In today’s environment of increased outsourcing in the Pharmaceutical and Biopharmaceutical industries, Sup-plier Quality Agreements play an important role in ensuring drug quality and compliance to current good manufacturing practice (cGMP). Quality agreements define the system and processes by which a client and vendor manage the quality aspects of drug manufacturing and controls through collaborative partnering. In order to be effective, a quality agreement and the supporting implementation process need to be focused, clear and executable.

Determining the Proper Breadth of Scope

The scope of a quality agreement needs to be in alignment with the services being provided to the client. Some quality agreements attempt to cover every possible type of work a client contracts out, or every type of service a particular vendor may provide, depending upon whose template was used to draw up the agreement. The most obvious benefit of using an all-encompassing quality agreement is to avoid the need for revision if the scope of work is expanded.

However, this benefit is outweighed by the value of keeping the agreement focused on those services that are most important, the ones being provided. It sounds simple but, for example, there is little to no value in addressing stability testing requirements for a contract relationship that only involves packaging and labeling services. The time it takes to discuss and negotiate quality terms for services that are not currently being provided is better spent dealing with more critical aspects of the agreement. A good approach is to keep the scope of the quality agreement consistent with that of the associated Master Service Contract (MSC).

For vendor-client relationships that involve services supporting the production of both investigational clinical trial materials and commercial products, it is best to delineate the investigational and commercial requirements in the quality agreement. Although most aspects of the cGMPs apply to both investigational and commercial products, there are some significant differences. For example, validation of the manufacturing processes is not required in early clinical phase production, but is required for commercial supply. It is often difficult and unreasonable to try applying one set of standards to both types of materials. In the case of a product making the transition from clinical phase to commercial, it is often easiest to upgrade an existing investigational-based quality agreement to a more commercial-focused agreement in conjunction with an associated MSC revision. For contract relationships that support multiple products of both types, it is recommended that separate investigational and commercial quality agreements be maintained, or a single agreement with separate sections for investigational and commercial services be utilized.

A scenario often encountered is corporate outsourcing, where services are provided to or from multiple sites or divisions within a single corporation. This type of relationship can be covered through a single corporate quality agreement or by a series of site-specific quality agreements. Both approaches have their advantages and disadvantages. The primary advantages of a corporate agreement are the harmonization of standards, responsibilities and expectations, and the need to manage only one agreement. The major disadvantage is that it is often incredibly challenging to come to consensus on terms between not only the client and vendor, but the different sites within the same corporation, and once terms are in place it’s nearly impossible to coordinate timely implementation of needed revisions.

In order to get a corporate agreement in place, the parties are often forced to generalize the specific aspects of the agreement to a point where the respective parties’ expectations are unclear and the value of the agreement is minimized. Sometimes the choice between corporate and site-specific agreements is dictated by the structure or history of the participating organizations. For example, if a vendor has recently undergone acquisition by a larger corporation, it is not uncommon to start off with a site-specific quality agreement which is later converted to a corporate format once the vendor has been fully integrated into the corporate parent company. Carefully weigh the pros and cons of each approach, and determine which provides for the most effective means of quality partnering.

The Quality Agreement Document

A typical quality agreement is composed of the following major sections:

• Purpose and Scope
• Abbreviations and Definitions of Terms
• Communication
• Responsibilities
• Changes and Revisions
• Dispute Resolution

It is important to carefully review the definition of terms in the agreement. Make sure that all terms are consistent with those covered in the associated MSC and Work Orders. Both parties should take the time to discuss those terms that impact decisions or follow-up actions. For example, “Major” and “Minor” manufacturing deviations typically will involve different levels of notification and approval. Most clients will require a vendor to notify them immediately when a major deviation has occurred or is planned to occur, and will want to have a co-approval role. Notification for “Minor” deviations may only be required in the form of a summary at the conclusion of a manufacturing run, and require no formal approval on the client’s part. Therefore, it is critical that both parties come to a common understanding of what is meant by “Major” versus “Minor” in order to avoid unhappy surprises at batch record review time.

The quality agreement should clearly outline how quality matters are communicated between the parties. Primary quality contacts should be identified with contact information such as phone and fax numbers, mailing and e-mail addresses. Consider including backup or secondary contacts to deal with time-sensitive or crisis issues when the primary contact is unavailable. Many quality agreements only include the heads of each organization’s quality unit, yet these folks are rarely the appropriate person to deal with for the day-to-day quality issues that may arise during production or testing runs. If the quality agreement covers multiple products and services, it may make sense to identify different quality contacts responsible for specific products or services. The contact section is often a living part of the document as employee assignments change and/or personnel move on to other employment. It should be noted in this section that periodic updates to the contact listing do not constitute a formal revision to the document and therefore do not require change approval.

