Managing the Quality Relationship for a Contractual Agreement: A CMO Perspective

Contract manufacturing organizations (CMOs) occupy a special niche in the bio/pharmaceutical industry and therefore face problems not encountered by traditional bio/pharmaceutical manufacturing companies. One particular challenge facing CMOs is how to define the responsibility for Quality in a relationship. Which party, the contract giver or the contract provider, has which responsibilities? Although the answer may be straightforward for companies with their own manufacturing operations, it is quite complicated for a CMO. When defining ownership of "Quality," a CMO must consider the compliance needs and regulatory commitments for multiple clients. The CMO also must look at Quality as a function of product lifecycle—in a similar manner to how their clients would look at Quality if they were manufacturing the product themselves.

THE BASIC EQUATION

If one views the Quality relationship as a simple mathematical equation, it may look something like this:

where A is the CMO needs, B is the compliance needs, C is the client's needs, D is regulatory commitments, and E is defined as the elements of the Quality relationship. By analyzing this equation, it is clear that there are no constants, only variables. Each variable is based on the consideration of certain elements from each party in the relationship.

Variable A: CMO Needs. A CMO's needs are based on maintaining as much operational consistency as possible when managing internal and subcontracted resources. This approach enables cost management for the CMO and cost savings for the customer. Variable A should take into account the audit, testing, sourcing, and customer-specific requirements needed to manufacture the product. The CMO should make sure these requirements are included as part of the Quality Agreement. When defining auditing responsibilities, consideration must be given to determining the appropriate involvement of the client for internal, external, and regulatory audits and should be somewhat consistent between clients.

Testing requirements (e.g., final product, raw material, and environmental) should include what is required not only to manufacture the product, but also to maintain the environment in which the product is manufactured. For example, testing requirements might be traditional compendial testing, but may also include product-specific testing as defined by the client. In the case of a raw material, the CMO must consider whether the item is used in multiple products and whether it is available from a single or multiple sources. Consider this example: in some cases, the client may dictate the supplier of the component in question because it has an established relationship. In other cases, the CMO may have the more established relationship with the supplier. In such situations, the CMO, in conjunction with the client, must determine who will be responsible for providing the qualification and follow-up audits of that supplier. This type of scenario should be defined in the Quality Agreement so that there is little confusion between the parties. A well-drafted Quality Agreement can save a lot of confusion and duplication of effort on behalf of the client and contract provider and facilitate productive communication.

Variable B: compliance needs. Multiple customers, regulatory agencies, and standard-setting organizations influence compliance requirements maintained by a CMO. Each requirement needs to be implemented to accommodate the broad spectrum of these influences. Variable B of the equation defines the compliance needs for the manufacture of all products at the given facility. Company standard operating procedures (SOPs), customer SOPs, audit observations, and compendial requirements need to be considered in discussion with the client and the CMO. Clients should make every effort to understand their CMO's SOPs.

It is equally important for the CMO to make sure that its SOPs are robust enough to accommodate multiple clients' needs. It is difficult for a CMO with multiple clients to operate using duplicate SOPs for the same process or procedure. The CMO and the client should therefore spend a sufficient amount of time ensuring that the compliance needs of both parties are defined and met.

Similar to variable A, variable B also has an audit element to consider. In this case, the effectiveness and appropriateness of a CMO's audit program is considered. The audit program must meet the regulatory expectations for internal and supplier audits while also meeting the client's expectations on these points.

In addition to these audit requirements, the CMO and the client must discuss the communication expectations for regulatory audits either conducted at the CMO's or the client's place of business. The need for the CMO to communicate with the client when a regulatory audit is being conducted at their facility is evident but it is equally important that the client communicate with the CMO when the positions are reversed. Two-way communication is crucial because each organization could be vulnerable for a regulatory audit based on the outcome of the regulatory audit being conducted at either facility.

In addition to SOPs and audit requirements, compliance to the compendia must be considered under variable B. The client should confirm that the CMO has a process in place for reviewing and updating test procedures to maintain compliance with the applicable monographs, test chapters, and informational chapters maintained by the United States, Japanese, and European pharmacopeial authorities.

Variable C: client needs. Customers bring requirements to the table that may be needed due to factors that are not within the purview of the CMO. These requirements might be influenced by development data, regulatory registration commitments, sourcing strategies, or partnerships. Under variable C, the CMO must consider the needs of the client in order to effectively provide them service. For example, the phase of drug-product development and whether the client is virtual or has in-house capabilities are elements that may affect the allocation of responsibilities within the Quality Agreement. If the product is under a cooperative arrangement with multiple companies, there may be more than one Quality Agreement associated with the manufacturing, packaging, and labeling of the product.

If this is the case, the client should let the CMO know of these agreements and of the expectations when the product is passed to another responsible party during the manufacturing process. In addition, it is important that the client communicate with the CMO whether another contract provider is having regulatory difficulties. Finally, the client and the CMO need to determine whether any special testing protocols are needed for products in Phase 2 or 3 of the development process. If the testing of excipients used in the product is being performed by another organization other than the CMO client, this fact should be disclosed to ensure that excipient compendial requirements are met. The same situation is important with regard to where the material is sourced—whether it be a single source or multiple sources.

Variable D: regulatory commitments. Regulatory commitments are an evolving body of knowledge that may necessitate flexibility to adapt to CMO and client interpretations of new or impending regulations. Variable D considers the regulatory commitments of the client and/or the CMO. CMOs can indicate which regulatory authorities have audited their facilities, when they were last audited, and the outcome of these audits. A CMO must also communicate to their clients the changes and commitments made to their Quality Systems based on the responses to the regulatory audits because these changes may affect the regulatory filings of the clients. Each client will have its own interpretation of how to comply with the audit observation and what filing strategy should be used to update their filings, if any.

The CMO must ensure that its responses to regulatory audits do not jeopardize any of their clients' commitments. On the other hand, clients must communicate with the CMO regarding commitments they have made in their registrations. Among other information, they should disclose to the CMO whether they are using novel excipients as opposed to compendial excipients and whether any special specifications or testing must be performed.

Variable E: The Quality Agreement. The solution to the equation noted above (A+B+C+D) is E, which represents Quality as a function of product lifecycle. The document that contains the information defining the various responsibilities that comprise E is the Quality Agreement. This master document should define the CMO's needs, the client's needs, the compliance needs for the product and both parties, and any pertinent regulatory commitments. The Quality Agreement should be a living document that is reviewed and revised as often as needed to clarify the responsibilities of the client and the CMO as the product progresses through its lifecycle. The Quality Agreement is akin to a marriage license between two parties and should clearly identify the roles and responsibilities needed for a successful partnership.

In general, Quality Agree-ments are legally binding agreements between the Quality functions of the contract provider and the contract giver. Many companies use a matrix approach for defining these activities which can include but are not limited to compliance, manufacturing, packaging and labeling, documentation, change control, nonconformance, out of specification (OOS), deviations, complaints, recalls, and auditing. Each document should be tailored to address the expectations of the specific operations to be undertaken by the CMO as well as external actions that may have an impact on those operations. Clients and CMOs should communicate frequently to make sure that the product being manufactured meets the necessary specifications required to meet the minimum Quality requirements. In order for the relationship between the client and the CMO to be effective, the two parties should communicate often.

CONCLUSION

Defining the Quality relationship between a CMO and a client is complex and requires extensive discussion and attention to detail. The relationship should be open and communication between the two parties should be as frequent as required to assure that the product being manufactured meets the highest Quality standards for the client and for the patients.

SUSAN J. SCHNIEPP is vice-president of Quality at OSO Biopharmaceuticals, susan.schniepp@osobio.com.