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The author describes the new IPEA excipient good-manufacturing-practice certification program that is now ANSI accredited. This article is part of a special issue on excipients and solid dosage.
This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."
International Pharmaceutical Excipient Auditing (IPEA), a subsidiary of the International Pharmaceutical Excipients Council (IPEC), recently completed the first-ever excipient good manufacturing practice (GMP) certification. At press time, IPEA had just received a positive decision from the American National Standards Institute (ANSI) to accredit the program. Accreditation of the program, officially called the IPEA Excipient GMP Conformance Certification Program, by ANSI signifies conformance to the International Organization for Standardization (ISO)/International Electrotechnical Commission (IEC) Guide 65 on general requirements for companies and organizations operating product-certification systems (1). Certification to excipient GMP is a logical extension of the IPEA Excipient Auditing Program, which launched in 2001.
LOGO COURTESY OF IPEA
During a series of discussions with the US Food and Drug Administration in 2008, it was expressed to IPEA representatives that excipient GMP conformance certification could have benefits to the excipient and pharmaceutical industry beyond the existing IPEA audit program. Certification assures excipient manufacturers that they are in substantial conformance with IPEC/Pharmaceutical Quality Group (PQG) excipient GMP guide, a recognized global document for excipient manufacturers. (2). Accreditation of IPEA provides additional assurance to FDA and pharmaceutical customers that conformity assessment of the excipient manufacturer was performed in accordance with Guide 65 requirements and that the excipient supplier meets appropriate GMP requirements. However, it is worth noting that the customer or end user remains obligated to assure excipient quality in terms of meeting compendial and mutually agreed-upon specified requirements.
The certification process
Excipient GMP Conformance Certification is open to all excipient manufacturers whether or not the excipient is compendial. The certification process for a typical excipient is based on a comprehensive site audit that ordinarily requires two auditors two days to complete. Off-site operations and other complexities may add to the audit time allocated. A Certification Audit Report is written, reviewed by IPEA Executive Management, and provided to the excipient manufacturer to confirm accuracy of the audit observations. The excipient manufacturer is encouraged to submit a corrective-action plan describing the remediation of adverse findings. The Certification Audit Report, along with the corrective-action plan, is then submitted to the IPEA Certification Board for consideration. Certification decisions are made by consensus of the ad hoc Certification Board, which is comprised of four excipient and pharmaceutical industry experts. Upon certification, a certificate is issued, and the excipient manufacturer, site, and excipient name are posted to the IPEA certification website.
IPEA offers the pharmaceutical customer the opportunity to review the basis upon which certification has been granted. The certification audit report is available for sale at nominal cost with the majority of the proceeds applied to the excipient manufacturer's annual certification fee.
Surveillance and recertification
Guide 65 requires that IPEA conducts surveillance audits of excipient operations to assure customers and regulators that the excipient supplier maintains GMP conformance. Although certification covers a period of two years, IPEA performs annual surveillance audits to follow up on previous audit findings and the implementation of corrective actions and to assess changes to the site quality system. IPEA also audits one-half of the quality system against excipient GMP requirements. Upon completion of the second surveillance audit, IPEA combines the two surveillance audit reports and issues a recertification audit report to the IPEA Certification Board. With Board concurrence, IPEA recertifies the site for another two years.
IPEA may suspend or revoke certification at any time if made aware of deviations to GMP. Such information is obtained from IPEA surveillance audits, regulatory or customer inspections, or complaints.
Critical Guide 65 requirements for accreditation of a certification body such as IPEA include:
Typically, ANSI Product Certification Accreditation uses an auditable standard as the basis for certification. Because there is no excipient GMP standard, IPEA issues certification to the current IPEC–PQG excipient GMPs (2). To compensate for the lack of a standard, IPEA established objective conformance criteria for excipient GMPs against which the excipient site is assessed.
The ANSI-accredited product conformity program must operate under a documented quality system. IPEA developed a quality system for the certification program with a quality manual that describes the principles of compliance to Guide 65 requirements and procedures that detail conformance activities. Records were established to demonstrate compliance with those procedures.
ANSI Conformity Assessment programs are required to operate without discrimination and are accessible to all applicants. IPEA met this requirement with a commitment to administer the program without prejudice. Although undue financial conditions can present an obstacle to accessibility, IPEA mitigated this concern by offering the audit report to the pharmaceutical user at nominal cost and with most of the financial benefit given to the applicant to offset the ongoing cost of certification.
