Global Regulatory Update – FDA, USP, EP and ICH Standards for Test Method Validation Jane Weitzel [email protected]
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Global Regulatory Update – FDA,
USP, EP and ICH Standards for Test
Method Validation
Jane Weitzel
Jane Weitzel Biosketch
Jane Weitzel has been working in analytical chemistry for
over 35 years for mining and pharmaceutical companies with
the last 5 years at the director/associate director level. She
is currently a consultant, auditor, and trainer. Jane has
applied Quality Systems and statistical techniques, including
the estimation and use of measurement uncertainty, in a
wide variety of technical and scientific businesses. She has
obtained the American Society for Quality Certification for
both Quality Engineer and Quality Manager.
She was pointed to the Chinese National Drug Reference
Standards Committee and attended their inaugural meeting
in Beijing for 2013 to 2016
For the 2015 – 2020 cycle, Jane is a member of the USP
Statistics Expert Committee and Expert Panel on Method
Validation and Verification.
Disclaimer
This presentation reflects the speaker’s
perspective on this topic and does not
necessarily represent the views of USP or
any other organization.
Abstract The ICH, USP and other global
organizations, such as Eurachem, have
provided guidances on method validation for
many years.
Understand the history of these guidances
Learn how their similarities and differences
Hear about the coming changes
See how tools such as measurement uncertainty
and QbD can be used today
Look at Warning Letter Examples
Prepare now for these changes
History of Method Validation
Before 1970s, not much
Errors, accuracy, precision
1970s papers published
1971 FDA approached (accuracy & precision)
1990s conferences and workshops
EPA, AOAC, Eurachem
1995 USP <1225>
1999 release of standard ISO/IEC 17025:1999
1994, 1996 & 2005 ICHA good discussion of history: Analytical Separation Science,
Jared Anderson, Alain Berthod, Veronica Pino, Apryll M. Stalcup,
http://ca.wiley.com/WileyCDA/WileyTitle/productCd-3527333746.htmlA
Similarities & Differences
Terminology
Accuracy & trueness is a good
example
We need to define the terms we use
and understand the differences
Statistical approaches
ISO, AOAC, USP, EP, IUPAC, FDA
The good news:
Becoming standardized
Coming Changes
Focus on good science
Quality by Design
Lifecycle approaches
Statistical Techniques
Bayesian Statistics
Link to fitness for purpose
Target Measurement Uncertainty
Decision Rules
Good Science
There are many types of pharmaceutical
materials
There are many types of analytical
procedures
There are many guidances
There are many regulatory bodies
Recent developments for analytical
procedures include Good Science
Good Science Includes
What Science Is – and
How and Why it Works
“Science … power to probe and understand
the behavior of nature on a level that allows
us to predict with accuracy, if not control, the
outcomes of events in the natural world.”
“Science especially enhances our health, …”
Scientific Method
The scientific method, which underpins these
achievements, can be summarized in one
sentence, which is all about objectivity:
Do whatever it takes to avoid fooling yourself
into thinking something is true that is not, or
that something is not true that is.
Quality
Total Quality Management
Statistical Process Control
Deming
Juran
Quality Control
Quality Assurance
American Society for
Quality
Quality Revolution
the Deming principle
8. Drive out fear, so that everyone may work
effectively for the company
the FDA is changing its regulatory approach
to drive out fear
Watch the Deming videos
Sound Science
Metrological approach
to measurements
Measurement
uncertainty
Target measurement
uncertainty
Completely
characterises the
variability
17
http://www.fda.gov/ScienceResearch/FieldScience/LaboratoryManual/ucm171878.htm
Scientifically Sound
and Appropriate
Laboratory controls shall
include the establishment
of scientifically sound and
appropriate specifications,
standards, sampling plans,
and test procedures …
CFR has always required
use of sound science:
Decision rules,
measurement uncertainty,
risk and probability have
been used in many
scientific areas for many
years.
21 CFR 211.165 (d)
(d) Acceptance criteria for the sampling and
testing conducted by the quality control unit shall
be adequate to assure that batches of drug
products meet each appropriate specification
and appropriate statistical quality control criteria
as a condition for their approval and release.
The statistical quality control criteria shall
include appropriate acceptance levels and/or
appropriate rejection levels.
19
Decision
Rule
FDA Guidance
The FDA Guidance
discusses the role of
the analytical
procedure in the
lifecycle of the
product
To meet its
requirements
Good science
Metrology
Japan
More sophisticated
guidelines will be created
Discusses
the role of ICH in managing
expectations for its
responsibilities
How ICH will remain relevant
Will there be more emphasis
on training?
QbD
The recognition that the current
pharmaceutical industry's manufacturing
performance was not as state of the art as
other industries has been a key driver behind
the increasing adoption of quality-by-design
(QbD) concepts.
The Role of Analytical Science in Implementing Quality by Design
Mar 02, 2013 By Lucinda Buhse, Graham Cook , Moheb Nasr, Phil Nethercote, Siegfried Schmitt
Pharmaceutical Technology Volume 37, Issue 3
ICH Organizational Changes
Held inaugural meeting Oct 27, 2015
The International Council for Harmonization
(ICH)—formerly the International Conference
on Harmonization
to establish a more stable operating
structure.
