USING A RISK ASSESSMENT PROCESS TO DETERMINE CRITICALITY OF PRODUCT QUALITY ATTRIBUTES - Quality by Design for Biopharmaceuticals - page 80

Figure 4.29. Prophylaxis of RSV infection in cotton rats by using palivizumab and buffer-
deamidated palivizumab. (See the insert for color representation of this figure.)

Results of nonclinical and clinical studies support that deamidation of motavizumab
and palivizumab is a minimal risk because (1) deamidation occurs naturally under
physiological conditions following dosing of motavizumab or palivizumab to patients
and therefore the resulting charge isoforms were evaluated during clinical safety and
efficacy trials; (2) deamidation occurs at common sites of the Fc regions in motavizumab
and palivizumab, which are not involved in the mechanism of action of the product; and
(3) deamidation does not impact the potency or pharmacokinetics of motavizumab or
palivizumab.

P ROCESS C APABILITY . Multiple lots were analyzed by native IEF and showed band
patterns consistent with reference standard. On the basis of process experience, theBand 1/
Band 2 OD ratio values for all lots is greater than or equal to 1.4.

C RITICALITY D ETERMINATION . Severity-Impact on Safety: On the basis of the fact that
motavizumab is normally deamidated in vivo, the safety risk from immunogenicity as a
result of deamidation is minimal.
Severity-Impact on Efficacy: It has been demonstrated that deamidated forms at OD
ratios

0.50 and with a pI greater than 8.65 exhibit biological activity (cotton rat
challenge assay and RSV microneutralization), potency (F protein binding ELISA), and
ligand binding capability to F protein (SPR). The risk to efficacy is minimal within this
range of prior product knowledge.
Likelihood: The process capability (OD

>

1.4) is within the range of the prior

product knowledge (OD 0.50). Therefore, there is a moderate likelihood of

occurrence.
Conclusion: Based on the risk assessment, the criticality was determined to be
moderate (Fig. 4.30), resulting in the classification of deamidated isoforms as a key
quality attribute with routine monitoring in the testing plan.
Native IEF can be used to assess the identity and purity of the product. In
additional, because the product is known to deamidate under accelerated temperature
conditions, this assay may also be a stability monitoring tool. Hence, native IEF