Harmonizing Quality Management Systems In Early Drug Development

By Bikash Chatterjee, president and chief science officer, Pharmatech Associates

Today, most biopharma development programs include the support of a contract service provider (CSP) for everything from early development contract research to commercial manufacturing and analytical support. The factors that drive the decision to engage a CSP for commercial manufacturing are many, and there are multiple collaboration elements that impact organizations’ ability to work together effectively. Let’s explore one of the most important considerations when establishing a relationship with a CSP for early development programs.

A LOOK AT DIVERGENT PRIORITIES
The challenges that face the sponsor company and CSP are often divergent. For example, a CSP must balance the unique requirements for a new program with the commitments and systems it has already in place for existing commercial clients and products. The compliance tolerance and philosophy of a sponsor, on the other hand, can be moving targets, complicated by evolving regulatory standards and industry best practices, and to a great extent, innovation and technology. The CSP’s ability to juggle and accommodate these customer variances will often define its suitability as a long-term and fully aligned partner.

In a recent industry survey, 315 respondents cited no less than 18 criteria for evaluating a CMO. But while every outsourcing decision has program-specific elements integral to the selection criteria, there are common elements to be considered that help avoid unexpected surprises – on both parties’ behalf.

HARMONIZING QUALITY MANAGEMENT SYSTEMS
A core challenge to a successful engagement with a CSP is aligning the quality management system (QMS) for both the sponsor and the provider. For virtual organizations, there may be very little to harmonize, and partners are often selected in large part based on the maturity of their QMS. However, as programs move through development, and the sponsor establishes its own internal expertise and oversight, the potential for divergent processes and practices increases. Here are several elements of a QMS that can become points of contention between a sponsor and CSP and should be considered when evaluating a partner.

CHANGE CONTROL
Change control processes are notorious for their ability to impede a program. Poorly designed change control programs are known to suffer from a myriad of weaknesses, including a poorly defined or missing risk component, poorly defined structure and content, and a propensity for subjectivity. Each of these weaknesses is magnified when engaging a CSP.

An initial due diligence audit is an excellent opportunity for determining how change control is administered at the development site, and how and when the sponsor will be involved in its evaluation. Often, it’s stated that “any change that could impact the sponsor’s product will include an evaluation by the sponsor.” But as always, the devil is in the details. For example, does a one-for-one replacement, typically described as a “like and kind” replacement, include a sponsor sign-off? When evaluating the change control process, consider the following four questions:

1. Does the procedure clearly articulate what constitutes a minor, major, or critical change?
2. Does the change control procedure clearly define under what circumstances and to what extent a sponsor can be involved in a change control process and decision?
3. Does the sponsor have a clear process for capturing changes in the CDMO’s process within its own QMS?
4. Is that process compatible with the CSP’s current process?

This last point particularly is often overlooked and can be a major point of friction for sponsors with their own well-developed QMS. Moreover, this can be especially critical for sponsors with products that utilize a device component, which could entail a cross-reference between the design history file, if changes are required.

INVESTIGATING DEVIATIONS/NONCONFORMANCES
Deviations require both the CSP and sponsor to understand the root cause and implications of a process or QMS excursion. Unfortunately, the thoroughness of the root cause investigation can also become a point of contention, particularly because it can impact both material supply and financial responsibility. Understanding whether a sponsor can be involved in an investigation — and to what extent — is critical to conducting and documenting an effective root cause investigation. For early development programs, where the technical insight is fluid, it is not unusual to have the sponsor intimately involved. In later stage programs, the sponsor may have only review and approve authorization. In fact, some CSPs will only allow review and approve authorization. This, though, can place a great deal of responsibility back on the sponsor in its assessment of the provider’s ability to effectively execute a thorough root cause analysis.

Most CSPs are, in fact, reluctant to modify their typical deviation template, because they would constantly be revising the document for each new customer engaged. In addition, deviations will reside in the provider’s QMS, and so the sponsor needs to decide if it is important to have corresponding references within its own system.

Another element of complexity, depending on the severity of the excursion, occurs when the CSP can choose to limit an observation to the sponsor’s specific lot, but the sponsor determines that the excursion is part of a larger, fundamental issue. It’s vital to have a clearly articulated process for handling this type of discussion.

LABORATORY SERVICES
One of the most challenging elements of any development program is the transfer and implementation of laboratory testing. Of course it is essential to have confidence in the tools being used to measure your product and process performance, and again, a thorough audit can uncover small differences – those that could have a meaningful impact on product testing. For example, how is the sample treated when placed in the sample log-in area? Can it sit for a day waiting to be logged in and placed in the appropriate storage unit? The ability to infuse technical considerations into the assessment is a typical way to prompt a dialogue regarding product-specific requirements.

Method transfer is another area where it is important to have clarity regarding what information will be provided to the sponsor. Since methods are not validated early in the development program, it is important to have access to all of the raw data associated with the testing performed. Some CSPs will only provide a summary report, so if raw data is required, a discussion regarding the prerequisites to release this information to the sponsor is a good place to start. Questions to ask include: Is all of the data QA reviewed and released? Will the CSP release data that has not been QA reviewed?

Out-of-specification (OOS) test results are another area where it is crucial to be explicit, especially in early development programs. If a method constantly has Phase 1 laboratory investigation reports (LIRs), then perhaps the method needs some adjustment. Understanding the level of partnership in the successful deployment of the method is important to establish early on in the relationship.

Engaging a contract service provider requires much more than evaluating the technicality, quality, and robustness of the organization. Understanding the roles, responsibilities, and expectations between sponsor and provider early in the engagement process will ensure a smoother and more effective relationship, and one of the keys in early development is harmonizing quality management systems.