FDA representatives stated that not all testing or measurements conducted to verify that a finished lot of excipient material
complies with its required properties must be performed on samples taken from the finished lot. The representatives do not
believe that testing or measurement of in-process materials to verify product quality constitutes skip testing. To ensure
that a lot of excipient material complies with its required properties, it is acceptable to rely on tests or measurements
conducted on samples of material taken at an in-process stage of production, provided that the in-process material will not
be affected by subsequent processing or holding with respect to the attributes being verified. There should be justification
that test results or measurements, or product performance characteristics, do not change from the in-process stage to the
According to FDA representatives, an appropriate determination to ensure that each lot conforms to appropriate specifications
could involve some combination of the following approaches:
- End-product testing
- In-process testing
- Continuous monitoring of an attribute with statistical process controls
- Documented rationale that, based on the method of manufacture, the test attribute cannot be present and therefore the test
is not applicable (e.g., residual solvents).
Using end-product testing alone requires testing each lot of excipient material for conformance to all specifications. In-process
testing might involve the use of an on-line test to determine whether a product attribute meets an appropriate acceptance
criterion, provided that the attribute does not change during the subsequent processing steps until the finished excipient
is produced. Continuous process monitoring with statistical process controls involves comprehensive testing of an attribute
using on-line monitoring and corresponding process and/or product adjustments to prevent lot-to-lot variation in the product.
Depending on the product and specification, any of the above approaches might be appropriate for conducting a determination
to ensure that each batch of the product conforms to the specification.
The term skip testing does not actually characterize how FDA perceives testing practices in the excipient industry, and FDA recommends that this
term not be used. The term skip testing implies that certain required testing is not being done. Rather than skip testing, FDA representatives recommend that the
excipient industry emphasize the development and use of sound sampling and testing plans for process parameters and product-quality
attributes. The sampling plans should provide for appropriate frequency of material sampling and testing, accounting for the
risks identified and assurance of quality to address them, including process control imperatives and intended use of the material.
The representatives stated for clarity, FDA prefers the term measurement instead of test as it relates to product quality, because measurement conveys the correct idea of analytical testing of material quality
using either nondestructive in-line or on-line analytical techniques as well as off-line destructive analysis commonly used
today. This approach gives excipient manufacturers more latitude to use various options to verify a given product attribute.
PAT for excipient manufacturing.
PAT uses appropriate design, analysis, and control of manufacturing processes, including in-process testing and controls
to ensure that a finished drug product is manufactured under appropriate controls. A benefit of using PAT is that finished-product
testing can be minimized by a drug-product manufacturer on their final dosage forms. One meeting participant asked, "Why can't
these same concepts be applied to excipient testing when the excipient manufacturer applies similar control strategies?" Additional
guidance or clarification is needed from the regulatory agency(ies) on these topics.
ICH Q6A applies to drug products, and an official clarification by FDA with a specific guidance for excipients is needed.
Alternatively, an industry group such as IPEC-Americas may wish to present industry guidance suitable for self-regulation.
Documents in this area are currently being developed by IPEC-Americas.
How characterization of excipient physical and chemical properties helps build quality into the drug product
This topic was described to the participants as follows:
Following the spirit of FDA's 21st Century Pharmaceutical CGMP and Quality by Design (QbD) initiatives, the workshop will
explore ways to improve product quality by characterization and control of physical and chemical properties of critical excipients
in a given product (8-10).