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Excipients are the hidden champions of drug development-no API works consistently without the right excipient. Pharmaceutical excipients, however, require stringent quality management. This article discusses how the supplier of pharmaceutical raw materials should take a central role in ensuring excipient quality.
A thousand different excipients can be used when formulating pharmaceuticals and, as a rough estimate, excipients can comprise more than 90% of a medicinal product's weight. Excipients are no longer characterized as simple inert additives to the API, and the need for stringent, quality management of excipients has grown rapidly. In 2010, FDA noted five drug recalls due to dissolution failures ascribed to excipients (1). In one case, FDA issued an import alert and an advisory to drug and dietary supplement manufacturers warning of high levels of peroxide in the excipient crospovidone manufactured in China (2). In the warning, FDA explained that drug manufacturers who used excipients containing high levels of peroxides would observe a loss of drug potency and the formation of excessive impurities during the product's shelf life.
Lack of regulation
Although pharmaceutical excipients are major components of dosage forms—and potential hazards to patients—there is a lack of binding regulation. In recent years, however, several industry standards have been developed. In the United States (US), the recently introduced Drug Safety Enhancement Act includes the following parameters (3):
According to the Act, inspections of the drug product and API will occur once every two or four years while inspections of excipient manufacturers "may occur." Further, inspections of foreign sites will occur with the same frequency as inspections of US manufacturing sites. Meanwhile the European Union has included pharmaceutical excipients in the recent amendment of Directive 2001/83/EC (4), providing member nations with guidance on how excipients should be regulated in pharmaceutical manufacturing and throughout the supply chain. Despite these efforts, however, there are no binding regulations for excipients. For example, although the US Pharmacopeia (USP) recommends industry standards, the adoption of these standards is voluntary for excipient suppliers and drug manufacturers (5). Matters are also further complicated by the fact that excipient safety requirements can vary between different countries.
The role of suppliers
While the move toward more stringent and harmonized regulations continues to make progress, it is incumbent on suppliers and manufacturers to jointly take the lead in ensuring excipient quality. This imperative was reinforced by FDA when the regulator warned about the presence of high peroxide levels in crospovidone, but it should apply to all excipients:
"It is essential that [excipient] users implement robust supplier management programs... Manufacturers should employ sound risk management principles in establishing appropriate scrutiny and actions to take for a given supplier, including but not limited to the following:
In the current regulatory environment, pharmaceutical manufacturers are under increasing pressure to develop better knowledge of their excipient supply chain. At the same time, excipient suppliers must also shoulder a significant responsibility for ensuring quality and mitigating possible risks, which may include excipient variability, trace impurities, the use of an inappropriate grade of materials, contamination, mix-up across the supply chain, and economically motivated adulteration.
In recent years, USP has revised its monographs for several excipients considered at high risk of contamination with ethylene and diethylene, providing limits of not more than 0.10% of these two contaminants. Contamination with these substances has been identified as the culprit in some high-profile incidents and appeared to be the result of failures in Good Distribution Practices (GDPs). In 2006, for example, at least 100 deaths were attributed to the presence of diethylene glycol in bottles of cold medicine prepared by the Panamanian government (6). What was believed to be 99.5% pure glycerin was actually counterfeit and passed through multiple trading companies on three continents. An investigation by the New York Times revealed that in the course of the supply chain, a certificate attesting to the purity of the "glycerin" was altered by eliminating the name of the manufacturer and previous owner (6). It was also found that the manufacturer was not certified to produce pharmaceutical-grade ingredients.
Purchasers of excipients should expect complete transparency from their suppliers with regard to transportation, storage, repackaging, and relabeling, and should also audit their supply chains using the GDP Guide for Pharmaceutical Excipients published by the International Pharmaceutical Excipients Council (IPEC) as a basis (7). IPEC recommends that pharmaceutical manufacturers to audit their excipient manufacturer and all distributors in the supply chain or use the results from a qualified third-party audit (8). As reinforced by the tragedy in Panama, it is also important for the user—in partnership with the supplier—to verify the chain of custody of an excipient to ensure the pedigree's accuracy.