Of particular concern to FDA and ANSI, as well as the pharmaceutical industry, is demonstration of impartiality of certification decisions through prevention of conflict of interest. IPEA stipulates that no individual involved in a specific excipient certification can have any incentive to certify the company (e.g., financial interests or as a consequence of past employment, consulting arrangement, or family employment). The composition of the four-member Certification Board is such that no portion of the industry, excipient maker or user, dominates. Finally, conformance to procedural requirements concerning conflict of interest is stipulated by contract between IPEA and consultants that requires conformance by the auditor, Certification Board members, and IPEA executives.
Qualification of IPEA Certification Auditors
Another concern to involved parties is the qualification of those individuals involved in the Excipient GMP Conformance Certification program. The program is administered by two industry experts, each of whom have been involved with excipient quality systems and GMP requirements for more than 25 years. These individuals have participated in the development of excipient GMPs since 1991 and continue with the development of an ANSI excipient GMP standard. Their careers in the industry include experience with both excipient makers and pharmaceutical users.
Recent business developments in the industry have significantly increased the availability of seasoned, experienced GMP auditors that IPEA has trained and qualified. IPEA contract auditors are skilled industry and/or government individuals who have maintained an interest in assuring the quality and regulatory conformance of excipients and who have received training in the Excipient GMP Conformance Certification program and excipient GMP expectations. IPEA auditor qualification concludes with their successful completion of an audit under the supervision of an IPEA executive.
The IPEA Certification Board consists of contract consultants whose careers have included relevant Quality-Unit experience or management responsibility. These individuals receive additional training by IPEA in the certification program, including certification criteria and the responsibilities of the Certification Board.
ANSI expects program operation and certification requirements to be made available upon request. To address this expectation, IPEA has publically disclosed program requirements by posting all applicable procedures, policies, and forms to the IPEA website (www.ipeainc.com).
The path to accreditation
IPEA initiated the path to accreditation with the development of an accreditation plan in October 2008 followed by the development of program documentation. Accreditation by ANSI began in August 2009 with their acceptance of an extensive application. The next step was an initial ANSI Documentation Assessment conducted in the IPEA headquarters by an ANSI assessor who reviewed the Quality Manual, procedures, policies, forms, and associated records.
With the successful completion of the Documentation Assessment, ANSI proceeded to the Witness Assessment. The ANSI assessor joined a two-person Certification Audit Team and observed the first day of a two-day on-site certification audit of Grace Davison (Baltimore, MD) for their Silicon Dioxide NF. (Note: This site was subsequently the first to be certified by IPEA.) Again, the assessor was satisfied with the operation of the Certification Program and submitted two reports, one for each assessment, to the ANSI Evaluation Task Group.
The Evaluation Task Group reviewed the reports and submitted their recommendation to accredit the IPEA certification program to the ANSI Accreditation Board. Their decision was announced in late April 2010 and the program has been officially accredited.
Benefits to industry
The excipient and pharmaceutical industry can now benefit from the IPEA certification program through assurance of the conformance of excipient suppliers to GMP requirements without the need for a site audit. The benefit to the excipient supplier is a reduction in their resources to host frequent customer audits and assurance that the excipient GMP audit is conducted against appropriate GMP conformance expectations. The supplier also has an opportunity to review the certification audit report to assure the accuracy of observations and can provide a corrective action plan if warranted.
The pharmaceutical customer benefits from assuring excipient-supplier GMP conformance without the expense of a site audit. More importantly, the assessment by the IPEA certification auditors, which is more extensive than excipient manufacturers typically allow for a pharmaceutical audit, results in additional confidence in the appropriateness of the excipient GMP quality system. IPEA's annual surveillance audit and biannual recertification assure the excipient site maintains their conformance to GMP. The pharmaceutical user also has an opportunity to review the Certification Audit Report at nominal cost for confirmation of substantial conformance to excipient GMP with approximately 80% of the proceeds used to defray the certification maintenance costs.
As noted earlier, IPEA is represented on the committee that is currently developing an ANSI standard for excipient GMP. NSF, an ANSI standards development body, has organized a committee of experts for this purpose in accordance with ANSI procedures. IPEA will certify conformance to the ANSI excipient GMP standard upon its adoption.
IPEA would like to thank FDA for encouraging IPEA to develop the Excipient GMP Conformance Certification program and to become ANSI accredited. It was with continuing encouragement and support by FDA that IPEA maintained the effort to become accredited.
Irwin Silverstein is vice-president and chief operating officer of International Pharmaceutical Excipients Auditing (IPEA), a subsidiary of the International Pharmaceutical Excipients Council (IPEC), tel. 732.463.8710, firstname.lastname@example.org, www.ipeainc.com.
1. ISO/ISE Guide 65 General Requirements for Bodies Operating Product Certification Systems, 1996.
2. IPEC–PQG, Joint Good Manufacturing Practices Guide for Pharmaceutical Excipients, 2006.