Paradigm Shift in Comparability Assessment - QbD and PAT can improve SAR evaluation
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Transcript of Paradigm Shift in Comparability Assessment - QbD and PAT can improve SAR evaluation
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Paradigm Shift in Comparability Assessment:
How Quality by Design (QbD) and Process Analytical Technology(PAT) can improve Structure-Activity Relationship (SAR)
evaluation and its relevance to comparability protocols andbiosimilars
Robert L. ZeidPrincipal Consultant
TLI Development
113 SE 5th St.
Oak Island, NC 28465
(910) 278-9176
www.tlidevelopment.com
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Overview
Key Concepts
Biologics development is complicated. An enormous number of variables influence productquality and process consistency. This has evolved into the product = process paradigmwith highly regulated change control for post-approval manufacturing changes.
No matter how controlled the manufacturing process may be, without using the centraltenets of Quality by Design (QbD) and Process Analytical Technology (PAT) linked tostructure- activity-relationships (SAR) of the active ingredient - one is limited to empiricalassumptions about the impact of a proposed change on safety or efficacy.
By using QbD and PAT in the development programs for API and finished product, andlinking those SAR changes to their impact on nonclinical and clinical programs, one cancreate enormous process and regulatory flexibility.
Comparability protocols can be significantly improved by this approach. By using forceddegraded samples of innovator and comparator product in the orthogonal analytical systems,this can also aid in the e development of biosimilars and biologics monographs.
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Quality by Design (QbD)
Key Concepts of Quality by Design (QbD)
Integrating prior knowledge and pharmaceutical development into CMC programs is basedon three tenets:
We know what is important. Product and process characteristics are defined by a combination of
prior knowledge and assumptions ; confirmed by experimental assessment during product development
We have established a framework of relationships and impact for each of these qualityparameters. A multivariate model links product & process measurements to desired attributes;defining an edge of failure for product quality and process parameters.
We can measure the combined impact on safety and efficacy. Clinical testing is viewed asconfirmatory performance of the predictive model.
Creating process and regulatory flexibility by design space
The product and process performance characteristics are scientifically designed to meet specificobjectives, not merely empirically derived from performance of test batches
An ability to define and defend particular product quality attributes or process parameters and theirpotential impact on safety and efficacy
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Process Analytical Technology (PAT)
Key Concepts of Process Analytical Technology (PAT)
Scientific, risk-based framework intended to support innovation and efficiency inpharmaceutical development, manufacturing, & quality assurance:
A system for designing, analyzing, and controlling manufacturing
Shifting process evaluation away from product testing and towards real, in-time measures
Identifying and measuring critical quality and performance attributes
Quality is built into the product through a comprehensive understanding of:
The intended therapeutic objectives, patient population, route of administration, and pharmacological,
toxicological, and pharmacokinetic characteristics
The chemical, physical, and biopharmaceutical characteristics of the drug
Design of a product and selection of product components and packaging based on the criteria above
Design of manufacturing processes using principals of engineering, material science, and qualityassurance to show acceptable and reproducible product quality over the shelf life
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Active Pharmaceutical Ingredient
(API) ProgramsHow do you go about implementing QbD and PAT for a program? The first step is to identify the sub-components of major areas and the variables. The major tasks for an API program include
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Finished Product Programs
The major aspects of the finished product program are comprised of
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Nonclinical Programs
The major aspects of the nonclinical program are comprised of
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Clinical Programs
The major aspects of the clinical program are comprised of
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Process Development Programs
The major aspects of the process development program are comprised of
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Comparability is imperative to an
integrated development programChanges in these programs over the development time line must be minimized by comparabilityassessments.
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Determination of Critical Parameters
Design of Engineering (DOE) Studies: Hi/lo experiments Spiking with impurities Extended process parameters Outcome is usually determine on purity
and yield Further confirmatory studies with
formulation of API into finished productand stability studies for both
Principle Component Analysis: Multiple variables assessed in a matrix
Statistical Process Control (SPC) Trending of established processes
Forced Degradation Studies Correlation of physico-chemical profiles
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Statistical Process Control (SPC)
Trending of established processes: Value is showing process performance Can be used to help address corrective
actions May be used to justify lot release for
some process parameters exceedingvalidation limits when it can be shown the (1) reason for excursion was
identified and corrected and (2) the impact on product quality
was not significant
Limits of this approach is that withoutcorrelation to SAR, the nature of somechanges cannot be fully understood. Some in vitroand in vivoassays may not
be sensitive enough to detect subtlechanges in physico-chemical profiles
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Structure-Activity Relationships (SAR):Mining SAR for its impact on other product quality attributes
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Defining SAR thru Forced Degradation:Evaluating the Sensitivity of Assay Methods
Evaluate SAR by a parallel assessment ofbiological activity and physico-chemicalprofile:
What is sensitivity of biological assay todetecting loss of potency?
