Replacing Analytical Methods for

Release and Stability Testing –

CBER Perspective

Presentation at the CMC Strategy Forum

January 27, 2014

Lokesh Bhattacharyya

Chief, Lab of Analytical

Chemistry and Blood Products,

Div. of Biological Standard

and Quality Control,

OCBQ/CBER/FDA

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Disclaimers

My comments are an informal communication and represent my own best judgment. These comments do not bind or obligate FDA.

All examples are based on typical review experience but are not taken from specific individual BLA or supplement

Introduction Method changes are normal part of product life-cycle

Triggered by variety of factors

● Technical/scientific reasons – replacing legacy methods

● Regulatory reasons

● Business Decision

● Other reasons

Welcomed and encouraged by CBER

● Better product characterization

● Better understanding of product quality

● More robust and rugged methods with greater sensitivity,

selectivity (specificity) and reliability

● Better insight into product stability – factors affecting stability

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Outline

Categories of change

Regulations and Guidances

Submission Requirements

(Perceived) Concerns

Comparability Study

Two Examples

Changing Method During Stability Study

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What do we do?

Work in an ISO 17025 compliant Laboratory Quality System

environment

Routine Lot release testing of Vaccines, Blood Products and

Blood Donor Kits for identity, potency, impurities and other

critical components (e.g., thimerosal, adjuvant) using

physicochemical, biochemical and biological assays

Testing in support of BLA and Supplements

Testing in support of CBER Reference Standards program

BLAs and supplements: Review of physicochemical,

biochemical and biological assays for the test methods and

their validations for vaccines and blood products

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Guidances

FDA Guidances

● Demonstration of Comparability of Human Biological Products,

Including Therapeutic Biotechnology-Derived Products, 1996

● Changes to Approved Applications: Biological Products, 1997

● Changes to an Approved Application for Specified Biotechnology

and Specified Synthetic Biological Products, 1997

● Comparability Protocols - Protein Drug Products and Biological

Products-Chemistry, Manufacturing, & Controls Information, 2003

● Changes to an Approved NDA or ANDA, 2004

● ICH Q2(R1) – Validation of Analytical Procedures, 2005

● ICH Q5E - Comparability of Biotechnological/Biological Products

Subject to Changes in Their Manufacturing Process, 2005

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Regulations

21 CFR 601.12 (a)(1) An applicant must inform the FDA,

through submission of a supplement to the original license

application, about changes in the product, production

process, quality controls or labeling established in the

approved license application.

(2) Before distributing a product made using a change, an

applicant must assess the effects of the change and

demonstrate through appropriate validation and/or other

clinical and/or non-clinical laboratory studies the lack of

adverse effect of the change on the identity, strength,

quality, purity, or potency of the product as they may relate

to the safety or effectiveness of the product.

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Regulations

The reporting categories for changes to an approved

application are based on the probability of the changes to

have a substantial, moderate or minimal potential to

adversely affect the identity, strength, quality, purity and

potency of the product as they may relate to the safety or

effectiveness of the product.

● Risk Based

601.12(b) (1) Major Changes – Substantial potential for

adverse effect on the product - Prior Approval Supplement

(c) (1) Moderate Potential - “Supplement – Changes Being

Effected in 30 Days”

(d) (1) Minor Changes - Annual Report

FDA Guidance : Major Changes Changes to Approved Applications: Biological Products, July

1997

Changes requiring supplement (PAS) submission and approval

prior to distribution of the product made using the change

(major changes) – 601.12(b)

Any change in manufacturing processes or analytical methods

that,

• Results in change(s) of specification limits or modification(s) in

potency, sensitivity, specificity, or purity

• Establishes a new analytical method

• Deletes a specification or an analytical method

• Eliminates tests from the stability protocol

• Alters the acceptance criteria of the stability protocol

FDA Guidance : Major Changes

New lot of, new source for, or different in-house reference

standard or reference panel (panel member) resulting in

modification of reference specifications or an alternative test

method.

● This is a critical issue for many biochemical, immunochemical

and biological assays, e.g., clotting assay for FIX potency

Extension of the expiration dating period and/or a change in

storage temperature, container/closure composition, or other

conditions, other than changes based on real time data in

accordance with a stability protocol in the approved license

application.

FDA Guidance : Major Changes Prior Approval Supplements – Content

● Detailed description of the proposed change

● The intermediates/drug substances/products involved

● The manufacturing site(s) or area(s) affected

● Detailed description of the new/revised method

● Description of studies performed to evaluate the effect of the

change – comparability report

– Describe the statistical method of evaluation in detail

● The data derived from those studies (report)

● Relevant validation protocols and data (report)

● A reference list of relevant standard operating procedures (SOPs)

FDA Guidance : Moderate Potential

Changes requiring supplement submission at least 30 days

prior to distribution of the product made using the change –

601.12(c)

Change in the site of testing from one facility to another

● From the license holder to a new contract lab

● From an approved contract lab to a new contract lab

● From a contract lab to the license holder

● Every thing else should remain the same – assay procedure,

standard, same/equivalent reagents and equipment, same

qualification criteria, etc.

