In recent years, there have been numerous articles written about requirements to meet good manufacturing practices (GMPs)
for excipient and active pharmaceutical ingredient (API) manufacture. This article, however, highlights some of the differences
between auditing an excipient manufacturer and a manufacturer of APIs.
There are significant differences between companies and facilities that produce these two types of ingredients. Companies
that manufacture an active ingredient are often manufacturers who produce it with support from their customer. In cases where
there is an active patent situation, the manufacturer typically will have just one customer and be expected to work closely
with that customer to meet its needs for product quality and quality-system conformance. In situations where the API is no
longer protected by patent, the API manufacturer may provide product to more than one customer. An API facility seldom provides
the material it manufactures for use in nonpharmaceutical markets so the requirements of the pharmaceutical industry drive
conformance to quality-system requirements.
This situation contrasts with excipient manufacturers who typically produce ingredients for general use for multiple industries
such as food and industrial applications. Because some common excipients are used broadly in the pharmaceutical industry,
the manufacturer would be expected to have many pharmaceutical customers in multiple industries. Excipient ingredients are
used in other industries, usually on a larger scale. Although excipient applications provide an important source of profit,
other markets often provide a greater revenue stream. The excipient manufacturer is thus driven to produce material in a cost-effective
manner without adversely affecting its competitive position in those other market applications.
API manufacturers recognize that hosting customer audits are a necessary cost of doing business and generally anticipate that
their customers will periodically visit the facility. However, excipient manufacturers are often reluctant to host an audit
except for important customers because they could not feasibly accommodate their large customer base if each customer requested
a site visit. In addition, API auditors customarily spend more days in a plant than an excipient manufacturer can manage.
Typically, API facilities are dedicated to the production of active ingredients whereas most excipient plants produce more
nonpharmaceutical-grade products than products that will be used as pharmaceutical excipients. Where API equipment is often
used for different ingredients, the production of excipients is usually in equipment dedicated to that type of material (e.g.,
pharmaceutical, food, industrial grade). This reduction in complexity at excipient manufacturers consequently reduces the
time required for assessing excipient GMP conformance.
Another difference between the two types of ingredients manufacturers is the need to ascertain the point within the process
where full GMP requirements are expected to be applied. Generally speaking, because facilities that produce APIs do not sell
the ingredients for use in other markets, the expectation is that full GMPs apply earlier in the process than for excipient
manufacturers where production of nonpharmaceutical grades can occur interchangeably.
A significant risk of contamination to active ingredients results from the use of nondedicated equipment and facilities, especially
when the equipment is used to produce other APIs. Thus, there is emphasis in API GMP requirements for adequate cleaning of
both the equipment and facilities. The source of contamination to excipients is very different because their manufacture usually
occurs in dedicated equipment and related facilities. An important contamination risk to the excipient can occur, however,
when the excipient is exposed to the environment, which can contain contaminants from other nearby processing operations.
Although the excipient auditor should assure the adequacy of procedures for cleaning equipment and related facilities, the
auditor must also assess the risk to the excipient from environmental contamination.
Exposure of employees to an API can result in an adverse pharmacological effect. For this reason, API packaging is performed
in a room under negative pressure to contain the ingredient. Exposure to an excipient, on the other hand, does not generally
present an imminent health risk to the worker. Because it is undesirable to expose excipients to airborne contaminants at
packaging, it is customary to have the packaging enclosure under positive pressure with filtered air to keep out such undesirables.