Arthur J. Falk, PhD, is president and CDO of International Pharmaceutical Excipient Auditing (IPEA).

Arthur J. Falk, PhD

Pharmaceutical companies have spent much time, effort, and money to ensure excipient quality. Whether an excipient travels through a short and direct, or long and complex supply chain, history has shown that, unfortunately, dangerous, often life-threatening changes are sometimes made to the excipient along its path. Consider the following examples: 					

In 1990, approximately 330 people died in Bangladesh after a paracetamol solution was flavored with glycerin containing diethylene glycol (DEG). 

In 1996, tragedy struck in Haiti, when a pharmaceutical company bought glycerin it believed was produced in Europe. The glycerin had been handled by at least seven distributors and was traced back to China. The contaminated glycerin contained a significant amount of DEG and led to the deaths of 80 children.

As a result of the Haiti incident and a subsequent investigation uncovering the involvement of numerous distributors and brokers, in 1998, the World Health Organization (WHO) developed the Good Trade and Distribution Practices  for Pharmaceutical Starting Materials (GTDP) guidelines. That same year, the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) published a position paper on vendor qualification.  IPEC-Americas, along with IPEC–Europe and IPEC–Japan, have since published numerous guidelines covering such topics as good manufacturing practices (GMPs), good distribution practices (GDPs), the use of certificates of analysis (COAs), and significant-change notification to help manufacturers protect their excipient supply chains. 

In spite of these efforts, supply-chain incidents involving excipients occurred agin in China in 2005 and in Panama in 2006.  As a result of these incidents and drug-importation discussions with the US Food and Drug Administration, IPEC-Americas and IPEC–Europe released a position paper on proper excipient pedigree in December 2008 (available for free download at 

Three basic approaches of tracking chain of custody were explored, including paper trail, barcoding, and radiofrequency identification (RFID). Because of the complexity of the excipient industry, the authors (including excipient manufacturers, users, and distributors) deemed that the quickest approach that could be implemented with the least disruption to the supply chain was a verified paper trail. (It's important to note that FDA reviewed the position paper; the authors considered the agency's comments and for most the part,  included them in the final version).   

Although a single program cannot prevent fraud, a pedigree approach—using existing paperwork (or electronic paperwork) to the greatest extent possible—is a strong deterrent. The IPEC Excipient Pedigree Position Paper is founded on four premises: 					

WHO and IPEC GDP guides already recommend documentation that can be used to support a paper-trail  

The 1998 IPEC–Americas position paper on the qualification of excipient vendors places a full obligation on the excipient user to be aware of the product's complete supply chain 

Distributors consist of all parties involved in trade and distribution, including (re)processors, (re)packagers, transport and warehousing companies, forwarding agents, brokers, traders, and suppliers other than the original manufacturer

Excipient makers, users, and distributors must cooperate to make this scheme work. 

The excipient manufacturers' role includes manufacturing the excipient according to the IPEC/Product Quality Group  GMPs, as well as following the GDPs for distribution operations performed. Additionally, the position paper states that a manufacturer is expected to provide documentation to verify it shipped the excipient to a distributor if it used this supply chain.   

Finally, if the manufacturer is using a distributor, it is recommended that the manufacturer ensure the distributor is in compliance with IPEC GDPs and that the distributor takes appropriate measures to prevent cross-contamination. IPEC and the authors of the position paper believe that verification is best accomplished by auditing the distributor. The paper also recommends that excipient manufacturers and distributors conduct mock recalls to test the effectiveness of their recall procedures. 

The IPEC GDP guide calls for a distributor to provide the user, upon request, with a chain-of-custody record for the excipient. This record might include bills of lading or air bills with the financial data redacted. The distributor should also provide a COA for each delivery (a copy of the COA from the original excipient manufacturer is acceptable). 

The data reported on the COA, however, must be based on the manufacturer's analytical testing results and include, as recommended by the IPEC COA guide, the identity and location (including country) of the manufacturer. When a distributor provides its own COA, the manufacturer and the site are identified. If the distributor repackages the excipient or packages from bulk, the distributor must sample, analyze, and include its results in its own COA.  A distributor-developed COA should identify the original manufacturer and manufacturing location. Traceability of the exipient manufacturer is required to enable the recall of material.   

Furthermore, the position paper suggests  that if a distributor receives material into a holding tank, only materials from the same manufacturer's site or terminal conforming to the same specifications should be mixed. Distributors that load or package from bulk excipient should follow the WHO GTDP and IPEC GDP principles regarding definition of batches, analysis of material, and preparation of COAs. The distributor also should have an effective change-management program in place. 

