Commentary
Managing uncertainty: A perspective on risk pertaining to product quality attributes as they bear on immunogenicity of therapeutic proteins

https://doi.org/10.1002/jps.23244Get rights and content

ABSTRACT

The critical question addressed in this paper regards how industry and regulatory agencies should manage the risk of adverse events to patients posed by product quality attributes for which a preponderance of evidence from clinical and/or non-clinical studies supports it as a risk, but for which the probability of clinical adverse events arising from the attribute is uncertain. We here provide our perspective on the principles that can be applied to determine the need for and the manner in which to control quality attributes when their impact on safety and/or efficacy is suspected, but uncertain. As an example, we use the risk of immune responses to protein therapeutics posed by sub-visible protein particulates in therapeutic proteins. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3560–3567, 2012

Section snippets

INTRODUCTION

In the April 2009 issue of the Journal of Pharmaceutical Sciences,1 a group of academic and regulatory scientists wrote a commentary that highlighted the potential for large aggregates of therapeutic protein products [referred to as subvisible particulates (SVPs) or submicron aggregates]2 in the size range of 0.1–10 μm, to cause adverse effects in patients. For the purpose of brevity, we will use “SVP” unless otherwise noted to include aggregates in the size range of 0.1–100 μm. The commentary

CRITICAL QUALITY ATTRIBUTES

To begin, it is useful to discuss the regulatory definitions describing product attributes and some clarification of these terms. According to the International Conference on Harmonisation (ICH) document Q5E, product quality attributes (PQAs) “are molecular or product characteristics that define the quality of a product.”11 ICH Q8(R2) expanded on this definition to indicate that CQAs are those “physical, chemical, biological or microbiological properties or characteristics that should be within

RISK AND UNCERTAINTY

Risk has been defined as the combination of the occurrence of harm and the severity of that harm (ISO/IEC Guide 5113 and ICHQ914). To facilitate the discussion for this paper, we distinguish risk from uncertainty as per Stirling and Gee's definitions.15 Thus, “risk” is defined as a condition under which it is possible both to define a comprehensive set of all possible outcomes (e.g., severity scale) and to resolve a discrete set of probabilities across this array of outcomes, whereas

PQAs AND UNCERTAINTY

There are many situations in which a change in a PQA may raise uncertainty as to the effects on clinical performance of an established product. For example, the finding of a novel product- or process-related impurity, appearing as a new band on a gel, may raise immunogenicity or other safety concerns. Such a novel impurity will not have been evaluated with respect to the potential effects on safety or efficacy in clinical trials. Moreover, the presence of this new band may violate product

IDENTIFYING AND EVALUATING THE RISK TO PRODUCT IMMUNOGENICITY ASSOCIATED WITH SVP

United States Pharmacopeia (USP) <788> particulate testing for injectable products, including therapeutic proteins, establishes limits for particulates >10 μm in size on the basis of the knowledge that particles of such size could occlude small blood vessels, particularly in the pulmonary vasculature, causing shunting in the vascular bed and potential microinfarctions of downstream tissues.24 It is important to recognize that USP limits were established to restrict extraneous particulate matter

RISK ASSESSMENT OF PQAs FOR BIOTHERAPEUTICS

Identification of a PQA that may prove critical is only the first step in a risk assessment. Establishing an appropriate limit, range, or distribution to ensure the desired product quality can be a challenging next step that requires knowledge of the attribute and how it may impact the safety and efficacy of the product. Investigation into the level of criticality of that attribute may involve direct studies in which the particular product attribute is isolated and then injected into humans,

CONTROLLING THE RISK TO PRODUCT QUALITY

When considering an appropriate level of control for PQAs, the US FDA guidance on “Process Validation General Principles and Practices” (April 2011) provides the overarching principle that “a potential risk to product quality …. should be evaluated in terms of product impact and controlled in a manner commensurate with the risk.” “Control” does not necessarily mean that specifications, defined as “a list of tests, references to analytical procedures, and appropriate acceptance criteria, which

CONCLUSIONS

Given the identification of SVPs as a CQA for which there is uncertainty regarding effects on the safety of therapeutic protein products, it is our contention that actions should be undertaken to lessen the probability of occurrence and severity of harm pertaining to such particles. Therefore, risk-reduction strategies should be undertaken that encompass a better characterization of the propensity to form aggregates, and correlative studies performed to address the probability of SVPs

Acknowledgements

The authors would like to thank the following meeting attendees and US FDA colleagues for critical evaluation of the manuscript: Drs. Wim Jiskoot, Jared Bee and Dean Ripple; and Drs. Steven Kozlowski, Christine Moore, and Patrick Swann.

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      Upon aggregation, much larger aggregates ranging from 100 nm to 10 mm and beyond can form.8 Potentially, large protein aggregates in therapeutic proteins could induce immunogenicity; therefore, ‘it is critical for manufacturers of therapeutic protein products to minimize protein aggregation’ as stated in Food and Drug Administration guidance.1,9,10,11 Protein aggregates in the size range between 2 and 100 µm are typically referred to as subvisible particles (SVPs).12,13

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    The contents of this article were partially discussed at the CASSS “Predictive Science of the Immunogenicity Aspects of Particles in Biopharmaceutical Products” meeting held on November 9, 2011.

    This article reflects the views of the authors and should not be construed to represent US Food and Drug Administration’s views or policies.

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