In the authors' experience, there is increasing pressure by regulators to perform audits of not only the API manufacturer, but of the excipient supplier as well. Typically, the marketing authorization holder is expected to qualify their suppliers, including those that provide excipients. However, the sheer quantity of audits has become a hot topic for discussion. At Merck Millipore's facility in Germany, the company receives approximately 100 customer audits every year relating to pharmaceutical raw materials, and an increasing number of these audits relate specifically to excipients. Preparing, organizing, hosting, and following up on these audits can put a strain on resources, and there is a limit to the number of audits that can be completed. Because of this, companies usually have to prioritize which audits must be performed.
Recent initiatives, such as those being developed by Excipact, an excipient manufacturing certification scheme developed by members of several industry organizations, and Rx–360, an international supply-chain consortium formed in 2009 (9, 10), suggest using third-party organizations to audit excipient suppliers and ensure continued conformance. After a successful audit, Excipact will issue the supplier a certificate that confirms alignment with GMP and GDP requirements. This certificate will be renewed as appropriate. Excipact includes representatives from the European Fine Chemical Group (EFCG), IPEC–Europe, IPEC–Americas, the European Association of Chemical Distributors (FECC), and the Pharmaceutical Quality Group (PQG), a special interest group of the chartered professional body for quality, the Chartered Quality Institute, who have agreed to work together on the development of an international certification scheme for excipients suppliers. A similar approach is taken by RX-360, which currently has more than 50 members and observers. The purpose of the consortium is to "enhance the security of the pharmaceutical supply chain and to assure the quality and authenticity of the products moving through the supply chain" (10). The consortium is preparing to launch an audit program that will supply members with reports of APIs, excipients, and other materials used in final-drug manufacturing. The audits will be performed based on well-accepted guidelines and standards developed by groups such as IPEC/PQG or the International Conference on Harmonization (ICH) (11–13). Audits conducted through Excipact or Rx–360 will cover general questions related to quality and GMP that will be useful to all excipient and pharmaceutical manufacturers. Audits of single customers will concentrate on specific drug-product related topics concerning the excipient.
Excipient suppliers are expected to be familiar with a wide range of analytical methods and possess cross-functional knowledge of chemicals, pharmaceuticals, and packaging materials. In addition, the excipient supplier should demonstrate competency in global regulatory requirements, and have broad expertise in toxicology, quality control, and method development. Another important factor in ensuring excipient quality is communication. Communication is imperative, and the drug manufacturer should be as open as possible with their supplier to convey their requirements. This exchange should include discussion of how the material will be produced, controlled, and delivered, as well as how changes to the initial specifications will be handled.
Proper documentation is also vital. Many companies provide regulatory documentation with their pharmaceutical raw materials. Merck Millipore provides password-protected access to information on pharmaceutical raw materials that can be used for qualification, such as certificates of analyses of three batches, a description of the manufacturing process, and an overview of the cross-validation of analytical methods. Analytical procedure and stability data are also available in line with ICH requirements. To simplify the search for information, the documents are structured according to the ICH M4 Common Technical Document (CTD) format (14). The agreement to assemble all the quality, safety, and efficacy information in the common CTD format has revolutionized the regulatory review processes and led to harmonized electronic submission that, in turn, has enabled implementation of good review practices. For industries, it has eliminated the need to reformat the information for submission to the different ICH regulatory authorities. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format of choice for NDAs submitted to FDA.
When evaluating suppliers, the total cost of excipient acquisition, including the possible risks associated with particular suppliers, should be considered. Inability to obtain the necessary documentation, lack of supply-chain security, or difficulties in re-supply are just some of the problems that can lead to significant operational, regulatory, and financial setbacks for the drug manufacturer. A trusted supplier should provide comprehensive product-related documentation and offer a regulatory service that helps the manufacturer minimize the risks associated with delivering the required excipient. Established quality systems and standards are also important to help ensure patient safety.