The excipient user bears the responsibility for all excipients used and, therefore, must know the origin and complete supply chain (i.e., excipient pedigree) for each batch of each excipient. Apart from performing appropriate testing of each incoming excipient lot, the position paper states that the user should audit both the excipient manufacturer and all distributors in the supply chain, or use the results of an audit. FDA has indicated that it is permissable to use a qualified third-party to conduct these audits and IPEC has published audit guides that can be used for this purpose. It's also important for the user to periodically verify the chain of custody described above to ensure the pedigree's accuracy. All these steps can be completed as part of supplier qualification and supply-chain management.    

The final topic addresed in the IPEC excipient pedigree paper is labeling. IPEC recommends excipients never be labeled as compendial material (e.g., 

) solely based upon test results. To protect the supply chain, non-GMP material should never be relabeled as compendial grade based solely on conformance to the compendial monograph. The original material must have been manufactured and distributed in conformance with appropriate GMP and GDP requirements, including testing, storage, repackaging, and relabeling. 

Verifying the pedigree of an excipient with a paper trail (or electronic paper trail) only works with the cooperation of everyone involved in the supply chain. If a single party fails to adopt these preventive measures voluntarily, verification may eventually be mandated by more burdensome and costly regulations.  

president and CEO of International Pharmaceutical Excipient Auditing (IPEA), tel. 908.735.812, 

. The IPEC documents mentioned in this article can be downloaded for free at 

Articles

It's time to maintain a thorough traceable excipient trail.

Inside IPEC: Excipient Pedigree as a Supply Chain Tool

Past events, and unfortunately some recent ones, provide evidence of threats to the pharmaceutical supply chain. It is clear that excipients, active pharmaceutical ingredients (APIs), and pharmaceutical products can be counterfeited, contaminated, purposely mislabeled, and adulterated. Although the authors concentrate on excipients in this article, a review of incidents involving all of these product types and similar ones show the diversity of causes and the complexity involved in preventing these incidents. As reported by the World Health Organization, the Center for Medicines in the Public Interest predicts that counterfeit drug sales will reach $75 billion globally in 2010, an increase of more than 90% from 2005. Just as dangerous is the counterfeiting or contamination of the ingredients used to manufacture pharmaceutical products. 

Recent deaths associated with heparin imported from China have drawn attention to APIs. The discovery of  over-sulfated chondroitin in heparin was directly linked to some of the deaths. The speculation of how this chemical came to be in the API ranges from accidental contamination to purposeful adulteration to a change in the process for harvesting the heparin from pigs as a way to increase yield and reduce costs. These situations show the importance of the process for receiving and approving pharmaceutical starting materials in a fully integrated and robust quality system. 

The most tragic incidents involving excipients have involved glycerin, an artificial sweetener (see Table I). These tragedies were caused by diethylene glycol (DEG). Most cases of DEG poisonings are believed to have occurred because of pharmaceutical counterfeits that contained glycerin (also known as glycerol), which is widely used in drug formulations and personal-care products. DEG and glycerin are both clear, odorless, sweet-tasting liquids, but DEG is much easier and cheaper to manufacture. As a result, DEG poisonings have typically occurred because of greed as well as poor quality control for receiving and approval measures during the formulation and dispensing of medications.  

Table I: Select incidents involving adulterated ingredients.			

Other recent examples include toothpaste containing DEG and pet foods manufactured with wheat gluten contaminated with melamine. These examples serve as clear warnings of threats to pharmaceutical supply chains and also provide insight into measures that must be taken to avoid similar tragedies.  

Excipients are used in food, beverages, nutritional supplements, personal-care products, and industrial products in addition to pharmaceutical applications. The food and beverage industry is the primary market for many excipient manufacturers. Facilities producing food ingredients or food additives that are also sold as excipients are usually dedicated to a single product or product families produced under food good manufacturing practices (GMPs) (1). These products typically ship from the manufacturer in finished-goods packages or in bulk to distribution facilities that may hold and package or transfer the product for regional delivery. This situation presents unique challenges in the excipient supply chain because food GMPs do not contain the appropriate controls for pharmaceutical excipients. The Joint International Pharmaceutical Excipients Council–Pharmaceutical Quality Group's (IPEC–PQG) Good Manufacturing Practices for Pharmaceutical Excipient Guide and the IPEC Good Distribution Practices (GDPs) Guide provide direction on the appropriate controls necessary to ensure pharmaceutical excipient quality. 

