Excipient Quality Agreements

Exploring the IPEC Quality Agreement Guide and Template

By William Dale Carter
IPEC Americas

In 2006 when the FDA published its Guidance for Industry document Quality Systems Approach to Pharmaceutical CGMP Regulations¹, it emphasized the importance of communication in the control of outsourced operations. This guidance explained that “Quality systems call for contracts (quality agreements) that clearly describe the materials or service, quality specification responsibilities, and communication mechanisms.” The document went on to stress that the pharmaceutical company “should ensure that a contract firm is qualified before signing a contract with that firm” and “that management of the contractor be familiar with the specific requirements of the contract.” The document also highlighted the importance of establishing agreement by stating that the quality standards of the contract firm and contract manufacturer should not conflict. From this guidance was born the avalanche of Quality Agreement documents that proliferated through the pharmaceutical manufacturing world.

The International Pharmaceutical Excipient Council (IPEC) of the Americas organized in 1991 around the need to establish better communication between the makers and the users of excipients. Our working committees have fostered mutual agreement between makers and users leading to the development of science-based guidance to ensure patient safety. We published guidance documents on GMPs, Certificates of Analysis, Significant Change and Excipient Qualification. We also recognized the importance of understanding the risk across the entire supply chain and published an Excipient Pedigree white paper to emphasize the need for supply chain control. The lively and open discussions during our committee meetings provide a sharing of experience from both users and makers perspectives that leads us to identify the pressing need for guidance documents.

It was during an IPEC Americas Excipient Qualification Committee meeting that excipient makers started sharing some of the odd requests being made in Quality Agreement documents. These included FDA Registration as a Drug Product Manufacturing Facility and the need for all print and labeling for finished product packaging to be approved by the customer’s quality unit. As discussion continued we realized that user companies were trying to apply the Quality Agreements written for their contract manufacturers and packagers to their excipient suppliers. What started as an avenue for open communication and understanding had pinioned the process in a maze of confusion and legal jargon that separated both groups in a sea of frustration. Realizing the need for guidance to make excipient quality agreements useful tools for establishing quality partnerships, IPEC-Americas together with IPEC Europe developed The IPEC Quality Agreement Guide and Template (2009) to provide a standard approach throughout the industry that covers most of the typical needs of the pharmaceutical user in a way that makes sense for excipient manufacturers.

Quality Agreements: Purpose and Benefits

The 1990 movie Home Alone provides a great example of what mischief befalls us when responsibilities are not clearly defined. In this movie an extended family and their children meet at the home of one branch of the family before a trip to Europe. The next morning in the flurry of activity involved in getting everyone to the airport, one child gets left behind. Each adult thought another was keeping the head count but in the end no one was.

Within a company, following the trail of “who is responsible” can lead you around a circle of individuals and back to the person originally asked, “Who is responsible?” Complicate this process by adding another company and a dense fog sets in on the “who is responsible” trail between supplier and customer. Quality agreements shine light on the path as to who is responsible and provide a structured process to clearly define responsibilities for quality activities and how quality issues will be resolved.

The IPEC Quality Agreement Guide and Template (2009) defines quality agreements as:

Legally binding agreements that are mutually negotiated between users and suppliers. They are intended to be an agreement between quality departments. A quality agreement is intended to be a formalized, joint agreement on quality responsibilities and activities defining both the users’ and suppliers’ respective obligations as they relate to quality. They are intended to address quality commitments between the parties and are based on the quality procedures in place.

Quality agreements are not commercial supply agreements for sale of product nor are they specifications for terms of sale. Quality agreements compliment these documents by defining the processes and responsibilities of each party that are necessary to ensure the supply of safe excipients suitable for the user’s drug manufacturing process. The agreement provides a starting point for negotiations and dialog so that the quality groups of both parties understand their obligations. These agreements are two-way and define both the maker’s and the user’s responsibilities. Changes made during this process lay the foundation for a strong supplier relationship and prevent future misunderstandings that lead to quality issues. Removing these discussions from the commercial agreements negotiated between sales and purchasing groups allow the quality groups of both parties to focus on building strong links in the supply chain.

By clearly communicating responsibilities and expectations, quality agreements provide a venue for each party to review its internal quality systems to prevent inconsistencies and to ensure their quality system processes support their commitments in the agreement. They are not intended to be a reiteration of the full GMP text or to repeat detailed procedures. Quality agreements instead provide the common reference such as The Joint IPEC PQG GMPs for Pharmaceutical Excipients, The IPEC Significant Change Guide or user-specific procedures that are included as reference along with the agreement. The agreement asks the maker to have certain procedures that the user considers critical to support the supply. The process also provides an opportunity for the maker to communicate its practices or limitations to the users so that adjustments can be made in the agreement.