FDA Guidance : Moderate Potential

Submission requirements – same as PAS (Major Change) at

least 30 days prior to distribution

● Submission should include adequate comparability data

● Reproducibility study (%RSD from replicate measurements in

two labs) alone is not sufficient

FDA Guidance : Minor Changes

Changes to be described in an annual report (minor changes)

– 601.12(d)

Submission requirements

● A list of all products involved

● A full description of the changes

● The manufacturing site(s) or area(s) involved

● The date each change was made

● A cross-reference to relevant validation report(s) and/or SOPs

● Relevant data from studies and tests performed to evaluate the

effect of the change on the identity, strength, quality, purity, or

potency of the product as they may relate to the safety or

effectiveness of the product

FDA Guidance : Minor Changes

Changes that can be reported in the annual report – 601.12(d)

Modifications in analytical procedures with no change in the

basic test methodology or existing release specifications

provided the change is supported by validation data

Tightening of specifications for existing reference standards to

provide greater assurance of product purity, identity, and

potency

Establishment of an alternate test method for reference

standards, release panels, or intermediates, except for release

testing of intermediates licensed for further manufacture

A change in the stability test protocol to include more

stringent parameters (e.g., additional assays or tightened

specifications)

FDA Guidance : Minor Changes

Addition of time points to the stability protocol

Change in the storage conditions of in-process intermediates

based on data from a stability protocol in an approved license

application, which does not affect labeling, except for changes

in storage conditions which are specified by regulation

Relocation of equipment within an approved operating room or

rearrangement of the operating area

(Perceived) Concerns What if I find something new in an approved product (after

changing to a new and improved method)?

What will happen after opening Pandora’s Box?

This something has been in your product all the time – your

previous methods just did not see it

Your manufacturing method is still the same – you product

composition is still the same

Your product has been used and proven safe and efficacious

Characterize this “new” thing (impurity)

If it is really something that has safety issues, you rather

want to know it now before it is too late

FDA may ask you to do some additional studies to show that

it is safe.

Comparability Study

Analysis of the same samples by multiple analysts using both

methods

Multiple analysis of the same lot vs analysis of multiple lots

● How many lots or replicates?

Clear understanding of what is changing/being compared

● Manufacturing process?

● Product characteristics?

● Ability to perform assay in a comparable manner?

– Comparability of analysts’ ability, equipment performance, reagents,

etc.?

Comparability Study Selection of appropriate statistical method(s) for the

evaluation of results

What is the question you are asking? – Understanding the

purpose of the comparability study

● Appropriate null hypothesis

● Selection of samples

● How many factors do you want to vary at a time?

● Can your statistical method handle multivariate analysis?

Number of samples/replicates should be large enough to have

adequate statistical power

Explain your statistical method in the comparability study

report

Comparability – Case Study 1

A SEC HPLC method is replaced by a RP-HPLC method for an

impurity assay in a drug product

Submitted as an annual report

Justification – Same basic methodology – HPLC

New method was reported as validated

No validation data or comparability data included in the

annual report

This change should be submitted as a PAS – a new analytical

method

All validation and comparability data should be included

Comparability – Case Study 2 A potency method is transferred from Lab A to Lab B

Data Submitted:

● Intermediate precision in each lab

– Three lots, three analysts in each lab

– Reportable results: %RSD – Met acceptance criteria

● Reproducibility study between two labs

– Reportable results: %RSD – Met acceptance criteria

● Comparability data for 6 lots, each analyzed three analysts in

each lab

● Data analyzed by paired t-test – PW > Fcrit at 95% CI but < Fcrit at

99%

Conclusion : Pass

My Observation: Lab 2 greater than Lab 1 for all 6 six lots;

Ratio of results for 6 lots from 1.5 to 3.4

Changing Method During Stability Study

Changing a method in the middle of an ongoing stability study

presents many questions and uncertainties that need to be

adequately addressed

Is the new method stability indicating?

Is the validation of the new method (as a stability indicating

method) alone sufficient to introduce the new method in the

middle of an ongoing stability study?

How to compare results from both methods?

What statistical method to use? How do you ascertain power

of the statistical method, particularly if you are monitoring an

impurity

Should you run a “pilot” to make a prior assessment?

Changing Method During Stability Study

Accelerated stability study evaluated using both old and

methods?

May often involve significant amount of additional work

My personal thought (not CBER’s position) – avoid if you can

If you plan to do so, draft your study-plan and discuss with

FDA review staff for concurrence before introducing the new

method in the stability program

Thank you

Questions?