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40 Pharmaceutical Technology ® Trends in Manufacturing eBook May 2024 PharmTech.com Qualit y 300 mg/mL, hydrochloric acid and/or sodium hydrox- ide in a quantity sufficient enough for pH adjustment, and water for injection. The liquid after sterilization by sterile filtration is filled into 20-mL vials under asep- tic conditions before being subjected to lyophilization. Water for injection used as a base is removed during lyophilization (4,5). For this case study, it is assumed that the manufacturing batch size is 500 L and the maximum contact time of the final sterilizing grade filter is 12 hours at a temperature of 22.5±2.5 °C. It is also assumed that there is no flushing or rinsing during the manufacturing process. Applying the risk evaluation matrix from Table I and Table II to this case study results in the risk level rating shown in Table IV. The risk sequence will therefore be 3211. As per the manufacturing process provided, there are no steps that can be considered for risk mitigation, and hence the risk mitigation factor is 0. The risk level for level of characterization will be Level A or B. Applying the clauses as defined in Table III, it can be determined that a characterization of Level B will be required for this component. Following the risk assessment, the next step will be to design and execute the extractable test correspond- ing to Level B, as per USP chapters <665> and <1665>, generating the extractables profile and PERLs. Ex- tractables will be further evaluated for patient safety assessment. If the results are proven to be safe for the patient, then the documents will be ready for regula- tory submission. If a patient safety concern arises, then possible risk mitigation steps will have to be included in the man- ufacturing process, or the component may need to be replaced. If the patient safety concern still exists, then the characterization will need to be done by leachables testing followed by re-evaluation for patient safety. If the results are proven safe to the patient, then the docu- ments would be ready for regulatory submission at that point. However, if after the re-evaluation the safety concern still cannot be resolved, then the component will need to be replaced to ensure patient safety. References 1. USP. General Chapter <665>, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. USP–NF (Rockville, Md., 2022). 2. USP. General Chapter <1665>, Characterization and Qualification of Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Prod- ucts and Biopharmaceutical Drug Substances and Products. USP–NF (Rockville, Md., 2024). 3. Shea, J. The Role of BioPhorum Extractables Data in the Effective Adoption of Single-Use Systems. Whitepaper, March 2022. 4. EMA. EMA/178637/2020—Rev.2. Summary on Com- passionate Use (April 3, 2020). 5. FDA. VEKLURY Label. fda.gov, October 2020. ■ Ramesh Raju Mavuleti * , rrajum@gmail.com, is head of operations, Validation Services India. Subhasis Banerjee, PhD, is principal technical application expert, Bioprocessing APAC. Tathagata Ray is consultant, Global Strategy Deployment; all at Merck Life Sciences Pvt, Ltd. K. Vasantakumar Pai, PhD, is professor and chairman, PG Department of studies & research in Industrial Chemistry, Kuvempu University. K. Sreedhara Ranganath Pai, PhD, is professor, Department of Pharmacology, Manipal Academy of Higher Education. Somasundaram Gopalakrishnan is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd. * To whom all correspondence should be addressed. TABLE IV. Risk level rating. Risk dimension Reference from the process stream Risk level rating Duration of contact 12 hours Level 1 Temperature of contact 22.5±2.5°C Level 2 Chemical composition of the process stream/pH of the process stream Aqueous pH of process stream is 3.0 to 4.0 Level 1 Chemical composition of the component/method of sterilization of the component The component is sterilized by gamma irradiation as a part of the assembly Level 3