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Transcript of Replacing Analytical Methods for Release and Stability ...€¦ · Replacing Analytical Methods for...
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
2 2
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
4 4
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
6
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
7
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.
8
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