What is variability of potency assay and howmany samples must be run to establishstatistical confidence?
What is rate of impurity formation undervarious stability conditions?
Does a rise in impurities correlate with loss ofbiological activity?
Is it possible to establish a threshold ofimpurity formation and/or other physico-chemical profiles with a loss in potency? Whatkey features are affected?
Can the combined data be used to establishQbD and critical process parameters?
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Formulating SAR into a QbD/PAT Matrix
Matrix is broken out by stage, process steps, parameters, and impact on product Data supporting these evaluations should be cross-referenced in a database or data
management system for easy retrieval and review
If impacted material was evaluated in a bioassay/potency method, nonclinical study, or
surrogate endpoint study, those data should be confirmed for characteristics consistentagainst other batches. How does the profile of a failed batch compare to a passing one?
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Some changes may be too significant tobe addressed solely through SAR
Significant manufacturing changes will require a tiered testing approach as basis ofcomparability assessment
Physico-Chemical Characterization of pre- and post-change material: Methods and assays must be sensitive enough to detect deamidated, oxidized, cleaved, and
aggregated forms, Post-translational modification testing such as glycosylation, sulfation, phosphorylation, or
formylation should also be compared to trended profiles of passing batches Vaccines should have comparable affinity from the same donor serum showing no difference in
binding
Bioassays & Animal Models Disease models need to be assessed for sensitivity of detecting failed material
ADME and Toxicokinetics can help show comparability for PK and PD
Human Studies PK/PD Studies: Where the pharmacokinetic (PK) action is much less than the pharmacodynamic (PD)
activity such as vaccines and immune modifying agents the human PK/PD study will need to belonger to assess the full range of PD effects and include more thorough safety analysis
Immunogenicity: This needs to be assessed in post-approval changes as part of the Risk EvaluationManagement System (REMS).
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Comparable, Therapeutically Equivalent,and Biosimilar
How might a QbD and PAT approach be useful in judging impact by SAR?
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Well characterized proteins allow detailed knowledge ofmechanism of action and impact of SAR on potency
Insulin Human Growth Hormone
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Creation of Biologics Monographs:Expanding knowledge of SAR beyond simple proteins will allow integration into
compendial monographs for use by regulatory authorities.
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Summary of Key Points
Process design requires integrated approach of SAR, protein expression systems, andcharacterization testing all linked to bioassay and manufacturing parameters.
Scale of manufacture will change depending on process development data and clinical/marketneeds. Try to arrange significant changes prior to Phase III to avoid costly delays in
comparability studies.
Process development can be optimized via PCA and linked to SAR.
Comparability studies will be vital to supporting consistency across manufacturing and processdevelopment changes.
Manufacturing controls must reflect product parameters well within edge of failure
Stability data must be supported by extensive characterization testing to show subtle changesdo not impact purity, potency, or safety
The QbD and PAT approach using SAR can be the next step in process design space forbiologics and open the door for improved biosimilars and compendial monographs of biologics.
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Conclusion
Using this approach will not replace the necessity of conducting confirmatory clinicalstudies for significant manufacturing changes but it should improve the confidenceof the comparability protocols being approved, of which > 97% of them are approvedwithout requiring clinical data.
With respect to biosimilars, a side-by side comparison of the sensitivity of thesemethods to innovator material should provide a thorough correlation of physico-chemical profiles to bioassay activity and clinical responses. With these data inhand, the regulatory authorities will have a better sense of what differences areclinically relevant versus those that are not as is currently done with todayscomparability exercises.
Finally, the ability to integrate these findings into compendial monographs shouldallow for a harmonized approach to regulators with respect to critical SARattributes that must be conserved in development for safety and efficacy.
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