Global Regulatory Update FDA, USP, EP and ICH Standards ... · PDF fileUSP, EP and ICH...

Global Regulatory Update – FDA,

USP, EP and ICH Standards for Test

Method Validation

Jane Weitzel

[email protected]

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.

[email protected] 2

Disclaimer

This presentation reflects the speaker’s

perspective on this topic and does not

necessarily represent the views of USP or

any other organization.

[email protected] 3

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

[email protected] 4

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

[email protected] 5

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

[email protected] 6

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

[email protected] 7

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

[email protected] 8

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, …”

[email protected] 9

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.

[email protected] 10

LOOK AT PHARMACEUTICAL

INDUSTRY


Relevance of People & Concepts


Deming


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


EMA Mentions Deming


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

[email protected]

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

[email protected]

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

[email protected]

Japan and QbD


Pharmaceutical and Medical Devices Agency (PDMA)

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?


Japan & ATP PF Article

Translating the article on ATP


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 (International Council for Harmonization)

http://www.ich.org/home.html


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


Adoption of Step 4 Document 2Q

2017


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


ICH Future

Proposed to address analytical requirements

in detail about 2017


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.


Eurachem Guides


Many Useful Guidelines

Setting Target Measurement

Uncertainty



Fit for Purpose is

in the title

New:

Setting TMU

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


FDA Policies and SOPs

Includes

Measurement

Uncertainty (MU)


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.


Added Training

Useful reference on training in a

laboratory


Statistics


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


BIPM.org


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

[email protected]

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


Trueness


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