The way forward
Ongoing dialogue is crucial. In June 2011, Merck Millipore hosted its second Pharma-Forum in Darmstadt, Germany, which included discussions regarding new legal requirements for pharmaceutical excipients. Representatives from the pharmaceutical industry discussed ways to secure the supply chain, and updated attendees on the activities of Rx–360 and the development of inspection programs. A key message that came from the event was that the pharmaceutical industry will lose credibility if new cases of contamination or adulteration occur. In parallel, the sentiment of participants was that regulators may be at risk of losing control of the increasingly global and complex supply chain. It was agreed that an important solution to prevent harmful incidents lies with improving risk-management approaches to manufacturing and supply.
The event also included discussion of the EU Directive 2001/83/EC (15) in which the EU Commission gave a mandate to the European Directorate for the Quality of Medicines and HealthCare to establish a risk-based annual program for inspections. According to the directive, inspections are to be performed both inside and outside of Europe and will involve manufacturing sites and brokers/distributers holding certificates of suitability to European Pharmacopeia monographs. It is hoped that the inspections will help detect noncompliance and will result in necessary actions that may include withdrawal of the certificate. Overall, it was agreed that finished-product manufacturers must improve their ability to select GMP-compliant pharmaceutical ingredients suppliers and to audit/monitor them accordingly.
In the past, the risks associated with excipients were underestimated. However, the quality of excipients should match the quality expected for APIs. Excipients are the hidden champions in pharmaceutical drug formulation; no API would work consistently without the optimal excipient. Today, industry organizations and regulatory authorities are evolving toward more stringent regulations. Once common standards are agreed upon, these should provide a basis for improving drug quality and patient safety. In the absence of stringent regulatory practices and in light of the growing complexity and global length of supply chains, selecting the right excipient is vital.
Frithjof Holtz is head of regulatory experts/customer audits and Najib Sehat is director of regulatory and technical services, both at Merck KGaA, Frankfurter Str. 250, D 64293 Darmstadt, Germany, firstname.lastname@example.org, email@example.com.
1. S. Wolfgang, presentation at ExcipientFest Americas (Baltimore, MD, 2011).
2. FDA, "Advisory to Drug and Dietary Supplement Manufacturers, Compounding Pharmacies and Distributors of Excipients and Dietary Ingredients — FDA Detects High Levels of Peroxide in Crospovidone" Drug Safety Alert (Rockville, MD, Oct. 21, 2010).
3. H.R. 1483, 112th Congress, 1st Session (Washington, DC), amended April 12 2011.
4. EC Directive 2011/62/EU, Amending Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use, as Regards the Prevention of the Entry into the Legal Supply Chain of Falsified Medicinal Products (Brussels, June 2011).
5. USP 32–NF 27 <1078> "Good Manufacturing Practices for Bulk Pharmaceutical Excipients."
6. W. Bogdanich and J. Hooker, New York Times, May 6, 2007.
7. IPEC, The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients (2006).
8. IPEC Position Paper, Excipient Pedigree (2008).
9. EFCG, IPEC, European Association of Chemical Distributors and the Pharmaceutical Quality Group, "Certification Standards for Pharmaceutical Excipients: Good Manufacturing Practices, Good Distribution Practices" (March 2011).
10. Rx–360, "Rx–360 Update," www.rx-360.org, accessed Aug. 4, 2011.
11. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices Audit Guideline for Pharmaceutical Excipients (2008).
12. ICH, Q7 Harmonized Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (2000).
13. Rx-360, Audit Guide for Basic Chemicals and Raw Materials (2010).
14. ICH, M4 Common Technical Document (1999).
15. EU Directive 2001/83/EC, Community Cod Relating to Medicinal Products for Human Use (Brussels, November 2001).