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Regulatory flexibility can make continuous improvement possible.
The International Conference on Harmonization (ICH) Q8(R2), Q9, and Q10 guidelines provide the foundation for implementing Quality by Design (QbD). Applying those concepts to the manufacture of biotech products, however, involves some nuances and complexities. Therefore, this paper offers guidance and interpretation for implementing QbD for biopharmaceuticals, from early-phase development steps such as identifying critical quality attributes and setting specifications, followed by the development of the design space and establishing the process control strategy; to later stages, including incorporating QbD into a regulatory filing and facilitating efficient commercial processes and manufacturing change flexibility post licensure.
This paper focuses on the factors to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9, and Q10 to biotechnology products. Although biologic and biotechnology products often present a higher level of complexity than small molecules in terms of manufacturing process or product structure, the concepts of QbD are the same as those for small molecules. This paper describes the nuances and complexities involved in implementing QbD in the manufacture of biotech products and offers guidance and interpretation for doing so. The scope of this paper is limited to well-characterized protein products, in which the natural molecular heterogeneity, impurity profile, and potency can be defined with a high degree of confidence.
(ELI LILLY AND COMPANY)
Part 1 of this three-part article, which appeared in the November issue, covered molecular design, the use of laboratory and clinical studies to identify critical quality attributes, setting specifications, and developing the design space. In Part 2, published in the December issue, we addressed the use of design of experiments (DOE) to define the design space, unique considerations for process development for biopharmaceuticals, the establishment of a control strategy, and the placement of QbD information in a regulatory application. Here, in this final Part 3, we discuss continuous verification and postapproval changes, including refining the design space, comparability protocols and expanded change protocols, and our overall conclusions for the three-part article.
Process change is an expected aspect of pharmaceutical manufacturing. Many process changes are made as a result of increased process knowledge to keep pace with advancing technologies and improvements to the manufacturing process. When a product is first approved, its manufacturing process represents the current technology standard for manufacturing and follows the current good manufacturing practices (cGMPs) standard for regulatory compliance. After approval, market demand, technological advances, GMP standards, raw materials (e.g., resins) sourcing or manufacturing experience may require that the approved process be modified. Traditionally, these postapproval changes have required regulatory agency endorsement before implementation. The intent of this section is to propose a path forward that fosters continuous improvement and innovation, and acknowledges the extensive understanding of the manufacturing process and product (process knowledge) gained through the development of the design space or through manufacturing experience. The demonstration of extensive process knowledge in the marketing application, combined with established robust and effective quality systems to monitor manufacturing process performance, provides health authorities the assurance, and thus the allowance, to reduce regulatory oversight and the burden of postapproval change supplements while still meeting legal and regulatory expectations. The future treatment of postapproval changes will be influenced by:
The data package for a market application (BLA or MAA) is enhanced by including data from full scale manufacturing runs, ideally from the intended commercial manufacturing site. These data confirm that the normal operating ranges or set points for process parameters lead to successful manufacturing at commercial scale. (GMPs) require formal process validation, and data from validation batches traditionally have been expected as part of the marketing application. A successful process validation exercise signals the beginning of the commercial life of the product and serves as the baseline for future process improvement efforts. Although important, process validation batches provide limited data for assessing the long-term variability and process capability of the manufacturing process. Rather, these data serve as one element in the larger dataset of process design and control experiments. The importance of including full scale data and data from process validation batches in the marketing application depends on platform experience and the state of qualification of small-scale models used to develop the process design space.2
A refinement of the initial design space for cell culture, drug substance purification, and finished product manufacture may be driven by several of the following factors:
The refinement of the design space is based on the same principles used to develop the initial design space. Starting from the quality target product profile (QTPP), a risk assessment should be performed to identify the process parameters that should be re-evaluated with respect to their potential impact on critical quality attributes using small-scale models and applying tools such as DOE.
Continued process verification has emerged as a key principle of process validation.3 During commercial manufacture, additional data will be collected from postapproval batches. These data will be reviewed periodically to confirm that the control strategy is appropriate. In some cases, this review may indicate that there is a need to modify specifications or in-process controls. Process changes may or may not require adjusting process parameter ranges to achieve a comparable quality in the drug substance or drug product. Testing for pre- and post-change comparability (see ICH Q5E),4 therefore, can result in refining the ranges for critical process parameters (CPPs) and extending or reducing the number of critical process parameters.
The prior existence of a design space can make it easier to characterize the influence of a change on the critical quality attributes of drug substance or drug product or to confirm the robustness of chosen process parameter ranges (e.g., in the case of scale-up, site transfer, or equipment changes).
The traditional comparability protocol (CP) has been available for more than 10 years in the US. The concept of a CP or similar reporting structure has not been adopted by the other regulatory agencies, however. CPs are pre-approved by the FDA with predetermined acceptance criteria that will be used to confirm product comparability following a discrete process change.5 The more recently adopted expanded change protocol (ECP) takes a more holistic approach and offers the use of a protocol providing the approach and acceptance criteria that can be applied to multiple manufacturing process changes or a process change across multiple related product types or manufacturing process platforms.1 The CP/ECP includes a quality risk assessment plan that provides assurance that changes to the process are formally assessed for impact to product critical quality attributes. This type of protocol or plan encourages incorporation of technical innovation, and process optimization, while maintaining product safety and efficacy.6
Table 1 provides an example of a proposed change control matrix that, if approved by the FDA (e.g., as part of the initial marketing application or a later supplement), could clarify the postapproval reporting requirements in the US for several process changes based on the impact to normal operating ranges, proven acceptable ranges, or design space limits. Postapproval manufacturing changes, covered under the manufacturer's approved CP or ECP (or approved CMC postapproval management plan;7 see below), should require regulatory review and approval before implementation only in very limited cases, such as when the change expands the existing design space of critical process parameters and alters the approved control strategy (see Table 1). This scenario would permit most changes to or within the design space that result in comparable post-change product, to be presented during inspections or during regular annual updates to health authorities.