 The difference between food processors operating under food GMPs and pharmaceutical makers governed by drug GMPs influences the quality systems and operational controls their suppliers adopt. Food GMPs focus on sanitation to prevent the introduction of contaminated or spoiled food. They do not include provisions on quality that ensure the taste, aesthetics, or health benefits of food. GMPs for finished drug products focus on the controls necessary to ensure the identity, strength, quality, and purity of the drug product. The rule of thumb of food regulation is that ingredients should not harm the consumer. The emphasis of drug regulations is that the products also must provide benefit to the health of the patient. Food GMPs do not require specifications for food ingredients. GMP requirements for incoming-goods inspections in the food industry involve inspection to ascertain that the ingredients are clean and suitable for processing into food. Raw materials are often purchased under a supplier's letter of continuing guarantee that assures the ingredient meets food GMP requirements for the absence of pathogens, natural toxins, pests, or extraneous matter. Food-ingredient suppliers provide a letter of continuing guarantee stating that the products shipped will not be adulterated under the Food, Drug and Cosmetic Act in place of certificates of analysis (COAs). Manufacturing personnel release food ingredients for shipment through process-control data monitoring. Their internal audits and controls focus on sanitation inspections, product protection, and cleaning schedules. 

 In contrast, drug GMPs require testing of each component for conformity with all written specifications to assure the purity, strength, and quality of the finished drug product. As a result of their customers' requirements, excipient suppliers have written release specifications for their products that rely on sampling and testing by a quality unit. Excipient manufacturers provide COAs for each lot that conveys the results of such testing. Internal audits and controls for excipient manufacturers ensure that procedures are followed to produce consistent quality excipients. 

 Fungible distribution practices in the food ingredients and industrial chemicals markets, where the same ingredient from multiple manufacturers and manufacturing locations are comingled in a common storage tank, are commonly used to reduce distribution costs. Compatible ingredients may be unloaded into storage with no cleaning, relying on the high dilution factor to maintain product conformance. Samples from these tanks are periodically collected by contract surveyors and tested in local laboratories against multiple specifications to identify suitable customers. When a food ingredient or additive is sold as an excipient, the test results on a COA may list each parameter in a 

) monograph with a statement such as "meets 

 specifications." This misleading statement, which indicates conformance to the monograph, implies to the pharmaceutical user that the excipient was manufactured and distributed following appropriate GMPs and GDPs. Conformance to food GMPs is insufficient to assure that the ingredient quality system adequately conforms to excipient GMPs. As such, product testing simply to determine compliance with a 

 monograph does not mitigate risk and does not indicate that a food ingredient or additive is suitable for use in drug manufacturing. 

It is paramount for the pharmaceutical manufacturer or user to know where and how the excipients were manufactured and to understand the excipient supply chain thoroughly. The pharmaceutical user is responsible for knowing the excipient pedigree (2). Qualification of the excipient manufacturer begins with the pharmaceutical user's request for information concerning regulatory, quality, and site-security details using the Excipient Information Package (EIP) (3). In the past, an excipient manufacturer would receive questionnaires from each customer, requesting similar information but in different formats and with differing expectations as to the details. IPEC developed the EIP in a standard format, based upon the material safety data sheets that are widely used to convey safety information, to facilitate the communication of this information. This standard document benefits the excipient manufacturer because it provides the essential information that all pharmaceutical users need while assuring the pharmaceutical customer receives detailed information and is notified of changes to the content of the EIP (4).  

Many times excipients are not sold directly to the user, but instead go from the excipient manufacturer to a distributor that sells them to the pharmaceutical user. Distributors should maintain the manufacturer's EIP on file to facilitate the delivery of the document from the excipient manufacturer to the pharmaceutical user.  

Qualification of the excipient manufacturer by the pharmaceutical user also requires confirmation that the excipient was produced and handled in conformance with excipient GMPs and GDPs. A site audit of the entire supply chain is the only suitable way to assure conformance. The excipient manufacturer and any and all distributors in the supply chain should be audited.  

The excipient manufacturer should be audited for conformance with excipient GMPs (5–6). IPEC has issued a companion audit guide to facilitate site audits (7). An audit should confirm that the excipient was produced at the site with a quality system that is in substantial conformance with GMPs. Although an audit of the excipient manufacturer is customarily done by the user, it is acceptable practice to use a qualified third party to perform these audits.  

The user should also audit all distributors that are part of the supply chain for conformance to GDPs (8). IPEC has also issued a companion audit guide to facilitate audits of distributors (9).  

