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As the excipient supply chain becomes more complex, industry must up the ante to comply with new standards and regulations.
A little over 18 months since it was established, the strategy and work programs of the International Pharmaceutical Excipients Council (IPEC) Federation have started to take shape. The federation's overall focus is to provide expertise on excipient regulatory and scientific issues, to assist in the harmonization of quality standards, and to promote global supply-chain security.
Originally formed with representatives from the four existing IPECs—IPEC-Americas, IPEC–Europe, IPEC–Japan (JPEC), and IPEC–China—the IPEC Federation is set to add IPEC-India to its membership. The federation also has formed partnerships in Latin America through trade associations in Brazil and Argentina and has a partnership with Mexico in the works. The following section summarizes recent progress made by the organization to date.
One of the federation's priorities is the global harmonization of excipient monographs. The organization has been working in partnership with the Pharmacopoeial Discussion Group (PDG), which brings together experts from the US, European, and Japanese pharmacopeias. The two groups met in June 2011, and made progress on several fronts, including the inclusion of additives in pharmacopoeia monographs, where additives are typically present in commercially available materials, as well as standardization of methods for measuring viscosity of cellulosics. An IPEC working group will continue to consult within an industry coalition and plans to run a global workshop on viscosity of cellulosics to develop recommendations for discussion with PDG.
Recognizing that additives can be components in excipients is a major step-forward and work is ongoing to compile a comprehensive list of additives and processing aids that are typically used in the manufacture of excipients. The goal is to collaborate with regulatory authorities, including FDA, to find a way to "grandfather" the permitted inclusion of such components in specific excipients where their historical and safe use can be demonstrated and justified.
One of the biggest projects undertaken since the formation of the IPEC Federation in 2010, is to support the third-party excipient-certification program known as EXCIPACT. The program is designed to complement other third-party schemes such as the ANSI-accredited International Pharmaceutical Excipient Auditing (IPEA) program set up by IPEC–Americas. The auditing program provides certification that an excipient manufacturer meets IPEC–Pharmaceutical Quality Group (PQG) Excipient GMPs. EXCIPACT will provide an equivalent certification for companies who already may be certified to ISO–9001, the international standard for quality-management systems, but that need their certification expanded to cover the additional requirements for excipient GMPs and good distribution practices (GDPs). The latter standards go beyond ISO–9001 to include requirement for contamination control, document traceability, cleaning, training, and so forth.
GMP and GDP legislation for excipients has been proposed in both Europe and the United States. As a result, excipient suppliers could be faced with an avalanche of quality audits and related requests to ensure customers and regulators that their facilities and products meet these new requirements. Excipient users will need to find a way to obtain physical audit information on every supplier they use and that cannot be done with available in-house audit resources.
Industry experts from the European Fine Chemicals Group (EFCG), IPEC–Europe, IPEC–Americas, PQG, and the European Association of Chemicals Distributors (FECC) developed the EXCIPACT certification scheme to provide industry with an alternative means to obtain independent assessment of manufacturers and suppliers of pharmaceutical excipients. Most suppliers are already ISO-certified, meaning that they meet a defined set of GMP and GDP standards. EXCIPACT and IPEA are two pathways that IPEC will be offering to achieve the same level of certification as ISO—one for companies that are already ISO-certified and one for companies that are not ISO-certified and want to go through a full certification to excipient GMPs.
IPEC–Japan recently established Self-imposed Standards for Manufacturing Control and Quality Control of Pharmaceutical Excipients and its Explanation. The English version of these standards will be published in 2011. IPEC–Japan also began a third-party certification system in 2005.
These programs demonstrate that excipient suppliers, distributors, and the pharmaceutical industry are fully committed to the use of high quality excipients and ensuring their integrity throughout the supply chain. The use of EXCIPACT and the IPEA certification schemes add a significant contribution to ensuring patient safety and supplier quality, while minimizing overall supply-chain costs.
