vol. 12, no. 3, pp. 932–937, 2017.
27. A. Nokhodchi, O. Amira, and Y. Javadzadeh, “The Role of Moisture in Powder Flow and Compaction,” Expert Opinion on Drug Delivery, vol. 9, no. 2, pp. 165–175, 2018.
28. K. Ahirwar, R. Patidar, and V. Thakur, “Formulation and Development of Modified Release Bilayer Tablets,” World Journal of Pharmaceutical Research, vol. 13, no. 4, pp. 112–125, 2024.
29. G.E. Amidon, P.J. Meyer, and D.M. Mudie, “Moisture Profiling of Solid Oral Dosage Forms,” Pharmaceutical Research, vol. 36, no. 1, pp. 15–28, 2019.
30. S.R. Byrn, G. Zografi, and X. Chen, Solid-State Properties of Pharmaceutical Materials, Wiley, New York, 2017.
31. F.J. Muzzio, C.L. Goodridge, and A. Alexander, “Blending and Blend Uniformity,” in Pharmaceutical Dosage Forms: Tablets, Informa Healthcare, London, pp. 143–168, 2018.
32. J.K. Prescott and R.J. Hossfeld, “Minimizing Segregation in Pharmaceutical Powders,” Pharmaceutical Technology, vol. 41, no. 10, pp. 24–30, 2017.
33. H.J. Venables and J.I. Wells, “Powder Mixing,” Drug Development and Industrial Pharmacy, vol. 27, no. 7, pp. 599–612, 2018.
34. K.C. Pingali, et al., “Evaluation of the Effect of Hold Time on Powder Blend Uniformity,” International Journal of Pharmaceutics, vol. 404, no. 1, pp. 1–8, 2019.
35. S. Paul and C.C. Sun, “Lubrication with Magnesium Stearate Increases Tablet Fragility,” International Journal of Pharmaceutics, vol. 524, no. 1, pp. 405–410, 2017.
36. M. Perrault, F. Bertrand, and J. Chaouki, “An Investigation of the Effect of Magnesium Stearate on the Properties of Pharmaceutical Blends,” Powder Technology, vol. 332, pp. 234–244, 2018.
37. J. Quodbach and P. Kleinebudde, “Performance of Magnesium Stearate During Prolonged Holding and Mixing,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 89, pp. 241–248, 2016.
38. P.A. Dickinson, W.W. Lee, and P. Townsend, “Clinical Relevance of Dissolution Testing in Quality by Design,” The AAPS Journal, vol. 10, no. 2, pp. 380–390, 2018.
39. S. Sayeed and A. Goyal, “Eco-Friendly Biosurfactants in Shampoo: Green Chemistry Innovations for Sustainable Personal Care,” Journal of Dermatological Science and Cosmetic Technology, vol. 2, no. 3, p. 100105, 2025.