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Comparability Assessment and Protocols as Enablers of Change
Management over Product Lifecycle
Ingrid Markovic, Ph.D.
Special Advisor to the Associate Director for Review ManagementOffice of the Center Director
CBERFDA
CMC Strategy Forum July, 2016
Rockville, MD1
Disclaimer
The views presented here are the views of the speaker and should not be used in place of regulations, FDA guidances or
discussions with the Agency
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Overview• Comparability Assessment (Definition and
Guidance) • Comparability recommendations for
different product categories • Comparability Protocols (CP)
Benefits Recommended uses Experience with CPs
• Concluding remarks 3
Regulatory Guidance on Comparability• CBER/CDER Guidance: Demonstration of Comparability of Human
Biological Products, Including Therapeutic Biotechnology-derived Products – April, 1996
• ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process (2005)
• EMA Q&A on Post approval change management protocols (10/2012)
• CBER/CDER Draft Guidance for Industry: Comparability Protocols -Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information, April, 2016
• ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management – [Post Approval Change Management Protocols are being addressed, in progress]
Considerations for Comparability Assessment: A multivariate system
Analytical capabilities including product complexity and possible matrix issues
Product-specific, e.g.,• Mechanism of action• Structure/function
relationship• Linkage b/w product
characteristics and safety/efficacy
Patient/indication-specific, e.g.,• Treatment regimen• Patient population and
disease state• Safety outcomes• Therapeutic window
Process-specific, e.g.,• Common-cause variation• Special-cause variation• Control strategy• Impact on the product
Comparability Assessment
Concepts in Comparability Assessment (ICH Q5E)
A determination that a product is “Comparable” indicates that products before and after a manufacturing change are highly similar and that no adverse impact on the quality, safety or efficacy of the drug product has occurred
Does not mean that pre- and post-change products are identical or indistinguishable
Concepts in Comparability Assessment (ICH Q5E) (cont.)
• A determination of comparability is generally based on a combination of analytical and biological tests and rarely on the nonclinical or clinical data
• However, if differences in the pre and post change product are identified and one can’t establish a relationship between observed differences and safety and efficacy, in that case….– a combination of quality, nonclinical, and/or clinical studies may be
appropriate (Note: a CP would not be amenable to this example)
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Comparability Assessments Throughout Development and Post-Approval
Comparability Assessments
Description
Toxicology to First-In-Human
Assesses characteristics of the product used in non-clinical studies to the product first introduced to humans
Note: Comparability assessment generally not required, generally assumed that process has not changed
Development to Pivotal
Pivotal to Commercial
Post-approval
Assesses characteristics of the product used during development to product used in pivotal clinical study(ies)
Process changes may have been introduced, comparability assessment may be needed
Assesses characteristics of the product during technology transfer from clinical to the commercial scale/site
Process changes are generally introduced, comparability assessment is generally needed
Assesses characteristics of the product pre and post change in the post-approval phase, comparability assessment is almost surely needed, may be submitted under a protocol
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Comparability Recommendations for different Product Categories
Cell Therapy product comparability challenges• Large variation in the cell source material
– Comparisons based on 3 lots may not be fully informative, yet conducting studies on a statistically powered number of lots could be unfeasible
• Source material availability– Source material for some autologous or allogeneic products can’t
always be taken from the patient population for comparability assessment - need to rely on healthy donor material as a surrogate
• CQA are not always well understood due to multiple potential MOA, multiple active ingredients, and other complexities for cell therapies
• Reference standards are not available• Manufacturing logistics can be quite challenging due to short
expiry for source material and/or product
Designing meaningful comparability studies• Perform risk assessment to evaluate if a change in
manufacturing could impact product quality- what is most likely to be effected and to what degree?– Leverage what you already know from product development– Include the most critical parameters for comparison purposes, and
rank them for your study design and analysis– Where does known variability exist and how will you try to control for
that?
• Justify in your submission the number and types of samples, tests, acceptance criteria, and the analysis/statistics you will perform
• What limits/assumptions does the study design place on interpretation?
