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

2

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• CBER/CDER Draft Guidance for Industry: Comparability Protocols -Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information, April, 2016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)

7

8

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

9

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

14

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

15

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)

17

Considerations in Establishing Comparability for Vaccine Products

• Viral vaccines• Bacterial vaccines • Extracts for treatment of allergies• Microbiota transplant products

18

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)

21

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

29

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

30

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?

32