Quality by Design for Biotechnology Products—Part 1 - A PhRMA Working Group's advice on applying QbD to biotech. - BioPharm International

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Quality by Design for Biotechnology Products—Part 1

Using Laboratory, Nonclinical, and Clinical Studies to Identify and Assess CQAs

An important step in the bioproduct development process is the identification of the CQAs of the product that drive the assessment of the ability of the bioprocess and bioproduct to deliver the intended performance of the product.11 The initial step toward identifying the CQAs is achieving a full understanding of the molecular structure and product variants. Next, all the molecular quality attributes and potential quality attributes are ranked using risk-based tools. The objective of this exercise is to determine which quality attributes may have the potential to affect the performance (safety and efficacy) of the product. A typical monoclonal antibody product may have dozens of such quality attributes and all are considered and assessed. They include but are not limited to product-related variants, process-related impurities, formulation parameters, and essential attributes such as appearance. Examples of process-related impurities include host cell DNA, host cell protein, adventitious agents, residual medium supplements such as protein hydrolysates, and components such as nucleases or residual Protein A from chromatography resins used in the purification process.

There are multiple approaches to assessing the criticality of quality attributes. One such approach is to focus on the severity and uncertainty of impact (to safety and efficacy), with the goal of process and product design and the control strategy to minimize the probability of occurrence to reduce overall risk. The ability to detect a quality attribute during product development is required to assess its occurrence, thus necessitating the development of methods suitable for this detection and quantitation. The need to detect a specific attribute can decrease as its severity and occurrence are eliminated or minimized to an acceptable level with product knowledge and process control. Other approaches do not incorporate an assessment of occurrence, because CQAs are not tied to the ability of the process to control an attribute.

Prior product knowledge plays a key role in the risk assessment and consists of the accumulated laboratory, nonclinical, and clinical experience for any specific product quality attribute. It also can include relevant data from similar molecules and data from literature references. With the increasing use of platforms in the development of biotech products and process, such as monoclonal antibody products, it is expected that investments in creating this knowledge can be capitalized by applying it to several products once the platform has been established.12–19 This combined knowledge provides a rationale for relating the attribute to product safety and efficacy. As mentioned above, the assessment of the severity of the impact (to safety or efficacy) results in a list of quality attributes in order of criticality. The list may evolve as more product and process knowledge are accumulated.

Process-related components may be handled by considering their potential safety risk. One approach to assessing this safety risk is to evaluate an impurity safety factor (ISF) with an appropriate target or lower limit. The ISF is the ratio of the impurity LD50 to the maximum amount of an impurity potentially present in the product dose:

ISF = LD 50 Level in product dose

in which LD 50 is the dose of an impurity that results in lethality in 50% of the animals tested, and the level in product dose refers to the maximum amount of an impurity that could potentially be present and co-administered in a dose of product. The ISF is a normalized measure of the relationship between the level of an impurity resulting in a quantifiable toxic effect and the potential exposure of a patient to an impurity in the product. In the absence of an assay to detect an impurity, a conservative assumption is that all of the impurity in the process co-purifies with the product, and no clearance is achieved by the purification process. In cases where a sufficiently sensitive assay is available, the actual level of an impurity in the product is measured. Impurities can be eliminated from further consideration at any step where the safety risk is determined to be minimal, with an eye toward any impurity being removed or eliminated to as low a level as possible. An alternative strategy for process-related impurities, such as DNA or host cell proteins, is to demonstrate multi-log removal by validation that is conducted in a fashion similar to the validation of viral reduction or removal, thus obviating the need for a specification.

The criticality of quality attributes may be explored in appropriately designed in vitro and in vivo studies. An example of the assessment of the affect of deamidation on the bioavailability, potency, and immunogenicity of a monoclonal antibody has been detailed elsewhere.15 A combination of tools may be used to establish correlations between quality attributes and preclinical or clinical performance. Examples include:

  • analytical tools such as native isoelectric focusing (IEF), ion-exchange chromatography (IEC), and online mass spectrometry to quantify the level of deamidation
  • preclinical pharmacokinetics studies with the native and deamidated molecules
  • in vivo potency studies with the native and deamidated molecules
  • preclinical immunogenicity studies using extended dosing with the deamidated molecule
  • determining the deamidation rate that would occur in vivo and assessing its relevance compared to the circulating half-life of the molecule.

All or a combination of some of these studies may help qualify the criticality of an attribute such as deamidation.


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