Managing Raw Materials in the QbD Paradigm, Part 2: Risk Assessment and Communication - Evaluate and communicate risk to stakeholders. - BioPharm International

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Managing Raw Materials in the QbD Paradigm, Part 2: Risk Assessment and Communication
Evaluate and communicate risk to stakeholders.


BioPharm International


Downstream Materials


Table 3. Selected downstream materials
The main purpose of downstream processes is to achieve the desired levels of product purity; the secondary objective is minimizing product loss. Product variants, process by-products such as host cell protein and DNA, and process materials such as media components have to be removed and the product transferred to the final formulation. Purification typically is through a combination of chromatography and filtration steps, but may include other process steps (precipitation, partitioning, and crystallization) as appropriate. Hypothetical scoring for a downstream step is provided in Table 3.

The materials used in chromatography resins generally are innocuous, although there may be some risk for leachables, notably after long-term storage. These usually are characterized by the supplier, and the information is available as a regulatory support file or drug master file. Solvents (ethanol, benzyl alcohol) frequently are used as preservatives, and this also represents the major risk for residual solvents later in the process. Ethanol is a class 3 solvent and represents a low severity (S = 3). Solvent is present in the material as shipped and after storage, but not in the material as used, because resins are washed by a validated washing process before use. Additional consideration should be given for affinity resins where the ligand leaches into the process and specific removal steps may be required for its removal. Protein A is not particularly toxic and is used in approved FDA processes, but does have biological activity as a superantigen,7 which would increase the severity score (S = 5) and require specific removal steps and controls, but is detectable (D = 3). Resins are the primary agent for product purification and poor performance would have a high impact on product quality and yield (S = 7). However, they are not the final step and typically are used in combination with other purification steps. Resin quality is good, and poor performance is seldom observed (O = 3), and normally is detected (D = 3) by changes in purity or yield. Column performance can be tracked by in-line procedures such as transition analysis to monitor continued fitness for purpose. Resins are not interchangeable because the base matrix and resulting profile of impurities from nonspecific binding will vary, depending on the source. Because this represents a single point of failure, supplier selection is critical, and risk may be managed by using different suppliers at different points in the process or in different processes. This is highlighted by the recently published case study from Toro, et al.8 The authors' company received a supply chain notification from a supplier of an ion-exchange resin. Laboratory experiments performed thereafter showed minor differences in the chromatographic profile and pressure drop across the column at different flow rates. The new resin was therefore deemed comparable to the old resin. However, when packed in 20-cm radial columns, significant differences were noticed in the packing properties of the old and the new resins.

Particle size analysis through a laser-diffraction particle size analyzer showed that the average size for the new resin was 126.9–141.7 mm versus 127.2–130.1 mm for the old resin. Thus, the difference in particle size could not be the reason for the difference in packing behavior. Per the authors, "Since we received the SCN sent by our chromatography media supplier, a significant amount of time and resources have been allocated to identify differences caused by that simple change in the supplier's resin liner source." They further state, "That investigation is ongoing, as is additional experimentation on our part." This case study exemplifies the problems faced when changes are made in critical raw materials.

In-line filters are used for maintaining sterility of process streams, concentration, buffer exchange, and virus removal. Filters usually are made of non-interactive materials, and the chief concern, as with guard filters, is the presence of leachables. The effect on the process depends on the specific purpose of the filters; where product passes through the filter there is minimal contribution to the process, but where product is retained, there is the potential for product losses (S = 5). Occurrence and detectability scores typically are low. In the case of viral filters, there are no specific detection methods for viruses. However, filters are validated for viral clearance and if the filter remains integral after use, this can be taken as evidence of successful performance.

Compendial chemicals are used as buffers and cleaning agents. These are well defined and typically well understood. However, problems may arise from handling issues such as clumping or deliquescence, which could affect dispensing, extraneous matter, insoluble materials, and filterability (S = 3). Compendial materials generally are intended to have minimal interaction with product, but the presence of trace components may result in undesirable adducts or modifications. These usually are not of concern until the final stages of the process where there are no remaining steps between the product and the patient. Final formulation and packaging processes transform drug substance to drug product. All remaining product components (active pharmaceutical ingredient, packaging, delivery systems, instructions, labels, and secondary packaging) should be viewed as high risk because of their proximity to the final product.


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