Quality by Design for Biotechnology Products—Part 3 - Guidance from the Quality by Design Working Group of the PhRMA Biologics and Biotechnology Leadership Committee on how to apply ICH Q8,


Quality by Design for Biotechnology Products—Part 3
Guidance from the Quality by Design Working Group of the PhRMA Biologics and Biotechnology Leadership Committee on how to apply ICH Q8, Q8R1, Q9, and Q10 to biopharmaceuticals.

BioPharm International
Volume 23, Issue 1

Next Steps

The increasing number of new products, combined with the number of marketed products seeking postapproval changes, has placed a considerable demand on the government and industry to submit and review data to comply with existing requirements. It is essential, therefore, that we identify a path forward that will leverage substantial product and process knowledge (i.e., QbD) using risk assessment tools and quality systems to ensure product safety and efficacy.

To reduce the regulatory reporting burden for both the health authorities and drug product manufacturers, thorough risk assessments, following ICH Q9 and Q10, must take center stage, and an avenue should be developed for using CMC postapproval management plans. These plans would be agreed on by the regulatory authorities, and the manufacturers would be responsible for collecting adequate data to ensure that a meaningful risk assessment could be conducted and that pre- and post-change product comparability could be ensured. At the same time, to allow for regulatory relief, the health authority and manufacturers will need to agree on the minimum requirements or thresholds for manufacturing changes based on the identification of an acceptable residual risk for a change. To date, health authorities have not presented clear guidance as to what they consider to be an acceptable risk for biotech products. The industry can work with health authorities to share examples of process changes and provide an assessment for postapproval changes and notification categorization. Currently, the mechanism to share process understanding for well-understood processes and products is not clearly defined. We believe that continued discussions about the utility of a CMC postapproval management plan will encourage innovation, and require less burdensome regulatory reporting while maintaining product safety and efficacy.


Quality by Design leads to a thorough understanding of product characteristics, with good quality being demonstrated by an acceptably low risk of failing to achieve the desired clinically relevant product attributes. Product and process performance characteristics are scientifically designed to meet specific objectives, not merely relying on empirically derived outcomes from studies. The sponsor establishes acceptable ranges for the critical process parameters and attributes to ensure clinically acceptable product performance that meets the patient needs identified in the quality target product profile (QTPP). The goal of QbD is to develop robust, well understood processes, run within a design space of operating parameters and control strategy, thus meeting critical quality attributes.

The QbD approach allows the process to be continually evaluated and updated to ensure consistent product quality over time. Quality management systems may ensure product quality dynamically in real-time. QbD advocates knowledge management principles in the transfer of an advanced understanding of the process and product from the development functions to the receiving functions (e.g., quality, manufacturing) all along the product lifecycle, from early phase development through commercialization. The demonstration of knowledge-rich process and product information held by the sponsor needs to be communicated to the health authorities in the marketing application and postapproval supplements.

QbD takes a lifecycle approach that encourages innovation and continuous improvement to the product long after initial approval to leverage knowledge gained and technology advancements. A QbD approach allows future manufacturing changes within the design space to be implemented without further regulatory reporting, thus meeting Janet Woodcock's oft-quoted vision of "a maximally efficient, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug product without extensive regulatory oversight."6

The benefits of QbD span the product lifecycle and center on areas that have the most impact to the safety, efficacy, and quality of the product. The benefits of this risk management approach include focusing on knowledge-rich development studies and reducing non-value added work. One benefit often cited is the promise of less burdensome regulatory reporting of postapproval changes. Even without the incentive of less burdensome regulatory oversight, however, the benefits of reduced material rejections and batch failures in manufacturing and reducing the three "re's"—reprocess, rework, recalls—make implementing QbD worthwhile. Several companies have reported developing a business case for QbD based solely on efficient, cost-effective manufacturing process needs. However, the promise of increased regulatory flexibility and less stringent reporting requirements is a powerful encouragement for implementing postapproval changes, because it encourages innovation and meaningful continuous improvement.

As previously stated, the concepts of QbD are the same for biologics as they are for small molecules. But the expression "the devil is in the details" aptly describes the nuances encountered and the complexities to overcome in implementing QbD concepts in the manufacture of biotech products. Cell-based manufacturing processes do intrinsically possess significantly more variability and complexity than classical pharmaceutical synthetic methods. Biopharmaceuticals lend themselves to fully leveraging prior learning in the establishment of unit operation–based and method-based platforms that leverage the experience and understanding from previously developed products within a product class.

The Biologics and Biotechnology QbD Working Group sought to articulate in this paper the factors to consider when applying QbD concepts to biologic and biotechnology products. Previous experience has shown that companies can get bogged down quickly when starting a QbD program by figuring out where to place content in the marketing application rather than beginning with the QbD thought process and the merits of performing QbD studies in the first place. This paper was thus structured to first articulate "designing quality into the product and process" and only then address content placement in the application and postapproval flexibility. Where ambiguity may still remain in the understanding and implementation of QbD concepts, it is the hope of the authors that this paper can serve as stimulus for further discussions among industry and regulators to clarify the concepts and how QbD should be implemented for biotech products. It is further hoped that ICH participants will reach out to global health authorities to request global acceptance of these QbD principles, thereby allowing for industry and regulators to fully leverage the benefits.

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