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38 BioPharm International eBook October 2020 www.biopharminternational.com Regulatory Sourcebook Process Development in the risk analysis, are controlled by means of suitable actions. The PPQ protocol should at least describe the following topics: • Validation approach (i.e., tra- ditional, hybrid, or continu- ous, according to references [6] and [7]) • CQA, CPP, and other param- eters (e.g., yield) to be inves- tigated including acceptance criteria • The number of batches to be manufactured • B r a c k e t i n g / m a t r i x i n g approaches, if applicable • Process for release and certifi- cation of batches, if applicable (prospective validation, con- current validation) • T he number of batches for which additional monitoring is proposed. At the end of the activ ities, data must be collected and reviewed against predetermined acceptance criteria of the validation protocol and fully documented in PV reports. Suitable statistical tools for tradi- tional PPQ data analysis are sum- marized in Table VI. CONTINUED PROCESS VERIFICATION (CPV) Aim of this stage (stage 3) is to assure the control of CPP and CQA through the entire lifecycle. Several aspects must be assessed (and possibly documented in a protocol) to establish an appro- priate level of process control and detect unplanned deviations from Formulation attributes and study design Applicability Liquid product Freeze-dried product Before freeze-drying After reconstitution Optimization of solubility and stability: solution pH and buffer composition to achieve target pH • Perform pH-solubility and pH-stability experiment aimed to optimize either the compounding step (e.g., API dissolution time) and/or the final pH of the solution • Optimize buffer concentration (stability for liquids; stability and/or solid state of the drug as a freeze-dried solid) X X X Optimization of compounding process: API stability as a function of temperature • Perform API solubilization studies on solution with optimized pH and buffer at different temperatures (influence on stability and/or process time) X X X Optimization of formulation: co-solvent • Evaluate the need to include an organic co-solvent to improve API stability in aqueous solution and/or reconstitution time X X Optimization of formulation: acid or base for titration (in case of in-situ salt formation of the API): • Evaluate concentration and addition rate of titrant (influence on localized, transient pH overshoot) • Evaluate solution temperature during titration (influence on process time and/or drug stability) • Evaluate stirring method (influence on both of the above) X X Optimization of formulation and process: drug concentration (fill volume and vial size) • Perform studies at different drug concentrations to evaluate the influence on drug stability (for liquids), the influence on the lyophilization process (e.g., resistance to water vapor transfer) and drug stability also considering solid state of the drug as a freeze-dried solid X X Optimization of formulation composition: stability and tonicity • Optimize the concentration and type (e.g., ionic or non-ionic) of the tonicity agent • Evaluate reconstitution diluent (for freeze-dried solid) X X Optimization of formulation composition: bulking agent • Perform studies at different concentrations to optimize the level • Evaluate the physical appearance of the cake, the solid-state properties of the cake and drug stability at different concentrations or at the optimized concentration of the bulking agent X Optimization of formulation: preservative level (if multi-dose presentation) • Perform antimicrobial effectiveness testing at different levels of preservatives and set appropriate stability specifications for preservatives to maintain antimicrobial effectiveness through shelf life of the product X Optimization of process: component order of addition • Perform experiments to evaluate the influence of order of addition on process time and/or drug stability X X Formulation characterization: thermal behavior and key temperatures • Temperature of complete solidification (e.g., with DSC) • Eutectic (for crystalline products) or glass transition (for amorphous products) temperature (e.g., with DSC) • Collapse temperature (e.g., with freeze-drying microscope) X Optimization of process: closure system formulation and design • Evaluate the influence of different rubber stoppers on drug stability (e.g., transfer of moisture from the stopper) • Evaluate the influence of different closure configurations (e.g., "igloo" or "flutes") on lyophilization process time and on machinability X X X Table V. Key formulation development studies for a freeze-dried and a liquid product. DSC is differential scanning calorimetry.