Qualification of the excipient manufacturer by the pharmaceutical user also requires confirmation that the excipient was produced
and handled in conformance with excipient GMPs and GDPs. A site audit of the entire supply chain is the only suitable way
to assure conformance. The excipient manufacturer and any and all distributors in the supply chain should be audited.
The excipient manufacturer should be audited for conformance with excipient GMPs (5–6). IPEC has issued a companion audit
guide to facilitate site audits (7). An audit should confirm that the excipient was produced at the site with a quality system
that is in substantial conformance with GMPs. Although an audit of the excipient manufacturer is customarily done by the user,
it is acceptable practice to use a qualified third party to perform these audits.
The user should also audit all distributors that are part of the supply chain for conformance to GDPs (8). IPEC has also issued
a companion audit guide to facilitate audits of distributors (9).
Requirements for a distributor to comply to GDPs vary based on the distributor's services, which can range from warehousing
and distribution to repackaging into smaller containers to packaging from bulk storage. For instance, a distributor that warehouses
and ships excipients only has to comply with GDPs. A distributor that packages or repackages excipients, however, must also
meet various GMP requirements regarding protection of the excipient from environmental contamination or degradation during
packaging operations, proper labeling, suitability of the packaging components, maintenance of retained samples, and ongoing
Receipt of materials
Proper receipt and approval of incoming components is the final step in assurance of the supply chain, and care must be exercised
for excipient security. Although it is customary for the user to inquire or specify excipient packaging and labeling, compliance
may not be verified at receiving. The emphasis at receiving is confirmation that the package has protected the excipient followed
by quality-control sampling.
To provide assurance that there has been no tampering with the excipient at the distributor or in-transit, it is important
to identify the original manufacturer's packaging, labeling, and tamper-evident seal. This review also applies when the excipient
has been repackaged or packaged from bulk at a distributor.
At minimum, the manufacturer's description of the excipient packaging, labeling, and tamper-evident seal should be available
to the people responsible for assessing incoming components. A catalog of electronic photographs of the excipient manufacturer's
packaging, including contact packaging, labeling, and tamper-evident seals, should be available at receiving. Procedures can
then be established to require comparison of the excipient received with those reference photographs to confirm the manufacturer's
original packaging, labeling, and tamper-evident seal.
Excipient sampling and analysis
Once the physical appearance of the excipient packaging has been confirmed, the excipient is sampled according to a scientific
sampling plan. This plan should be developed with an understanding of the homogeneity of the excipient lot. Care should be
taken in combining samples from individual containers and subsequently removing an aliquot for testing because it is important
to first assure the homogeneity of the combined samples. The practice of only performing the identification tests on an aliquot
of the combined samples is not recommended. Identification tests should be performed on each sample taken in the scientific
Examination of the COA is ordinarily the final step in the incoming inspection of components. Although it is important to
verify that the test data conform to the appropriate monograph or specification, it is also important to confirm the veracity
of the document. Ordinarily, there are no concerns with the authenticity of the COA when provided to the site electronically
directly from the manufacturer. When the COA is received along with the shipment, the appearance of the COA should be examined
for any signs that it may have been altered.
Periodically, it is important to confirm the security of the supply chain. This process involves the following:
- Verifying there is a current assessment of the manufacturing site and all distributors that provide the excipient.
- Tracing the shipping papers for a lot (i.e., the manufacturer's bill of lading) back to the excipient manufacturer. This trace
can be achieved by having the excipient manufacturer confirm that the lot in question was produced at its facility and shipped
as indicated on the bill of lading that the manufacturer provided for shipment to its customer or distributor.
- Confirm that the COA for a lot has come from the manufacturer indicated on the document by asking the manufacturer to send
the customer a duplicate COA or by asking the manufacturer to confirm the identity of the COA received in conjunction with
a designated lot of excipient.