DEVELOP A RISK- BASED, DATA INTEGRITY AND METRICS-DRIVEN ... · engineering. The best scientific argument may fail to convince The best scientific argument may fail to convince if

CONFIDENTIAL © 2017 PAREXEL INTERNATIONAL CORP.

DEVELOP A RISK-

BASED, DATA

INTEGRITY AND

METRICS-DRIVEN

QUALITY MANAGEMENT

PROGRAM

ENTERPRISE-WIDE

February 2017

Siegfried Schmitt

© 2017 PAREXEL INTERNATIONAL CORP. / CONFIDENTIAL2

AGENDA

• Let’s talk about quality -

seriously!

• Risks, what risks?

• We all love to measure -

measure what?

• Interactive Exercise

• FDA Quality Metric

Initiative - Latest News!


DEFINING QUALITY - QUALITY + CULTURE = ???

Definitions abound! The editors of Quality Digest say that defining the

word "quality" is "no simple endeavour."

Juran said quality meant “fitness for use”

Deming said only the “customer” can define quality (begs a new

question, “who is the customer”?)

ISO Definition: “Quality is the totality of features and characteristics of a

product or service that bear on its ability to satisfy stated or implied

needs.”

The FDCA Sections 501(b) and (c) define adulteration of compendial

and non-compendial drugs, respectively, in part, as

[501(b)] “…(its) strength differs from, or its quality or purity falls below,

the standard set forth in (the applicable) compendium…” or

501(c)] “…If it is not subject to the provisions of paragraph (b) of this

section and its strength differs from, or its purity or quality falls below,

that which it purports or is represented to possess”


THE TERM “QUALITY” IS USED IN VARYING WAYS IN

THE BIOPHARMA AND MEDICAL DEVICE INDUSTRY

Sometimes it means “floor level” GMP compliance

21 CFR 210.1(a) states in part “The regulations set forth in this part

…contain the minimum current good manufacturing practice for

methods to be used in, and the facilities or controls to be used for, the

manufacture, processing, packing, or holding of a drug …” (emphasis

added)

Sometimes it means elevating the standard to the maximum

feasible level

Sometimes it refers to attributes of a product

Sometimes it refers to the Quality Unit , as in “Let’s ask Quality

what they think…”

Sometimes it refers to a mindset or approach to the job one is

doing

“Big Q” – the attributes of quality of the product

“Little q” – Quality Operations; the job of the Quality Unit


QUALITY IS NOT EASY

TO DEFINE! For the purpose of this

discussion, let’s use:

A “Quality” drug product

always meets specifications

that are designed to ensure

proper clinical performance,

and is manufactured under

conditions that are controlled

to assure consistently correct

results.

We can argue about the

details later.


“QUALITY” IS NOT EASY TO SELL TO COMPANY

LEADERSHIP - WHY?

Because, for the most part, it does not drive sales in the drug

industry. (Maybe in devices, to an extent.)

The case usually made for a strong quality system involves

primarily avoidance of adverse consequences:

We’ll reduce deviations

We’ll have fewer defects and rejections

We’ll have fewer recalls, complaints and adverse publicity

We’ll have less of a regulatory problem and associated costs

You never hear anyone say “If we have a better quality system we will

sell more products!”

In other industries that works: Cars, consumer electronics,

barbeque grills, furniture, etc. Pharmaceuticals? Not so much.


FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY

CULTURE PROBLEM” - #1

Benign Ignorance - Symptoms include:

Focus on clinical trial progress, particularly when successful, and ignoring

need to assure sound manufacturing processes and process

understanding

Leadership that has no experience running manufacturing operations

and simply has no idea of what it takes. Often seen in companies that

mature from a development focused environment to one where

someone decides to commercialize something themselves rather than

sell it off and start over.

“Virtual” organizations that think if you outsource everything you have no

responsibility for anything other than to sit back and reap the rewards

A

B

C




Pipeline panic. Symptoms include two mirror images:

The blockbuster product that has sustained us for years is

going off patent and we have nothing coming down the

pipeline to replace it. We have to push product out the door

while we still can.

Or alternatively:

Our new product is a blockbuster, we need to shove as much

of it out there as fast as possible to satisfy impatient investors,

recoup our development costs and drive up the stock price.

Don’t slow that process down for “bureaucratic reasons”!


FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY CULTURE PROBLEM” - #3

Our product is high medical need (or A and B together).