The committee is also now a legal entity
under Swiss law.
Global & Regulators
The reforms will mean that ICH is a truly
global initiative, expanding beyond the
current ICH members. More involvement
from regulators around the world is welcomed
and expected, as they will be invited to join
counterparts from Europe, Japan, USA,
Canada and Switzerland as ICH regulatory
members.
Q12 EWG
Q12 EWG Technical
and Regulatory
Considerations for
Pharmaceutical
Product Lifecycle
Management
ICH Q12 & Analytical
Q12: Technical and Regulatory
Considerations for Pharmaceutical Product
Lifecycle Management
Enable control strategy lifecycle (e.g., model
maintenance, analytical lifecycle)
Q12 - Control & analytical
Q12 will
Support continual improvement of the
manufacturing process and the control
strategy which can result in decreased
product variability and increased
manufacturing efficiency
ICH Q12
The efforts of the EWG are focused on
lifecycle of the product from the perspective
of the introduction of post-approval
manufacturing changes. There is no specific
focus on "lifecycle of methods" but up-to-date
methodology is always encouraged; and so it
would be desirable to lower the regulatory
burden associated with making changes to
methods during the product lifecycle.
ICH Q12 cont’d. There has been discussion on which types of methods,
and what aspects of methods, are part of the
"established conditions" for the product approval; i.e., for
what changes to methods used to analyse the product
does one need to communicate directly with the
regulatory agency (either requesting or notifying).
There is some consideration that if the description of the
analytical method can justifiably focus on the outcomes
for the product, then many types of method changes
would not need to be reported so long as the "outcome"
does not change.
The EWG is considering ways to try to illustrate this
issue with examples of specific method parameters.
Q12 Point 1
1) for what changes to methods used to
analyse the product does one need to
communicate directly with the regulatory
agency
Briefly, what we are looking at is the use and
estimate of measurement uncertainty which
is extremely helpful in identifying these
changes
Q12 Point 2
2) There is some consideration that if the
description of the analytical method can
justifiably focus on the outcomes for the
product,
What we are looking at is the Target
Measurement Uncertainty which clearly
defines the link between the performance of
the analytical procedure and its "fitness for
purpose" which is the outcome for the
product.
Q2
Analytical Procedure Development and
Revision of Q2 (R1) Analytical Validation
Proposed 3 year timeline to review
Include lifecycle
Aligned with ICH Q8-Q12
Scientific Journals
Fit for Intended Purpose
Assays must therefore be suitable for the
purpose of their respective applications.
Harmonizing Best Practices in Bioanalytical Methods
Citation: Tutunji L (2015) Harmonizing Best Practices in
Bioanalytical Methods. MOJ Bioequiv Availab 1(1):
00001. DOI: 10.15406/ mojbb.2015.01.00001
History Eurachem
Eurachem was founded in 1989, and on the
occasion of the tenth General Assembly, Alex
Williams, the convenor of the initial meetings
set up to consider establishing a forum for
traceability in analytical chemistry in Europe.
ISO 17025
Meeting internationally accepted criteria for
validation and measurements of uncertainty
as defined in ISO standards 9000 and 17025
will increase the likelihood of acceptance by
international and national regulatory
agencies.
http://www.ivtnetwork.com/article/analytical-method-validationValidating Immunoassays Using the Fluorescence Polarization Assay for the Diagnosis of
Brucellosis An Example and as an Application to ISO Standards 9000 and 17025
By David Gall and Klaus Nielsen
ISO 17025 Revision
Includes:
Decision rule
TMU
Risk
Sampling
Expected early 2018
FDA Lab Quality Manual
ORA labs have been
accredited to ISO
17025
Recently added
training information to
the website
Expanding to other
FDA and State labs
Food initiative, FSMA
4. Background
Every measurement or test has an error of
measurement. If repeated, a test or measurement often
gives a different result, even though it usually is very
similar to the original result. Therefore, a test or
measurement gives only an approximation of the true
value of the quantity to be measured. A measurement or
test is only complete if it includes the measurement
uncertainty of the test. This can be thought of as a
quantitative indication of the quality of the result.
USP <1210>
New proposed USP General Chapter <1210>
Statistical Tools for Method Validation.
This new proposed chapter, which was
published in PF 42(5) [Sept-Oct 2016], will be
a statistical companion chapter for USP
General Chapter <1225> Validation of
Compendial Procedures.
USP PF
The USP Pharmacopeia Forum (PF)
Stimuli Articles and Proposed new general
chapters articles are freely available from
the USP.org website under the
Pharmacopeia Forum (PF). You have to
register once, but there is no charge
USP Stimuli Articles - USP.org Proposed New USP General Chapter: The Analytical Procedure
Lifecycle <1220>;USP PF 42(6)
Fitness for Use: Decision Rules and Target Measurement
Uncertainty; USP PF 42(2)
Analytical Target Profile: Structure and Application Throughout the
Analytical Lifecycle; USP PF 42(5)
Analytical Control Strategy; USP 42(5)
Proposed new USP General Chapter <1210> Statistical Tools for
Method Validation.
