Inside IPEC–Americas: Excipient Audits and API Audits are Worlds Apart

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.

Customer audits

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.

Contamination concerns

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.

Regulatory and cost benefits

In addition, GMP requirements for API manufacture are more explicit because of FDA requirements and guidelines from the International Conference on Harmonization. Official GMP requirements do not exist for excipients but standards are expressed in industry produced guidelines, whose application can vary greatly because of the range of processing involved. For example, the application of GMP standards for a salt producer that mines, purifies, and packages salt for use as an excipient would probably be very different from that of a synthetic excipient manufacturer.

There is one final significant difference between auditing excipient and API manufacturers. Because excipient manufacturers have numerous customers as compared with API manufacturers, it is feasible for excipient manufacturers to reduce audit assessment costs for their customers (and to themselves through a reduction in customer visits) by allowing the sharing of audit reports. It was for these reasons that IPEC–Americas formed its excipient GMP auditing subsidiary, International Pharmaceutical Excipients Auditing, Inc. (IPEA) in 2001 to assist excipient producers and their pharmaceutical customers. For example, the report of an IPEA third party audit requested by an excipient manufacturer can, if the company wishes, be shared with its potential customers. When this is publicized, it has served to reduce the number of new audit requests producers have received for up to two years after the IPEA audit.

Of note: An IPEC–China organization is being formed to join IPEC–Americas, IPEC–Europe and IPEC–Japan.Nevin Cheng of Shanghai Coating Technology, Ltd. will act as general manager for ongoing organizational efforts.

Irwin Silverstein, PhD, is vice-president of International Pharmaceutical Excipients Auditing Inc., the GMP auditing subsidiary of the International Pharmaceutical Excipients Council of the Americas. For more information, he can be contacted at irwin.s@verizon.net