Control strategies concerning excipient functionality and/or performance-related tests should be based on excipient manufacturer's
process capabilities and be negotiated between the excipient user and excipient maker. The test parameters and control strategies
that are mutually agreed to should be included in contracts between the excipient maker and user. Workshop participants generally
agreed with this approach.
IPEC also is supporting the development of educational programs in formulation science. Only through education will the industry
have the formulation scientists required by the QbD approach for pharmaceuticals.
Significant change in excipient properties.
Communication to excipient users about a significant change in excipient physical and chemical property(ies) should occur
in a timely manner, even when the excipient would otherwise continue to meet all of its compendial specifications. IPEC has
defined significant change as "any change by the manufacturer of an excipient that alters an excipient physical or chemical property outside the limits
of normal variability, or that is likely to alter the excipient performance in the dosage form."
Such changes may necessitate notifying the local regulatory authority if required (as in Europe). Regardless of whether there
is a regulatory requirement, the excipient manufacturer has an obligation to notify its customers of a significant change
so that the customer can evaluate the effect of the change on the customers' products. Examples of significant change include
differences in the methoxylated content of hydroxypropylcellulose, particle-size distribution profile, and change in polymorph
or crystalline properties. The issue of change control should be part of the quality agreement between an excipient user and
Within a company, a drug-product manufacturer should ensure strong oversight of supply chain management decisions by research
and development and other quality assurance and technical groups. There must be improved communication between supply chain
management and technical functions as well as improved communication between excipient user and excipient supplier. In particular,
it is very important to define and evaluate significant changes to the excipient. Changes to site, scale, equipment, process,
packaging and labeling, and specification are considered in the IPEC-Americas Significant Change Guide for Bulk Pharmaceutical
Excipients (13). To assess, evaluate, and agree upon such details, audits of excipient suppliers should be a team effort by
members such as CGMP compliance auditors and technical personnel. In addition, education programs should be developed with
a focus on formulation science and QbD collaboratively between academia and industry.
The closing session of the workshop also identified the need to define significant change in quality agreements as a key issue.
Highlight advantages of increased use of third-party audits
This topic was described to the participants as follows:
Third-party audits of excipient manufacturers, especially outside the United States, are critical to a control strategy for
the global excipient supply chain. The use of independent third party audits may provide a cost effective way to accomplish
control and ensure quality of excipients, especially for smaller pharmaceutical manufacturers. The concepts and advantages
of independent third party audits will be described.
An on-site visit by a drug-product manufacturer's company auditor is the most common practice in auditing an excipient manufacturer.
Survey results indicated that 87% of drug-product manufacturers have performed auditing of their excipient manufacturers for
some to all of their excipients. Most drug-product manufacturers do not audit every one of their excipient manufacturers but
instead have some type of risk prioritization process for selecting the ones to audit. Only 29% of the audits were performed
by a third party. This is an opportunity to have third-party auditors provide an alternate view of the excipient supplier
and reduce the number of independent audits of excipient suppliers. Of the 17 excipient manufacturers' responses, 1 stated
that, on average, they have an on-site visit by their customers every week. Of the remaining responses, 5 are visited by at
least one customer once in 2 weeks; 2 manufacturers are visited by their customers every 4 weeks and 8 weeks, respectively,
and 7 stated that they have a customer at their site less often than every 8 weeks. The advantages of using independent third-party
audits were discussed.