Standardizing Excipient Information to Achieve Supply-Chain Security

Efficient and controlled information exchange among excipient manufacturers, distributors, and excipient users is crucial to ensure that the optimal information is obained by the user to better control the drug product. The author discusses the use of various documents and guides by the International Pharmaceutical Excipients Council to facilitate this information flow.

On July 6, 2012, FDA issued a Notification to Industry indicating that oils, glycerin, and proteins commonly used in the production of human and animal food, medical products, cosmetics, and other FDA-regulated products may contain toxins if they are derived from the Jatropha plant (1). A common response to this type of notification is for pharmaceutical manufacturers (i.e., excipient users) to inundate their excipient suppliers with questionnaires requesting information regarding raw-material sourcing of their excipients regardless of the excipient purchased or its origin. This approach rarely results in a successful exchange of key information and will many times slow the flow of crucial information to companies that need this information to provide to regulators and other interested parties.

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A more proactive approach would be to adopt the standardized excipient-information approaches afforded by documents provided by the International Pharmaceutical Excipients Council (IPEC). By using these documents, excipient users have information about excipient raw-material sources and other information needed to answer regulators' questions without the need to ask further questions of their suppliers. Instead of reacting to a regulatory or industry news headline by sending out questionnaires pertaining to a supplier's source and method of manufacture of an excipient, a pharmaceutical manufacturer can take a more beneficial and economical approach by first reviewing existing information already available from its supplier. These approaches are explained in IPEC guides, including among others: the IPEC Excipient Information Package (EIP) Template and User Guide; the IPEC Quality Agreement Guide and Template; the IPEC Excipient Composition Guide; the IPEC Excipient Qualification Guide; and the IPEC–PQG Excipients GMPs Guide, which offers GMP appropriate for the manufacture of excipients and is a joint initiative between IPEC and the Pharmaceutical Quality Group (PQG).

A recent example potentially concerning excipients was the use of "gutter oil" to manufacture antibiotic APIs. Gutter oil is a term used in China to describe illicit cooking oil, which has been recycled from waste oil collected from various sources, such as restaurant fryers, drains, grease traps, and slaughterhouse waste. The potential health effects of gutter oil are unclear because experts have expressed opposing opinions on the safety of the intermediate produced using this oil. The topic, however, became a source of questions from pharmaceutical manufacturers to their excipient suppliers regarding the security of the supply chain of excipients sold in the United States, irrespective of whether or not the excipient could be derived from this material. This incident is another example of where a standardized excipient information package could be used to obviate the need for customer questionnaires and improve the flow of information between excipient manufacturers and users.

Pharmaceutical companies' understanding of the source, quality, and performance of the excipients they use in their drug products is crucial to ensure the safety, quality, and efficacy of the medicines they produce. Excipients have a wide range of applications and are essential components of the drug-product formulation. Characteristics that excipients bring to formulated drug products include appearance, manufacturability, stability, and delivery of the active ingredient. Understanding their composition, performance attributes, manufacturing, and supply chain is essential.

Pharmaceutical users should refer to excipient information previously provided from their suppliers during the user's supplier-qualification processes, such as through the EIP. In the Jatropha and "gutter oil" examples, pharmaceutical companies would have been able to quickly identify excipients that were not subject to the alert and that needed no further follow-up. The informed pharmaceutical user could focus their efforts on the few relevant excipients and APIs.

The pitfalls of questionnaires and surveys

Regulatory bodies make no statements regarding any regulatory requirements for suppliers to respond to questionnaires and surveys for their customers. Additionally, many excipient suppliers sell only a small amount of their products into the pharmaceutical market and may have little interest in supplying any type of nonstandardized information to pharmaceutical users. Excipient users typically send detailed questionnaires and surveys to obtain information using their own individual formats, which makes answering these questionnaires difficult for the excipient manufacturer.

The excipient supplier must carefully read each user inquiry to try to interpret the intent of the user's question, which may or may not relate to the supplier's specific excipient. This situation is obviously more difficult when a language barrier exists. Completion of questionnaires and surveys is time-consuming due to their length and complexity as well as the numbers received by the supplier in all different formats. Furthermore, because these surveys and questionnaires are specific to a particular user, it is impossible for the excipient supplier to identify which responses to inquiries are affected by a change in their operations, and therefore, which customer to alert to the change. Significant resources are expended, both by the user and supplier, to send, complete, return, review, and track these questionnaires and surveys. Finally, for each instance, these responses are a one-time activity and would rarely be updated by a supplier when something changes because these are not the supplier's own documents.

Use of the EIP for such information provides not only a document controlled by the excipient manufacturer but also ensures that the pharmaceutical customer will be provided with each revision. The nature of the EIP, as a dynamic, controlled document with a revision history that is continually updated to address new issues as they arise, supports and benefits both suppliers and users. The EIP allows both parties to have the most current document from which to make assessments of their excipients. Changes to the EIP result in a formal revision and notification to the customer.

The primary goal of the EIP is to provide a standard template for the exchange of information between excipient suppliers and users to simplify the process of information exchange. By responding to surveys, questionnaires, and other requests for information using the standard format outlined in the EIP, excipient suppliers can respond in a timely and efficient manner to all such information requests as well as ensure that consistent information is provided and revisions are tracked. The most appropriate course of action when an emerging issue arises should include notifying IPEC-Americas so that the EIP can be updated, if appropriate.

