This paper provides a comparison of three comprehensive programs—Rx–360, EXCiPACT, and IPEA—available to pharmaceutical manufacturers for the purpose of auditing excipient suppliers and ensuring drug efficacy and patient safety.
Ingredient adulteration has been a growing concern for regulators. In June 2009, FDA sponsored a conference on economically motivated adulteration. In October 2009, the results of a study conducted on imported povidone analogs showed there was substandard excipient offered for sale (1). After confirmation, FDA issued an import alert for povidone analogs from an overseas manufacturer (2). Since then, FDA inspections of pharmaceutical manufacturers have added emphasis on supplier qualification. FDA announced at the FDA/Xavier University Global Outsourcing Conference in 2010 that site inspection of component suppliers will become a future requirement (3). Similar expectations are developing in Europe. The Falsified Medicines Directive (FMD) 201⅙2/EU requires the holder of the manufacturing authorization to ensure that appropriate GMP is applied to the manufacture of ingredients (4). Although the FDA and EMA requirements for site audits have not yet been mandated for excipients, the excipient industry must be prepared to receive increasing numbers of audits.
Excipient manufacturers often host 10 or more audits performed by their direct customers per year, which is a small fraction of their many direct and indirect pharmaceutical customers. These audits do not include potential audits by excipient users that purchase material through distributers. The excipient manufacturer usually has no knowledge of the identity of those customers. Thus, it becomes impractical both physically and economically to host an audit from all direct and indirect pharmaceutical customers. Regulators worldwide recognize this conundrum and now allow the pharmaceutical company to rely on third-party audits and certification. As stated by FDA, an important consideration for acceptance is proper qualification of the third-party audit or certification provider. This article provides an overview and comparison of a third-party audit, Rx–360, and excipient GMP certification programs EXCiPACT and IPEA.Rx–360
The Rx–360 International Pharmaceutical Supply Chain Consortium is a nonprofit international industry organization established in 2009. The mission of this organization is to develop and implement enhanced global quality systems and processes that will help ensure product quality and authenticity throughout supply chains. Members of Rx–360 include pharmaceutical companies and suppliers, working in partnership to achieve the mission of Rx–360. Pharmaceutical associations and industry groups, auditing firms, and regulatory agencies are updated on the status of the audit programs and other initiatives of the consortium. In support of the mission, the consortium developed a Joint Audit Program and a Shared Audit Program, both of which aim to provide knowledge on the quality and authenticity of supplies and their suppliers.
Joint audit program. Pharmaceutical companies that are Rx-360 members (sponsors) can confidentially submit a request to the Rx-360 secretariat to have an audit performed by an Rx-360-qualified third-party audit firm, at a supplier site. Currently, Rx-360 supports audits of API, excipient, raw material, basic chemicals, and packaging suppliers, with potentially more categories to be added into the program (e.g., laboratories). As part of the audit request, the number of additional sponsors required for the audit to progress is stipulated. This can result in a single sponsor or multiple sponsors per audit, depending on the sponsor's needs. The sponsor's confidentiality is sustained throughout the entire audit process. A supplier that is targeted for an audit through Rx-360 must also agree to the third-party audit.
The program benefits both pharmaceutical companies and suppliers. For pharmaceutical companies, the cost of the audit is shared by the number of sponsors, which has the potential to significantly reduce the cost per audit. Additionally, Rx-360 provides a supplemental means to complete routine audits required by regulators worldwide. Suppliers benefit by having a potential reduction in time and resources spent hosting and responding to numerous audits, especially in cases where multiple sponsors are interested in auditing the same supplier.
Auditors from select qualified third-party auditing firms perform each audit. Each auditor must have the education, experience, and accreditation to be eligible to perform an audit. The experience required is specific to the type of audit being performed, whether API, excipient, raw material, or packaging material. Auditors use audit guides during the audit, which have been developed by Rx-360 and agreed to by the pharmaceutical company members. These guides ensure consistency of the audits performed and are based on industry standards such as ICH Q7, Good Manufacturing Practice for Active Pharmaceutical Ingredients for APIs and EXCiPACT GMP or GDP standards (see below) for excipients.
Each sponsor reviews the draft audit reports to ensure clarity of the report, completeness of the audit, and validity of observations. Following sponsor review, the audit report is returned to the auditor to address any questions and any needed revisions for clarity, before the report is issued to the supplier. Responses to any observations are provided to the auditor for review and concurrence. If a sponsor determines that a specific audit observation requires additional follow-up due to its company procedures, or if the response is not adequate per sponsor standards, the sponsor has the responsibility to negotiate further with the supplier.
If a pharmaceutical company is not an initial sponsor for an audit, the company may purchase the given audit report following approval of the report and permission from the supplier. Rx-360 non-member companies can also purchase audit reports, again pursuant to supplier agreement.
Shared audit program. Rx-360 member pharmaceutical companies, with agreement from the supplier, can elect to submit an audit report performed by the pharmaceutical company (rather than through an Rx-360 third-party audit), into the shared audit program. Information is redacted to protect any confidential information from both the pharmaceutical company and supplier perspective. These audit reports can be purchased by another Rx-360 member company, pursuant to supplier agreement, as a means of obtaining additional information about a supplier. This can be quite useful for companies evaluating a new supplier. Suppliers benefit by gaining visibility to a large number of potential customers, and a potential reduction in pre-audit paperwork as well as audit frequency or time spent on a single audit.
For both Rx-360 audit programs discussed, confidentiality is strictly maintained to ensure that only the appropriate information is visible to a sponsor or supplier.