Establishing Patient Centric Specifications for Drug Substance and Drug Product Impurities

Abstract

In this paper, we remind readers of several ICH guideline documents such as ICH Q3A, Q3B, Q3C, Q3D, Q6A, Q6B, M7, and ICH S9 which are related to the drug substance and drug product impurity limit setting. In particular, ICH Q6A clearly states that "specifications should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product"; however, recent negotiations between health authority and applicants (company) related to proposed marketing applications show that on a global level, batch experience, even when limited, plays an overwhelming role in developing impurity acceptance criteria rather than clinical relevance. The drawback of such practice and the great need to establish patient centric specifications (PCS) are highlighted. Secondly, this paper proposes approaches on how to establish patient centric criteria for drug substance and drug product impurity limits based on the principles outlined in ICH guideline documents and scientific literature. Three case studies are presented to illustrate the challenges in establishing PCS and the divergence of regulatory acceptance to such specifications. We propose some approaches that can be considered for specification setting based on clinical relevance in the drug development, registration and post-approval phases of a product life-cycle. Lastly, we give thoughts on the future perspective of this movement and offer recommendations to foster discussions between regulatory agencies and pharmaceutical industry on getting medicinal products that are safe and effective to the patient sooner to meet unmet medical needs without supply interruption concerns.

Strategies for Setting Patient-Centric Commercial Specifications for Biotherapeutic Products

“…The proposed acceptance criteria may, as a result, be wider than those based either on patient exposure in clinical studies or on limited manufacturing experience at the time of market application. Notably, process experience-based acceptance criteria may present adverse long-term supply constraints, 4 and the challenges are even greater when accelerated product development timelines allow very few batches to be available for patient treatment or to be used for projection of long-term process capability. Thus, the risk-based approach described here enables appropriate control over high risk attributes to ensure product quality for the patient while allowing appropriate flexibility for low risk attributes, for a robust supply chain.…”

“…More recently, improved platform processes have led to more consistent clinical manufacturing, often with production of few clinical batches, so a process experience-based approach can lead to tight specifications that overly constrain long-term commercial supply or may prohibit consideration of the development of convenient dosage forms or other innovations that improve the experience of patients; the concept of patient centric specifications has been introduced to emphasize the use of riskbased approaches based on product knowledge. 4 More recent guidance (ICH Q8, Q9, Q10, Q11) provides a scienceand risk-based approach for product development and describes a comprehensive control strategy. 5e8 A control strategy is defined as "a planned set of controls, derived from current product and process understanding that ensures process performance and product quality".…”

Control Strategy Expectations in Early Clinical Phase Synthetic Oncology Programs: Two Global Regulatory Case Studies

“…Rather than attempting to set specifications/impurity limits based on unoptimized, early phase DS/DP process variants, patient-centric specifications (or clinically relevant specifications) have been proposed. As discussed in an industrial perspective by Bercu et al, patient-centric specifications focus on clinical relevance instead of process capability . To evaluate these potential life-saving medications in the target populations globally, risk-based assessments are important to rapidly assess the clinical benefit of the drug versus the risk of implementing a wider specification in early development.…”

“…To date, both industry and global health authorities have published proposed improvements in the process of establishing clinical phase/patient appropriate specifications and control strategies. Industry recommendations from Bercu et al include continued dialogue between regulators and industry to align on terminology and strategy as well as additional ICH guidance and/or Q&A publications to reduce uncertainty . As global health authorities continue to evaluate the quality and data packages to facilitate accelerated development timelines while assuring patient safety, efficacy, product quality, and supply, published industry case studies and panel discussions will provide important information for future regulatory and scientific development.…”

“…As discussed in an industrial perspective by Bercu et al, patient-centric specifications focus on clinical relevance instead of process capability. 20 To evaluate these potential life-saving medications in the target populations globally, risk-based assessments are important to rapidly assess the clinical benefit of the drug versus the risk of implementing a wider specification in early development. Examples of such risk-based assessments include assessments for impurity specifications and dissolution specifications.…”