Excipient users will be able to anticipate the type and format of the standard data packages they receive from their excipient suppliers when using the EIP. This approach will assist users and suppliers in the management of such information. In the future, electronic transmission of such data packages for direct download may be possible. Additionally, such standardization will facilitate the necessary change notifications pertaining to previously supplied information, thereby further strengthening the excipient suppliers' change-notification program and the excipient user's knowledge and understanding of their excipients and the sources of the excipients.

Format of EIP documents

Each section of the EIP covers specific topics. The minimum information that should be covered in each section are defined; however, additional related information also can be provided at the discretion of the excipient supplier. If particular topics are not applicable to a particular excipient or site, it is indicated in the document. Where information is considered confidential, the document reflects how the excipient user can obtain this information. For example, the document may state that particular information may only be obtained under a confidentiality agreement.

EIPs do not require signatures (similar to material safety-data sheets, which also are not expected to be signed) as signatures do not add value or authenticity; however, they must be an official company document. Alternatively, a supplier may create a document that provides comprehensive details and explanations rather than immediately updating an EIP. The provision of the necessary information by the supplier by means of the EIP is more efficient than filling out specific individual customer questionnaires and surveys and the EIP usually has better, more complete information.

The presentation and format of the information is at the discretion of the supplier. Short, bulleted formats are encouraged. Specific phrasing is not prescribed, but suggested phrasing is provided in some sections and can be used if desired. Job titles are used rather than names.

The EIP documents are version-controlled by the excipient supplier. Suppliers should have a process, in association with their management of change policy, for updating EIP documents in a timely manner, including updates to company and product information, EIP template revisions, and notification to customers. The current version of the EIP Template and Guide can be found on the regional IPEC websites (see, http://ipecamericas.org/content/download-ipec-guidance-documents-here).

Application and use

The EIP documents are intended to provide useful information to individuals experienced and competent in the area of evaluating excipient suppliers and are not to be viewed as a replacement for audits. They may serve as pre-audit information to help prepare for a supplier audit so that the auditor's time at the site can be most effective. Although the documents are intended to form a complete package of information, each document within the EIP was designed as a stand-alone document. Some basic information, therefore, may be common among the documents.

To provide additional guidance on specific topics, IPEC–Americas maintains a Regulatory Reference Guide. The Regulatory Reference Guide lists links to the specific regulatory references applicable in different regions to various sections in the EIP documents. These references provide preparers of EIP documents detailed guidance on the information that needs to be included in the various sections. IPEC–Americas' Regulatory Reference Guide is accessible through the IPEC–Americas website (www.ipecamericas.org).

Provisions of standardized excipient information

Because not all products are sent from the manufacturer directly to the end user, it is beneficial for a user to create distributors' quality agreements when buying from distributors. Similar principles apply for distributors and manufacturers with regard to information sharing. It is imperative that the distributor has similar agreements with its excipient manufacturers, particularly with regard to change notification.

IPEC recommends the use of its guides (e.g, Quality Agreement, Excipient Composition, Excipient Qualification, EIP, Excipient GMPs, and Significant Change) for users to obtain information about the excipient distributor, manufacturer, and the excipient itself. The EIP is one of the best tools for sharing information using a standard format as it allows excipient suppliers to respond in a timely and efficient manner to all requests as well as ensure that consistent and up-to-date information is provided.

The EIP User Guide explains the standardized excipients information package and is available at http://ipecamericas.org/content/download-ipec-guidance-documents-here. It is divided into the following sections:

• Product regulatory datasheet: The product regulatory datasheet includes information that the maker and/or supplier provides regarding the product in general, manufacturing, the packaging release site, supplier information, physicochemical information, regulatory information, revision control, and contact information. This section would contain animal origin and raw-material sourcing information.

• Site quality overview: The site-quality overview includes the site overview information, compliance evidence, IPEC–PQG GMP compliance details, and miscellaneous site details.

• Supply-chain security: Supply-chain security information includes the scope of the supply chain, details on supply-chain security, and specific security information while the excipient is within the supplier's control, subject to agreements with, for example, the distributor, and safety and environmental information.

IPEC–Americas encourages excipient suppliers to prepare and keep EIPs up to date for their excipients and to react proactively when alerts are issued for the latest concern or perceived threat. By updating their EIPs and re-issuing them to their customers, much additional work is avoided by all parties, and patient safety is better ensured.

IPEC–Americas encourages excipient users to use information provided in the EIP format to obtain reliable details regarding the excipients they buy and their related supply chains by supporting the use of a standardized format that facilitates open communication in a more efficient manner. Excipient users should always ask their suppliers if they can provide them with an EIP document rather than requesting that suppliers fill out a questionnaire. Only if the excipient supplier declines to supply an EIP should the excipient user send a questionnaire. By adopting such an approach, the entire paradigm for information exchange between excipient makers, distributors, and excipient users will change and become much more productive for all parties while ensuring that the best information is obtained by the user to be able to better control their drug product and ensure patient safety.

Reference

1. FDA, Notification to Industry: Products Using Oils, Glycerin, or Protein That Were Derived from the Jatropha Plant May Have Toxic Effects (Rockville, Md, July 6, 2012).

Bretta Erskine Lichtenhan is North American regulatory affairs manager, MM-Q Regulatory Services, Pharm Chemical Solutions, EMD Millipore, member of the International Pharmaceutical Excipients Council (IPEC)–Americas Executive Committee and chair of IPEC–Americas Excipient Qualification Committee, bretta.erskine@emdmillipore.com.