 Requirements for a distributor to comply to GDPs vary based on the distributor's services, which can range from warehousing and distribution to repackaging into smaller containers to packaging from bulk storage. For instance, a distributor that warehouses and ships excipients only has to comply with GDPs. A distributor that packages or repackages excipients, however, must also meet various GMP requirements regarding protection of the excipient from environmental contamination or degradation during packaging operations, proper labeling, suitability of the packaging components, maintenance of retained samples, and ongoing stability testing. 

Proper receipt and approval of incoming components is the final step in assurance of the supply chain, and care must be exercised for excipient security. Although it is customary for the user to inquire or specify excipient packaging and labeling, compliance may not be verified at receiving. The emphasis at receiving is confirmation that the package has protected the excipient followed by quality-control sampling. 

To provide assurance that there has been no tampering with the excipient at the distributor or in-transit, it is important to identify the original manufacturer's packaging, labeling, and tamper-evident seal. This review also applies when the excipient has been repackaged or packaged from bulk at a distributor. 

At minimum, the manufacturer's description of the excipient packaging, labeling, and tamper-evident seal should be available to the people responsible for assessing incoming components. A catalog of electronic photographs of the excipient manufacturer's packaging, including contact packaging, labeling, and tamper-evident seals, should be available at receiving. Procedures can then be established to require comparison of the excipient received with those reference photographs to confirm the manufacturer's original packaging, labeling, and tamper-evident seal. 

Once the physical appearance of the excipient packaging has been confirmed, the excipient is sampled according to a scientific sampling plan. This plan should be developed with an understanding of the homogeneity of the excipient lot. Care should be taken in combining samples from individual containers and subsequently removing an aliquot for testing because it is important to first assure the homogeneity of the combined samples. The practice of only performing the identification tests on an aliquot of the combined samples is not recommended. Identification tests should be performed on each sample taken in the scientific sampling plan. 

Examination of the COA is ordinarily the final step in the incoming inspection of components. Although it is important to verify that the test data conform to the appropriate monograph or specification, it is also important to confirm the veracity of the document. Ordinarily, there are no concerns with the authenticity of the COA when provided to the site electronically directly from the manufacturer. When the COA is received along with the shipment, the appearance of the COA should be examined for any signs that it may have been altered. 

Periodically, it is important to confirm the security of the supply chain. This process involves the following:								

Verifying there is a current assessment of the manufacturing site and all distributors that provide the excipient. 

Tracing the shipping papers for a lot (i.e., the manufacturer's bill of lading) back to the excipient manufacturer. This trace can be achieved by having the excipient manufacturer confirm that the lot in question was produced at its facility and shipped as indicated on the bill of lading that the manufacturer provided for shipment to its customer or distributor. 

Confirm that the COA for a lot has come from the manufacturer indicated on the document by asking the manufacturer to send the customer a duplicate COA or by asking the manufacturer to confirm the identity of the COA received in conjunction with a designated lot of excipient. 

By following the measures described in this article, the excipient supply chain can continue to provide excipients that are suitable for use in pharmaceuticals. 

, is vice-president and chief operating officer, and 

, is president and CEO, both at International Pharmaceutical Excipients Auditing,1655 N. Fort Myer Drive, Suite 700, Arlington, VA 22209, tel. 703.351.5266, 

, is global director of quality of J.M. Huber's silica business unit. 

, is director of quality and regulatory policy for worldwide pharmaceutical sciences at Pfizer. 

 is director of global regulatory affairs at Colorcon, chairman of the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas), and a member of 

*To whom all correspondence should be addressed. 

 (US Government Printing Office, Washington, DC) Part 110, pp. 216–226.  

 2. IPEC, "White Paper on Excipient Pedigree," manuscript in progress as of Sept. 3, 2008. 

 Standardized Excipient Information Protocol User Guide

 4. D. Klug, A. Van Meter, and Laura Horne, "The Excipient Information Package, A Win–Win Solution," 

 26  General Chapter <1078>, "Good Manufacturing Practices for Excipients." 

The Joint IPEC–PQG Good Manufacturing Practices Guide for Bulk Excipients

The Joint IPEC–PQG Good Manufacturing Practices Audit Guide for Pharmaceutical Excipients 

The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients 

Securing the integrity of the excipient supply chain is a crucial task in ensuring the overall pharmaceutical supply chain. The authors outline excipient-control strategies and practices for the manufacture, distribution, and receipt of excipients.

Excipient-Control Strategies

Two FDA final rules issued in response to the Bioterrorism Response Act of 2002 may significantly affect the supply and importation of pharmaceutical excipients.