The IPEC Quality Agreement Guide

The IPEC Guide consists of three introductory pages that explain the use of the Quality Agreement Templates and Table of Responsibilities that follow. The “Scope and Purpose” section of the guide defines the two templates offered.

1Manufacturer Template: Designed for use between the original manufacturer and either the end user or a distributor. The original manufacturer is the company manufacturing a material to the stage at which it is designated as a pharmaceutical starting material.

2Distributor Template: Designed for use between the distributor and the end user. Distributors are those parties handling the excipient after the point at which the excipient is transferred outside the control of the original manufacturer’s material management system. Distributors include those parties involved in trade and distribution, reprocessors, repackagers, transport and warehousing companies, forwarding agents, brokers, traders and suppliers other than the original manufacturer.

The “Format” section explains the legal-style format of the template and the table form used for the Quality Responsibil-ities. Quality agreements are binding legal documents that should be reviewed by the legal counsel of both companies. The legal-style format of the template covers the terms and conditions and scope of the agreement. While the template is designed to be flexible, the legal structure and elements common to excipient agreements found in the agreement template should be modified with advice from someone familiar with the structure and content of legal documents. The tabular format of the quality responsibilities serves as a quick reference and facilitates the editing, additions and omissions necessary to form a mutually accommodating agreement and accurate reflection of how the quality systems of both companies function together.

The “Responsibilities and Review” section provides instruction on the negotiation process and on consolidating quality provisions from other documents into the quality agreement. Guidance is offered for maintaining the agreement and ensuring proper review when the amendments or addenda are added. Caution is also offered to check that each person signing the document has the authority to sign on behalf of the company.

Quality Agreement Templates and Responsibility Tables

The templates contain example wording that could be used in a quality agreement for an excipient manufacture or a distributor. Notes and comments are included to help guide the writer of the quality agreement. Each Template consists of 12 sections:

1. Introduction/Purpose
2. Compliance
3. Manufacturing, Packaging and Labeling
4. Documentation and Records
5. Storage and Distribution
6. Change Control
7. Non-Conformance
8. Auditing
9. Quality Contacts
10. Signatories
11. References
12. List of Attachments

Section one defines the parties to the agreement, the excipients covered, and quality criteria such as IPEC PQG GMP. It names both parties to whom the quality agreement will outline the responsibilities with regards to quality activities. It gives the sites involved and defines the use of third parties. It provides the terms of agreement, assignment of obligations, confidentiality, other agreements and choice of law. Some of these parts are omitted or simply referenced if already included in the supply agreement.

Sections two through eight reference the “Quality Agreement Responsibility Table” (see figure 1). This table provides details on activities and quality system references that should be included in the quality agreement. The organization of this table allows for easy access to the activities included in the agreement.

Sections nine through twelve include the names of the quality contacts for each company and facility, the signature section, references, and attachments. The contacts will be responsible for maintaining the agreement and ensuring company processes stay aligned with the original obligations.

This article provided an overview of the IPEC Quality Agreement Guide and Template (2009). This document and all other IPEC Guidance documents are available for download free of charge by both IPEC members and non-members at the IPEC-Americas website, http://ipecamericas.org/. Excipient manufacturer, distributor, and user companies are invited to join IPEC-Americas and participate in the work of developing excipient guidance documents and articles that serve to enhance patient safety. Associate membership is also available to consultants and the academic community. Information on membership is available from the IPEC-Americas website.

References
1 Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations; US FDA September 2006

Acknowledgements

IPEC-AMERICAS

Alexa Smith, Colorcon
Priscilla Zawislak, Ashland Inc.
Craig Scott, JRS Pharma LP
Laura Horne, Mutchler, Inc.
David B. Klug, sanofi-aventis
Maria Guazzaroni Jacobs, Pfizer
Londa Ritchey, Wyeth
Chris Armstrong, Evonik
Judy Emmert, Abbott
Ann Van Meter, Dow
Cindy Libonati, Purdue Pharma L.P.

IPEC EUROPE

Johanna Eisele, Evonik Röhm GmbH
Karen M. Hudson,, Lilly UK
Iain Moore, Ph.D., Croda Europe Ltd,

William Dale Carter is the Chair Elect and GMP Committee Chair for the International Pharmaceutical Excipient Council (IPEC) of the Americas. He is the Global Director of Quality for the Silica Business Unit of Huber Engineered Materials, where he is responsible for quality systems, product quality and compliance with IPEC/PQG GMPs for the manufacturing of Silica products at facilities in Tennessee, Maryland, India, Finland, and China. He can be reached at dale.carter@huber.com.