Recommendation
• Include all relevant CQA testing used for product release• Include other relevant tests, including those that may
normally be used for informational purposes only, as long as you have confidence in the results
• In evaluating data consider which measurements are likely to be the most sensitive and relevant indicators for the change being made
• Verification of product stability may be needed depending on the type of manufacturing change
Possible strategies for cell therapies to demonstrate consistent manufacturing or
establish comparability• Split manufacturing:
• Process validation approach with comparison to manufacturing history (data mining)- Compared to similar historical starting material, did you end up with a similar final product?
• Data trending to continuously monitor manufacturing quality after the change
Split source
material
Direct compariso
n
Final product
1Final product
2New process
Original process
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Considerations in Establishing Comparability for Coagulation Factors
• High level view: product quality is built into the manufacturing process
• Manufacturing process is generally well defined but often has specifics unique to a particular product – plasma-derived vs. recombinant
• Changes to starting material and/or manufacturing process are assessed in light of both product quality and safety (e.g., adventitious agents)
• Tiered approach is used in establishing product comparability: assessment of analytical data - assessment whether animal studies are warranted -assessment whether clinical studies are warranted
• Strategy for comparability assessment of product analytical data is well defined because coagulation factors have clear biological function and known impurity profile
• Challenge: coagulation factors and especially their modified versions often show discrepant values in potency assays – clotting and chromogenic
Comparability for Coagulation Factors:Process Characterization
• Risk assessment of process changes: – Unit operations; Scale; Critical Equipment; Hold Times; New Materials
• Assessment of comparability of process performance: – Impact of process changes on CPPs, in-process controls and CQAs– Yield: overall and for each unit operation
• Analysis of intermediates– Increased sampling scheme – Stability of intermediates
• Clearance of process- and product-related impurities– Overall and for each unit operation
• Process consistency (especially for new manufacturing facilities)– Control of cGMP compliance status– Successful consecutive batches
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Comparability for Coagulation Factors:Product Characterization
• Functional activity and structure: – Potency: clotting and chromogenic assays using adequately qualified
standards– Specific activity– Interactions with relevant physiological molecules (phospholipid surface,
enzyme/cofactor, activators, inhibitors, etc.)– Post-translational modifications that can affect the biological function
(for recombinant proteins); e.g., glycosylation, sialylation, gamma-carboxylation, etc.
• Product-related substances/impurities– HMW (aggregation) and LMW (degradation)– Activated forms (stability-indicating and thrombogenic impurities (e.g.,
FIXa in FIX products)– Biologically inactive forms (denatured or oxidized forms)– Biologically active isoforms 16
Comparability for Coagulation Factors:Product Characterization (continued)
• Process-related impurities:– Source material and host cell impurities:
• Plasma-derived protein impurities (for plasma-derived products)• Host cell proteins and DNA, co-expressed proteins (for recombinant
products)– Leachables from chromatography columns (heparin, monoclonal
antibodies)• Stability
– Accelerated and real-time conditions supported by trend analyses of stability data
• Pharmacokinetics– In animals and/or humans (tiered approach according to Q5E Guidance)
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Considerations in Establishing Comparability for Vaccine Products
• Viral vaccines• Bacterial vaccines • Extracts for treatment of allergies• Microbiota transplant products
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Case #1: Change in the container closure system (e.g., change in construction material with no change
in dimension)Supporting information: • Description and rationale for the proposed change• Demonstration of fitness for use (e.g., compatibility inc E&L assessment
and protective properties inc CCI) Release testing results for at least 3 consecutive commercial DP
lots filled into new containers, including results for CCI test Stability:
− Comparative pre- and post-change results for stability-indicating attributes for 3 commercial DP lots including E&L assessment and CCI
− Partial stability data and accelerated temperature conditions may be acceptable when justified
• Post-approval stability protocol and stability commitment 19
Case #2: Change in a dosage form and formulation (e.g., change from liquid to lyophilized DP)
Supporting information:• Description and rationale for the proposed change + revised labeling• Description of batch formula, DP manufacturing process, process
controls, and process validation reports• Test methods and validation report for new analytical procedures and
