Strategic Changes to a Legacy Cleaning Approach Result in a More Sustainable Process

A standard pharmaceutical or biopharmaceutical process equipment cleaning cycle consists of an initial rinse, caustic wash, intermediate rinse, acid wash, and then a series of post-acid rinses ending with a final purified water rinse and drying step. The current good manufacturing practice (CGMP) regulations define critical process parameters (CPPs) and predetermined critical quality attributes (CQAs) applicable to a cleaning cycle. The desire for a more environmentally sustainable cleaning cycle had previously led to recovery of final rinse water to be used for the initial rinse step; change to formulated chemistries to reduce chemical consumption, impact on the environment and waste treatment; and change in cleaning temperature to decrease energy and cycle time. In this article, the authors explore removing the intermediate rinse and blow down step before the acid wash for a biopharmaceutical upstream and downstream process step resulting in both rinse volume and time savings. A short blow down will still be recommended to reduce residual liquid in the system between washes.

An acid wash may not be required for all cleaning cycles, but this step helps remove inorganic residues (e.g., iron oxide) on the surface, provides continuous maintenance of the chromium oxide passive surface, neutralizes wastewater, and reduces bioburden.

Risk assessment of process change

The elimination of a water rinse and blow down between the caustic and acid wash steps seems practical, but before being considered, an evaluation should be performed with an assessment of the risks, controls in place to mitigate the risk, and monitoring of the cleaning process to ensure continuous control of the validated state. A list of questions and answers (see Table I) based on the International Conference for Harmonisation (ICH) Q9 Quality Risk Management guideline helps in the risk assessment process (1). Common sources of hazards in the pharmaceutical industry include handling and storage, human error, emissions, use of volatile organic compounds, reactions, and leaks of effluents (2). The identified concerns from the risk assessment include: a change in the cleaning solution temperature due to an exothermic reaction when mixing caustic and acid solutions, potential off gassing of chemical compounds, and redeposition of residues removed during the caustic wash step (3–5). To investigate these concerns, it is important to know the exact chemical formulation of both caustic and acid cleaning agents. The physical properties of the acid rinse solution were assessed with temperature and pH checks, using different ratios of caustic and acid solutions. The volatile chemicals were assessed using gas chromatography with mass spectrometry (GC–MS). The cleaning and rinsing of the caustic cleaner, followed by the acid cleaner was also investigated using 304 stainless-steel coated surfaces.

Testing strategy to investigate process risk

All changes to CGMP processes require a change review, and based on the significance of the change, a new validation or revalidation may be required. For an automated cleaning process, this may include repeating the spray device coverage testing, ensuring the cleaning equipment has been commissioned and validated, and confirming that the rinse water recovery is consistent with surface cleanliness.

Peer-reviewed

Submitted: Aug. 5, 2024
Accepted: Aug. 30, 2024.

References

1. ICH. Q9 Quality Risk Management, Step 4 version (2005).
2. Bhusnure, O. G.; Dongare, R. B.; Gholve, P. S.; et.al., Chemical Hazards and Safety Management in Pharmaceutical Industry. J. Pharm. Res. (Mohali, India) 2018, 12 (3).
3. Dermaut, W. Chapter 3: Process Safety and Reaction Hazard Assessment. In Chemical Engineering in the Pharmaceutical Industry: Active Pharmaceutical Ingredients,2nd ed.; am Ende, D. J.; am Ende M. T., Eds.; John Wiley & Sons, 2019. DOI:10.1002/9781119600800
4. Allian, A. D.; Shah, N. P.; Ferretti, A. C.; et.al., Process Safety in the Pharmaceutical Industry—Part 1: Thermal and Reaction Hazard Evaluation Processes and Techniques. Org. Process Res. Dev. 2020, 24 (11), 2529–2548. DOI: 10.1021/acs.oprd.0c00226
5. Agarwal, P.; Goyal, A.; Rajat, V. Chemical Hazards in Pharmaceutical Industry: An Overview. Asian J. Pharm. Clin. Res. 2018, 11 (2). DOI: 10.22159/ajpcr.2018.v11i2.23160

About the authors

Dayna Turner is group leader, Science & Technology; Dijana Hadziselimovic is laboratory manager, Technical Services; Paul Lopolito is director, Technical Services; Mary Schanne is senior account manager; and Amy Thanavaro is manager, Science & Technology; all at STERIS, Saint Louis, Mo. Jeff Felker is deputy director, Cleaning Validation SME, Sanofi MSAT Swiftwater, Pa.

Article details

BioPharm International®
Vol. 37, No. 9
October 2024
Pages: 23–28

Citation

When referring to this article, please cite it as Turner, D.; Hadziselimovic, D.; Lopolito, P.; et al. Strategic Changes to a Legacy Cleaning Approach Result in a More Sustainable Process. BioPharm International 2024, 37 (9), 23–28.