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


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

BioPharm International


Before performing a risk assessment, it is necessary to establish a list of CQAs from the target product profile (TPP) of the molecule in question to establish what is being affected by the material in question.3,4 These can be product related, such as aggregates, deamidated isoforms, incorrectly folded product, or different glycoforms; or process related, such as DNA, host cell protein, cell culture medium components, or purification components.5 Drug product materials also may include materials of construction, dimensionality, labels, and instructions. A more detailed list of product quality attributes, and a discussion of quality attributes is given elsewhere.6

A risk assessment is also a valuable exercise in knowledge management, because it brings together cross-functional teams from quality, manufacturing, and early- and late-stage development. Teams should assemble internal and external knowledge, and information from in vitro, animal, and human clinical studies. The quality of the risk assessment can be highly dependent on the team composition and dynamics, and it is critical to have experienced team members and facilitators available to ensure that all voices are heard. It is strongly recommended to run the meeting face-to-face. It is also recommended that the team begin with the most critical operations near the end of the process and work backwards, because these are the most effective. Lastly, teams should benchmark their scoring against the outcome of previous assessments for similar products and materials to ensure a consistent view of risk.

Risk assessment examples of materials commonly used in antibody purification are provided in this section. The risk assessments that follow are not specific to any product or material, but represent risks that may be present in a class of materials. No specific supplier is identified or scored in the examples, but they are mentioned where there may be general concerns over the source.

Upstream Materials

Table 2. Selected upstream materials
The purpose of upstream processes is to express the product of interest. Materials are chosen to maximize productivity and consistency without impairing quality. The process also must be protected from adventitious agents, which could result in the loss of a batch, but are unlikely to affect quality because no product would reach patients. A hypothetical scoring of selected materials used for upstream unit operations is given in Table 2. Complex nutrients such as hydrolysates and yeast extracts are added to cell culture media at various points from thaw to production. They affect growth, titer, cell viability, and product quality, and are a known cause of variability. Functional performance testing is required at great cost to distinguish between lots. Complex nutrients may be a source of viral contamination, resulting in a high severity score: S = 9. This usually is controlled by suppliers, resulting in a lower occurrence score: O = 3. Viral contamination would be observable in the bioreactor, with a detectability of D = 3. Complex nutrients also contain immunogenic materials which typically are removed by downstream processing, so occurrence in the final product is low, and removal of host cell protein can be considered a surrogate marker for the presence of high molecular weight (immunogenic) material, so detectability is good for that parameter as well.

There are known process problems with growth media, which can result in differences in product variants (glycosylation, protease activation) caused by inherent variability and the presence of trace elements. These variants may have similar clinical properties; there may also be variability in titer, cell viability, and filterability, resulting in a lower severity score (S = 7). Such lot-to-lot variability has been observed (O = 5). The variability in product performance is clear if cell growth is affected, but variability in product quality may not be observed until further downstream. Detectability is good (D = 3) and in many cases, downstream purification is likely to remove the variants. Guard filters are used as peripheral filters to protect the main process streams from microbial contamination. They may be 0.45 or 0.22 μm filters that can be used elsewhere as sterilizing filters. Guard filters have contact with process fluids and may be a source of leached materials. Severity scores are low (S = 3), and occurrence and detection levels also are low because contact times are limited and filters typically are characterized for leachable materials. The low risk attached to such filters mean that it is relatively straightforward to qualify alternate sources. Complex nutrients and growth media, on the other hand, may require more extensive qualification, but because a disruption in supply could have severe consequences on process performance and product quality, it is important to consider and qualify alternate sources.

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