updated lot release protocol (LRP)• Characterization of DP physicochemical properties, biological activity,
and impurities, inc immunogenicity to demonstrate that the antigen is comparable in the new and old dosage forms
• Release testing results for at least 3 consecutive commercial DS lots produced pre- and post-change
• Stability: Comparative pre- and post-change test results for stability-indicating attributes for 3 commercial DS lots produced with the proposed change, including E&L and CCI, if applicable 20
Comparability Protocols (CPs)
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Changes to an approved application – 21 CFR 601.12(e) – Comparability Protocols
Comparability Protocols are submitted are reviewed in the original BLA or as Prior Approval Supplements
Protocol submitted should describe the nature of the change, tests, and acceptable limits
Upon approval of the comparability protocol, subsequent supplements may have a reduced reporting category
Also defined in 21 CFR 314.70(e)
Definition of Comparability Protocol• A comparability protocol is a comprehensive,
prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity, strength, quality, purity and potency of a drug product or a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality)
Regulatory submission of a Comparability Protocol
• May be submitted as part of an original BLA or after the approval as a supplement
• May be submitted as a one-time change or used repeatedly for a specified change over the lifecycle of a product
• May cover an identical change for multiple BLA applications
Examples of submissions of comparability protocols
• In original BLA submission:– For new master and working cell banks– For new master and working viral seeds– For extension of shelf life beyond the date approved at the time of
licensure• After licensure:
– When repetitive changes are made to a single product (e.g., introduction of new products into an approved facility, addition of duplicate equipment, etc.)
– When a single change is made across multiple products - trans-BLA (e.g., container closure system, QC assays)
– When a single change is made for a single product
Use of a Comparability Protocol• Submission of a comparability protocol allows
the agency to review:– A description of one or more proposed CMC
changes– Analytical and risk assessment activities to
support the intended change– Plans to implement the change(s)– A request for reduced reporting category when
the data is submitted for review.
Submission and review of comparability protocols
A two-step process:• Submission of a supplement (PAS) that contains a well-
defined, detailed, written plan that describes changes covered by the protocol and specifies the tests and studies, analytical procedures and acceptance criteria– The supplement requires approval by the regulatory authorities
before implementation of proposed changes
• Submission of the actual results/data based on the studies specified in the comparability protocol – A reduced reporting category will be designated if the results/data
meet the pre-specified acceptance criteria27
Benefits offered by a CP • Predefined regulatory expectations
– Greater predictability regarding the expectations and timing of implementation
– Shorter review time for implementation
• Will lead to a reduction of regulatory oversight:– Associated with reduced reporting category – Applicable to future changes – Additional information is less likely to be requested to support
changes proposed under the protocol
• An opportunity for a more expedited product distribution 28
Experience with CPs
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Comparability Protocols Received from 2004 - 2014
Attribute Percentage*/range
Total CP per total CMC Supplements
~12.4%
Total trans-BLA per total CP ~58%
Trans-BLA members in trans-BLA applications
2 - 22
PAS resulting inCBE30
~39.3%
PAS resulting inCBE0
~50%
*Presented % may vary depending on the timing of CP receipt, revision, implementation, or discontinuation
Types of CMC changes submitted as CPs
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Comparability Protocols Received from 2004 - 2014CMC Changes (arranged in the order from most to least frequent) Percentage*
Facilities/equipment-specific:• Facility renovation/upgrade
• Equipment qualification/upgrade
• Introduction of new products into a licensed area
• Site transfers (testing, filling, purification, etc.)
~79%
(trans-BLA dominate for this category of changes)
Product/process-specific:• Process changes (e.g., scale-ups, purification, cell culture, etc.)
• Working Seed/Working Cell Bank Qualification
• Container/closure system
• Analytical methods
~21%
*Presented % may vary depending on the timing of CP receipt, revision, implementation, or discontinuation
Summary• Comparability is an important aspect of assuring
product quality while optimizing process and product performance
• Robust product and clinical development enhances one’s knowledge and, as such, may greatly facilitate in establishing comparability
• It is critical to have an understanding of the relationship between product quality attributes and their impact on safety and efficacy.
• Comparability protocols offer a mechanism to expedite review and implementation of post approval changes and realize greater regulatory flexibility
Comments/Questions?
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