This new proposed chapter, which was published in PF 42(5) [Sept-Oct
2016], will be a statistical companion chapter for USP General Chapter
<1225>Validation of Compendial Procedures.
Proposed New USP General Chapter: The Analytical Procedure
Lifecycle ⟨1220⟩USP PF 43(1)
Law
This bill requires the Food and
Drug Administration to issue
guidance that addresses using
alternative statistical methods,
including adaptive trial design
and Bayesian methods, in
clinical trials and in the
development and review of
drugs and biological products.
u definition
Measurement uncertainty - The
measurement of uncertainty is the parameter
associated with the result of a measurement
that characterized the dispersion of the
values that could be reasonably attributed to
the measurand.
GUM & BIPM
Setting TMU
This document discusses how
to set a maximum admissible
uncertainty, defined in the
third edition of the
International Vocabulary of
Metrology as the “target
uncertainty”, to check whether
measurement quality
quantified by the
measurement uncertainty is fit
for the intended purpose.
Let’s Look at FDA Guidance
The FDA Guidance
discusses the role of
the analytical
procedure in the
lifecycle of the
product
To meet its
requirements
Good science
Metrology
Life Cycle
Used 6 times
Refers to the life cycle of the product
Once an analytical procedure (including
compendial methods) is successfully
validated (or verified) and implemented, the
procedure should be followed during the life
cycle of the product to continually assure that
it remains fit for its intended purpose.
Continued Verification
Over the life cycle of a product, new
information and risk assessments (e.g., a
better understanding of product CQAs or
awareness of a new impurity) may warrant
the development and validation of a new or
alternative analytical method.
Improvements in analytics
In anticipation of life cycle changes in
analytics, an appropriate number of retention
samples should be maintained to allow for
comparative studies.
Intended Purpose
Intended purpose is mentioned 5 times
Data must be available to establish that the
analytical procedures used in testing meet
proper standards of accuracy, sensitivity,
specificity, and reproducibility and are
suitable for their intended purpose.
Stage 1, Design & Development
Early in the development of a new analytical
procedure, the choice of analytical
instrumentation and methodology should be
selected based on the intended purpose and
scope of the analytical method.
Stage 2 Analytical Procedure
Qualification
Analytical method validation is the process of
demonstrating that an analytical procedure is
suitable for its intended purpose.
Stage 3 Continued Verification
… the procedure should be followed during
the life cycle of the product to continually
assure that it remains fit for its intended
purpose. Trend analysis on method
performance should be performed at regular
intervals to evaluate the need to optimize the
analytical procedure or to revalidate all or a
part of the analytical procedure.
Change
The new method coupled with any additional
control measures is equivalent or superior to
the original method for the intended purpose.
Warning Letters 1
3. Your firm does not have, for each batch
of drug product, appropriate laboratory
determination of satisfactory conformance to
final specifications for the drug product,
including the identity and strength of each
active ingredient and freedom from
objectionable microorganisms, prior to
release (21 CFR 211.165(a), (b)).
Warning Letter 2
In your response to this letter, include:
a list of the current quality control criteria and test
methods you currently use to test each drug product
batch prior to release.
a thorough assessment to determine insufficiencies in
chemical, physical, and microbiological specifications
and analytical methods established for each of your drug
products. Include a full remediation plan with appropriate
specifications and analytical methods to be used for
testing each batch of drug product.
Warning Letter 3
1. Failure to ensure that test
procedures are scientifically sound and
appropriate to ensure that your API
conform to established standards of
quality and/or purity.
Warning Letter 4
You have not shown how you will ensure that
your test methods are appropriate to
determine whether your API conform to
established standards and specifications.
Consequently, the summary data you
provided does not demonstrate that
previously released lots do not contain
excessive levels of unknown impurities.
Good Science
The methodology and objective of the
analytical procedures should be clearly
defined and understood before initiating
validation studies. This understanding is
obtained from scientifically-based method
development and optimization studies.
Lifecycle of Analytical Procedure
Session 1 – Analytical Procedures and Method
Validation
Develop a Quality by Design (QbD) Approach
for Analytical Method Development
Session 6 – Analytical Procedures and Method
Validation
Method Validation Characteristics through
Statistical Analysis Approaches
Session 8 - Investigating Laboratory OOS Test
Results
Manage Risk and Improve Efficiency in the
Laboratory
Stage 1
Design Development & Understanding
Stage 2
Performance Qualification
Stage 3
Continued Performance Verification
Career search
Job descriptions are starting to include the
knowledge and understanding of QbD, Life
Cycle, and uncertainty.
Proficiency with Quality by Design (QbD)
concepts, statistical process control (SPC) and
complex data analysis
Conclusion
History – we have come a long way
New concepts meet the need
MU, TMU, QbD, Life Cycle
Regulatory bodies have adopted and
continue to adopt these useful concepts
Because
They are based on sound science
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