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www.biopharminternational.com Partnerships for Outsourcing eBook May 2023 BioPharm International ® 15 Process De veloPment This package of information, alongside knowledge of the process in question, allows a developer to use its in-house toolbox for design of experiments (DoE) and process characterization. If it is a different type of mAb, or the assumptions do not fit, then the FMEA will help to define the specific CQAs and process pa- rameters for that molecule. CQAs have been documented for typical mAbs, and this information can be combined with experience as part of a mAb platform approach. It is important to consider that some molecules will (or may) fall outside of the typical CQA range, and it is therefore important to assess what is known about the molecule in ques- tion in the early stages of its development. A list of some of the common CQAs for a mAb is given in Table I. Based on a risk assessment, a test- ing plan that considers the criticality of product attri- butes should be formulated with at least one analytical method associated for each CQA. A f low chart, such as the one shown in Figure 2, can be used to assist in classifying all of the process parameters for each unit operation. If their variability has an impact on the CQA, the parameters may be considered critical. FMEA is a common risk assessment tool used to identif y potential points of failure. If a process pa- rameter is outside of a defined range, the subsequent impact on the quality attributes is assessed. If a pro- cess parameter is deemed to be well-controlled by the risk assessment, with variability unlikely to fall out- side the normal operating range (NOR), then the risk may be small, and further experiments may not be required. If uncertainty is at a higher level, then ex- perimentation should be discussed and, for high-risk classifications, is highly recommended. While these experiments are performed on a small scale in the laboratory, it is important to ensure that they remain representative of large-scale current good manufacturing practice (CGMP) manufacturing. De- pending on the scale-down model, either low-volume bioreactors or laboratory-based systems can be used to perform the experiments required by the FMEA. Further downstream, bench-scale equipment will also be used, and with the process being flexible, can be adapted as required to meet the needs ofan individual project. Studies may be one factor at a time (OFAT), or a min- imum and maximum challenge, which evaluates the extremes at either end of the range. An alternative ap- proach is to use a multifactor DoE, which investigates multiple variables simultaneously, and the potential interactions between them. The most appropriate for- mat will then be selected based on the input of a team of subject matter experts with prior knowledge of the process for that particular product. Ultimately, the ex- periments will enable a risk matrix to be constructed for each unit operation, whether it is running a process in a bioreactor, for example, or a downstream process, such as a column chromatography purification. If a process is not completely locked or optimization is not fully completed, there is a risk that rework will be required. TABLE I. Typical critical quality attributes for a monoclonal antibody. Product variants Process impurities Purity/potency Aggregation Microbiological Purity SEC Purity Conformation Viral Purity Glycosylation Profile C-Terminal Lysine DNA Concentration Deamidated Isoforms HCP pH Disulfide Bonds Protein A Bioburden/Sterility Fragmentation Selective Agent Appearance Glycation Cell Culture Media Particle Free (Essentially) Glycosylation Components Product/Excipient Conc Oxidation Purification Buffer Osmolality Thioether Link Components pH Sterility PFS/Device Functionality