An excipient-product risk assessment is performed by the excipient manufacturer that has expertise and knowledge in excipient
manufacture and inherent characteristics. For raw materials:
- Physical and chemical characteristics are typically unique to an excipient regardless of the manufacturing location
- Type, source, and history of supply for raw materials used in excipient manufacturing may be common to a given excipient
- Excipients can be made from different sources and/or materials sourced from different regions with associated risk.
Risk-assessment outcomes may differ for a specific excipient based upon manufacturer and location. The differences in outcomes
increase exponentially when the variables associated with excipient manufacturing are considered (see Figure 2). The same
excipient made by the same process methodology can have different risk-assessment outcomes depending on variables, such as:
- Type of equipment used
- Facility floor plan
- Physical location of the manufacturing plant
- Dedicated versus multiple use operations
- Conveying methodology
- Open versus closed systems
- Choice of processing aids
- Recycle and recovery in process
- Robustness of the engineering design
- Process cleaning operations
Effective implementation of excipient GMPs helps equalize these differences to an acceptable level of potential risk. However,
a true and complete risk assessment for the realization of an excipient must be unique to a given manufacturing location.
Figure 2: Excipient risk-assessment categories.
Risk-assessment outcomes can also change over time due to changes in GMP expectations and to the manufacture of the excipient.
For example, risk assessment for excipient storage and distribution can be generalized, but also depends on the particular
circumstances. An excipient that is susceptible to degradation or modification during storage or transport, for example, has
more potential for failure in than a stable excipient. Good distribution practices (GDP) require adequate control and monitoring
of storage conditions for excipients susceptible to environmental conditions. While GDP conformance lowers risk during storage
and distribution of an excipient, poor storage practices or distribution methods may heighten the risk associated with an
excipient. For example:
- Using dedicated vessels or single-use containers versus allowing back hauls or reusable containers
- Short-direct distribution paths minimize the risk of tampering or contamination during transfer versus a longer route that
may offer greater opportunity
- Trace contaminants introduced from packaging, storage, or transfer may react slowly over time with the excipient
- Changes in ownership, repackaging, and relabeling operations bring unique opportunities to adversely affect the quality or
the reported characteristics and increases the risk of mislabeling.
These acts may result in the same excipient having different risk levels based on the differences in distribution. Excipient
manufactures whose primary sales outlet for excipients is through distribution companies do not always have a sufficient view
of the supply chain necessary to perform adequate risk assessments and likewise the excipient users may not have a clear view
of the supply chain beyond their immediate supplier. This lack of clarity in the supply chain creates a knowledge gap that
in and of itself increases risk in terms of potential adulteration or contamination. Product testing is an impractical remediation
for unknown gaps in the supply chain because one often does not know what tests to perform. It's crucial to know and understand
the excipient's full supply and distribution chain.