Risk assessment and the supply chain
Another IPEC Federation priority has been the development of guidance on risk-assessment principles for excipients, along the lines of the recent European Directive on Falsified Medicines, which was issued earlier this year. The aim is to develop a set of guidelines that can be used by users and suppliers of excipients to determine how GMP principles should be applied for a specific excipient. Excipient risks can come from both the intended uses of an excipient as well as the way the excipient is manufactured and distributed.
The federation responded quickly to extraordinary events affecting the excipient supply chain around the world in 2011, notably the earthquake and subsequent nuclear incident in Fukushima, Japan, and adulteration of clouding agents with phthalate plasticizers used in pharmaceuticals and foods in Taiwan.
When the earthquake occurred in Fukushima in the Tohoku district of Japan in March 2011, followed by a large tsunami, the Fukushima Dai-ichi Nuclear Power Station shut down. There were collapsed houses and a cutoff of transportation networks along the Pacific coast of the district. IPEC–Japan investigated the situation promptly and found that there were few excipient-manufacturing facilities in the area, and therefore, little influence of the radioactive contamination from the nuclear power station. Consequently, the Federation announced that the pharmaceutical excipients in Japan were safe and provided regular updates to the public and the industry.
Similarly, the IPEC Federation developed a frequently asked questions (FAQs) document to address the Taiwan phthalate contamination situation in Taiwan in order to help companies evaluate any risks related to the two contaminants (DEHP and DINP) involved in the Taiwan incident. In the wake of that incident, IPEC has begun to investigate, along with other trade groups, the possibility that packaging may play a role in contamination of drug products and whether migration of certain phthalates into drug products poses any significant safety risks.
One of the IPEC Federation's key roles is to provide input from the industry perspective into global regulatory expectations. To that end, the organization has taken a position on the US Pharmacopeia's (USP) draft General Chapters on elemental impurities (<232>, <233>, and <2232>), which in IPEC's view, call for unrealistic for implementation timeframes (September 2013). USP's timeline does not give industry enough time to obtain needed data for impurity levels in the majority excipients, which could lead to a regulatory compliance issue.
The International Conference on Harmonization's (ICH) expert working group on elemental impurities (Q3D) is developing draft guidance on this topic that will provide the impurity limits that are likely to supersede those set in current monographs. The federation is gathering information on elemental-impurity levels in multiple excipients through an industry coalition, with the goal of submitting data to ICH. The IPEC Federation is also considering holding a workshop in 2012 (after the working group finalizes the limits) to begin sharing actual test data, which will need to be developed within the excipient industry.
Visible particles in excipients
A primary cause of drug recalls during the past year has been the presence of visible particles in pharmaceutical products, and the IPEC Federation has responded with the formation of a working group to explore the role that excipients can play in this area. The group plans to develop a guideline on how to measure and properly assess the significance of visible particles that can be found in excipients. The guidance will ideally dispel any confusion around the presence of particles in excipients and clarify that it is not possible to achieve zero visible particles in these materials.
A relatively new area of the federation's work is an attempt to monitor nanotechnology developments with respect to their impact on excipient monographs, as well as in the context of draft guidance on nanotechnology published by FDA in June 2011 (1). A major concern for the excipient industry is that excipients not developed for their "nano" properties may fall within particle-size range definitions being discussed for "nano" materials and therefore may be required to comply with potential new safety-assessment requirements.
Particularly, the federation is looking to change the particle-size range expansion from less than 100 nm to a range of 100 nm to 1 µg. There is a need for global harmonization of these initiatives within US, Europe, and other countries. IPEC has worked with various trade associations to submit comments regarding these issues to FDA in response to their draft guidance.
Overall, the federation's 2011 work plan is full, but much remains to be done. Many of the initiatives mentioned here will continue into 2012, as will the organization's member-expansion program.
The author would like to thank David S. Schoneker with IPEC–Americas for his contribution to this article.
Patricia Rafidison is chair of the IPEC Federation, and the global regulatory affairs and compliance manager at Dow Corning.
1. FDA, Guidance for Industry: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology (FDA, Rockville, MD, June 2011).