Regulatory Challenges in the QbD Paradigm - The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical

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Regulatory Challenges in the QbD Paradigm
The authors demonstrate how an integrated model is helping to achieve regulatory flexibility. This article is part of a special section on biopharmaceutical trends.


BioPharm International
Volume 25, Issue 9, pp. 44-53

The eCP approach leverages existing regulation as contained in 21 CFR 601.12(e) and current FDA initiatives. In addition, this approach leverages product and process knowledge to develop a design space and control strategy through the use of quality risk management. The potential applications of quality risk management in quality systems, regulatory operations, development, facility and equipment design, material management, production, laboratory control, stability, and packaging and labeling are described in ICH Q9 Quality Risk Management (7). The use of these principles allows for defining the scope of an eCP and presenting an appropriate quality risk management plan to prevent and mitigate sources of risk. For example, a manufacturing site transfer eCP could define the scope of the protocol based on the licensed product to be transferred, the approved process, and facility knowledge. When similarities between processes and equipment exist, the eCP elements are easier to define.

There are two primary cases where the eCP approach has been used successfully. First, is the multi-use eCP for introducing multiple products into multiple manufacturing sites covering the introduction of previously approved commercial products and new clinical products into licensed manufacturing facilities with an acceptable cGMP compliance status. The products can be produced from the same host or from different hosts but must be from well characterized cell lines (e.g., ICH Q5A) and not highly toxic or potent. The second case is the site transfer eCP and covers the introduction of an approved product into an additional licensed multiproduct facility. This eCP establishes a network of sites that provide the approved commercial product and those that receive the transferred product. In the site transfer eCP, there are additional considerations such as scale modifications, raw materials changes, and the use of disposable materials that may be different from the first manufacturing site. Cross-contamination considerations are more concerning for the multi-use eCP, while comparability considerations are crucial for the site transfer eCP. In any case, all eCPs must provide adequate quality risk management, and predefined requirements and acceptance criteria in enough detail to allow for subsequent reduced reporting requirements following eCP approval.

It is important to note that eCPs are recommended for already licensed products and manufacturing facilities. They are not indicated for nonapproved products and facilities. However, the manufacture of clinical material may be allowed as long as the cross-contamination risks are considered and included in the eCP. It is also important to make a distinction between drug substance and drug product manufacturing operations and facilities for biotechnology products, because each case would require the consideration of different risks. Although potentially both drug substance and drug product manufacturing site changes could be included in an eCP, the broader the scope, the more complex the elements of the eCP become. Another consideration is that firms wishing to follow the eCP approach are advised to request and hold meetings with the agency to discuss the proposed approach and risk management plan and agree on scope, strategy, and submission requirements. Although this can be time consuming at the beginning of this approach, the benefits can be reaped immediately once the eCP is approved. Additional products can subsequently be transferred without submitting prior approval supplements and waiting for FDA approval for market release. In addition, the preapproval facility inspection can be waived based on licensure and cGMP compliance status.

The eCP approach helps to identify the various risks across the subject manufacturing sites and to develop a quality risk management plan with site-dependent versus site-independent risks. Such a plan should be an integral part of the quality system and address risks from environmental, personnel, material, equipment, measurements, and methods. There are multiple considerations to be integrated into an eCP. The authors present some factors that are relevant to drug substance manufacture as examples.

Equipment and layout of a production facility should be reviewed to address multiproduct or multihost facility aspects for drug substance manufacturing operations, as risks will vary significantly. If containment is a concern, it should be appropriately addressed when introducing a product to another facility. Additionally, supplier and raw material concerns can impact the risk assessment considerably. The acceptability of risk by a firm may vary depending on whether it uses manufacturing sites within its network or contract manufacturing facilities. When contract facilities are used, a well-written and enforced quality agreement is cruical.

Embedded in the site transfer may be changes to the manufacturing process resulting from facility equipment and layout (i.e., fit) or continuous improvement considerations. These changes may affect controls for contamination or cross-contamination of product and should be assessed. When scale-up of the process is part of a site-transfer eCP, comparability process and criteria should be well defined, along with control parameters and strategy to ensure product quality and safety. Based on the risk assessment, existing validation studies may be used or new validation studies may need to be performed. As with traditional comparability protocols, the comparability of product based on test method and acceptance criteria and technology transfer aspects should be part of the eCP. As indicated in current guidance, change of the manufacturing site or addition of a new site to an approved application is reported as a prior approval supplement and triggers a facility inspection. The site transfer eCP can address compliance risks leading to a waiver for the inspection.

There are many opportunities today to leverage all available information relevant to compliance and cGMP requirements as regulatory agencies work on harmonized guidance and inspection cooperation (e.g., the Pharmaceutical Inspection Cooperation Scheme). Consistency in risk management and change control operations across sites and well defined thresholds for acceptable risks are helpful in understanding management of an eCP once approved. Following approval, other products can be introduced with more regulatory flexibility when the principles outlined in the approved eCP are followed.


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