The client’s and vendor’s respective quality roles and responsibilities should be stated in a clear, straightforward manner. Some companies employ a minimalist approach, incorporating a matrix based table which simply lists the major quality activities and identifies the primary responsible party by an “X” or check mark (see Table 1). This approach alone, often leads to confusion concerning expectations and deliverables resulting in a less-than-optimal working partnership. Elements such as notification levels, shared roles, specific deliverables, and turnaround expectations should be clearly presented either in the text of the agreement of in some other type of documentation. Table 2 represents an example of detailed expectations integrated into the text of the responsibility matrix. Other options include covering specifics in joint operating procedures or documenting detailed expectations in the form of meeting minutes.

Changes to the quality agreement will be inevitable. The scope of work, responsibilities, and quality requirements are all subject to change. It is important to cover how review and revision of the agreement will be managed. Define periodic review periods to ensure the agreement is up to date with current practices and to address any issues that have arisen since the last review. Also define under what conditions the agreement may be brought up for non-routine review, such as when major changes in services are to be provided.

Lastly, terms for dealing with quality and performance disputes should be included. It is important to predetermine 1) how disputes will be communicated and resolved, 2) how notification of issues is to be carried out, and 3) what management level in each organization is required for decision making. Timing expectations for carrying out investigations, generating investigation reports and making decisions should be defined along with the format for capturing and communicating the decisions.

Getting the Quality Agreement in Place

Achieving timely implementation of a quality agreement requires a focused and collaborative effort. The agreement is typically linked to the MSC approval process and thus requires the participation of multiple stakeholders from both parties. Stakeholders in the process include:

• Quality Assurance
• Quality Control
• Customer Groups (Manufacturing, Process Development)
• Regulatory Affairs
• Legal Affairs
• Sourcing
• Business Development

In order to minimize approval time, a defined internal process should be established within the organization to streamline internal reviews and provide for rapid response to the other parties draft review changes. All participants within an organization should have a clear understanding of the company’s quality expectations and their role in the implementation process.

Probably the most difficult aspect of implementing a quality agreement is negotiating the terms and requirements. It is important for both parties to take time to discuss and understand each other’s quality systems, philosophies and business models. Each party should take a risk-based approach to pre-determine those conditions that they consider critical “must haves” versus those that are negotiable. The ultimate goal is to have a sound working partnership that produces quality drug in accordance with cGMP, so efforts should be focused on those key elements that are most important to each party, with minimal time spent on less important issues that don’t impact the overall goal.

Consideration that vendors service many different clients should be taken into account when negotiating the terms of the quality agreement. Forcing a vendor to work outside of its routine systems can cause non-value added cycle time increases and higher deviation rates. Where applicable, a client should utilize the vendors document formats and processes. For example, clients should consider using the vendor’s format when drafting the quality agreement. Presenting requirements and terms in a format with which the vendor’s personnel are readily familiar will most likely increase the probability of full compliance and limit the number of misunderstandings concerning expectations and deliverables.

Monitoring Effectiveness

The approved quality agreement sets the stage not only for monitoring the quality and compliance of services provided, but also for monitoring the client-vendor relationship. Both parties should identify and monitor key metrics regarding product quality, adherence to the agreement and overall performance. Here are some key metrics to consider:

• Product failure rates
• Out of specification rates
• Testing failure rates
• Major product deviation rates
• Quality agreement deviation rates
• Turnaround times
• Notification times
• Response times

Focus should be placed on a limited number of important metrics that provide the most useful information. Too many metrics dilute the attention from key issues and take time away from more pressing matters. Metrics should be shared between the parties on a regular basis. A metrics review could be included as part of the annual quality agreement review, or more frequent meetings could be established during which time is specifically dedicated to discussing compliance and performance measures.

In summary, the quality agreement can be a powerful tool for maintaining product quality and a productive client-vendor partnership. To ensure effectiveness, the agreement needs to be written in a clear and focused manner, and must set the stage for managing the quality relationship between client and vendor.

Marc Wolfgang is director, quality assurance, at Millennium Pharmaceuticals, Inc. He can be reached at show_email(“wolfgang”, “mpi.com”, “”, 1);