Table 1. Example of a change control matrix of postapproval reporting requirements for process changes
This approach could lead to a future state in which prior approval supplements (assuming a satisfactory site inspection) would be reserved only for changes where the post-change product or the control strategy are NOT comparable to the current product.
Products that have been on the market for a considerable amount of time have extensive manufacturing data but may not have a formally developed design space. Following the current regulatory guidance, incorporating new technology or process changes requires regulatory agency review and approval. Manufacturing changes are initiated and controlled through internal change control processes. Comparability studies and protocols are an integral component in the evaluation of manufacturing changes, and include acceptance criteria and a side-by-side comparison. These processes ensure that the products comply with registered details and that critical quality attributes have not been affected.
Because there is significant process and product knowledge about these well-understood marketed pharmaceuticals, and a large number of patient years of pharmaceutical usage associated with them, there is an opportunity to use a risk management system for assessing changes that may be managed internally and without direct regulatory agency oversight. This opportunity is built on the process knowledge gained through process changes, and the subsequent safety and efficacy information that has been generated from long-term manufacturing experience. These data could be used to define a design space retrospectively for single or multiple unit operations.
When a design space is intended to be established after a medicinal product is on the market, the same principles apply as for design space evaluation during development, including the use of qualified small-scale models and experimental approaches such as DOE. For a postapproval design space, the QTPP would include the approved drug substance or drug product specifications. The risk assessment has the advantage of building on the established criticality of process parameters as well as experience with a number of full-scale batches.
With the advent of the QbD approach providing additional knowledge-rich information in the initial marketing application, the concept of a CMC postapproval management plan (PMP) has been suggested in the US. The PMP is a proposed mechanism to capture the commitments and reporting requirements in the marketing application that are submitted to and approved by the agency for these well-understood products. The PMP would address the distinction between information provided to demonstrate knowledge of the process and product, and the lifecycle regulatory commitments. With the inclusion of increased data that supports items such as critical quality attributes, process parameters, and the design space, it will be imperative to clearly delineate between information that is provided for review and approval of the initial application and commitments that will continue throughout the lifecycle of the product.
The PMP commitment section of a marketing application would contain a summary of the overall control strategy commitments: raw material controls, CPPs, in-process controls, the design space, final specifications, excipient controls, primary packaging, the container closure system, in-use stability, and storage conditions. The PMP also would clarify the sponsor's commitment with respect to reporting postapproval changes, with the understanding that a robust demonstration of knowledge would result in more flexible regulatory approaches to change management. The PMP would outline in clear terms how future process changes will be reported —i.e., whether the company must submit a supplement or may rely on internal site change control. One approach to providing these regulatory reporting commitments would be using a change control matrix, an example of which was described earlier in Table 1. For example, a CMC postapproval management plan would consider typical changes expected to occur during the lifecycle of the product and establish reporting requirements that permit innovation and improvements to be implemented while using inspections and regular annual updates to health authorities as the means for demonstrating that regulatory expectations have been met. The implementation of PMP for a well-understood product should require less regulatory agency oversight than for products that lack such an understanding.
The PMP would be subject to FDA approval before taking effect and could be submitted in section 3.2.R.3 or module 1 of the common technical document (CTD). Although the CPs and ECPs could reside separately in section 3.2.R.3, these protocols also could be contained within the PMP.
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.
Taruna Arora is a principal scientist, protein science, Roger Greene is the director of regulatory affairs, Jennifer Mercer is the director of regulatory affairs, CMC, and Paul Tsang is the executive director of quality, all at Amgen Inc.; Meg Casais is the director of global regulatory affairs, CMC, and Stuart Feldman is the director/CMC, global regulatory affairs, both at Schering Plough; Jutta Look is the senior manager, CMC Regulatory Affairs at Novartis Pharma AG; Tony Lubiniecki is the vice president of biopharmaceutical development & marketed product support at Centocor R&D, Inc.; Joseph Mezzatesta is the assistant director of regulatory CMC, corporate regulatory affairs, at Sanofi-Aventis; Stefanie Pluschkell is an associate research fellow in global CMC, biologics and devices, at Pfizer Inc.; Mark Rosolowsky is the executive director of global regulatory sciences–CMC at Bristol Myers Squibb; Anurag Rathore is a biotech CMC consultant and faculty member at the Indian Institute of Technology, Delhi, India; Mark Schenerman is the vice president of analytical biochemistry at MedImmune; Tim Schofield is the director of US regulatory affairs at GlaxoSmithKline; Samantha Sheridan is the director of regulatory affairs at Shire Pharmaceuticals; Paul Smock is a director and quality product leader in Wyeth Biotech, Wyeth Pharmaceuticals; Sally Anliker is the director of regulatory affairs CMC, Lois Atkins is a principal consultant, CMC regulatory affairs, Bernerd McGarvey is an engineering advisor in the process engineering center, Bruce Meiklejohn is a principal fellow, regulatory COE-biotech, Jim Precup is a research scientist in manufacturing, science and technology, and John Towns is the senior director of global CMC regulatory affairs, all at Eli Lilly and Company. Towns is also the chair of the working group, 317.276.4079, Towns_John_K@lilly.com.
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