Our product is the only modality for use in this disease condition.

FDA has inspected us several times over many years and never found

anything seriously wrong (abdication of quality responsibility to the regulator).

We have small numbers of complaints and adverse events reported.

Our product has been sold in “Whoknowswhereistan” for years with no issues.

False sense of regulatory invulnerability, which may be caused by these

or other things:

A

B

C

D

E

F

Our product is in short supply.




Egotism and arrogance. Exemplified by:

We are the recognized industry leaders! We set the

standard!

We are unique!

A

B

C

The regulators do not understand our process!

With special thanks to David Chesney, formerly PAREXEL Consulting




The well worn “science versus compliance” debate:

A. We have the science to support this, who needs those stubborn

bureaucrats and their documentation rules!

B. Following GMP impedes creativity and slows the advance of

science!

C. We are the experts, don’t tell us how to do our job!

D. “Everybody knows that”!

Some thoughts on this to bear in mind:

Compliance without good science behind it is an empty exercise

and basically worthless.

No matter how good the science, you cannot test compliance into

a product, you must build it in, which requires the application of

sound quality management practices, and, yes, that involves

compliance.

You need both. There is no debate.


THE FLEXIBLE, CAPABLE, APPROPRIATE QMS - FROM

SCRATCH OR FROM THE AS-IS


PROCESS VISUALIZATION VERSUS TEXT


THE QUALITY MANAGEMENT SYSTEM (QMS) -

CONCEPTUALLY

Quality System

Policy

Organization

Documents

Processes

Resources

Objectives & Planning

Support continuous

quality improvement

for processes and

product.

Demonstrate the constant

commitment of senior

management to quality.

Specify who is responsible for

each quality-related activity.

Explain how quality

commitments should be

performed (procedures)

and documented

(records).

Identify and monitor all

processes that affect

product quality.

Identify and provide the

resources and knowledge

needed in order to achieve

quality objectives.


THE THREE LEVELS OF COMPLIANCE

Product and service quality – to be competitive

Product and service quality – to be competitive

Quality mindset – to strive for excellence

3

2

1


THE THREE AREAS FOR COMPLIANCE

• Strategic quarterlyRisk Management,

Auditor and inspector satisfaction

• Tactical monthlyDocumented Key Compliance processes

• Operational daily Technical support for all

compliance matters


THE QUALITY MINDSET IS ABOUT:

Being beyond compliance

Cooperation

Being open to

inspection

Taking responsibility

Innovation

Learning

Being accountable

Delivering quality in

everything we do


FROM BEING REACTIVE TO BEING PROACTIVE


COMPLIANCE AND QUALITY MANAGEMENT SYSTEM


THE COMPLIANCE PYRAMID - RISK-BASED


QUALITY RISK MANAGEMENT

Risk Management

Identify and

asses risks Develop

controls

and action

plan

Implement

controls and

evaluate


BENEFIT / RISK CONSIDERATIONS HOLISTICALLY


THE ACCEPTABILITY OF RISK

A few real examples:

• 1,000 open CAPAs, 90% between 1 and 5 years overdue

• Critical audit observation still unresolved after 1 year, with 5 minor

observations from the same audit now resolved

• No maintenance activities in the past 2 years

• Validation of large configurable Enterprise Resource Planning system

terminated 6 months before completion by senior management

• Requests by regulatory agency inspectors are never questioned,

challenged or discussed - they are always fully accepted

• The company is understaffed by around 200 quality unit personnel


THE ACCEPTABILITY OF RISK - THE BASELINE

What is your acceptance level?

How is this communicated? - Dashboards?

Is it defined by senior management?


THE RISK REGISTER

1

2

A listing of all risk assessments. How to list them, where

and who is in charge?

A risk register compliant with EU regulations.

Should sites have a formal risk register and management

process?

Yes, a risk register (or equivalent title document) should list and track all key risks

as perceived by the organisation and summarise how these have been mitigated.

There should be clear reference to risk assessments and indeed a list of risk

assessments conducted should be included or linked to the register. A

management process should be in place to review risk management - this may be

incorporated into the quality management review process.

SOURCE: http://tinyurl.com/zgv3y99

http://tinyurl.com/zgv3y99


BEYOND THE FAILURE MODES AND EFFECTS ANALYSIS

(FMEA)

While FMEA is useful and versatile, some organizations

consider it a complete QRM tool in itself. This is in part

because typical FMEA worksheets include columns for risk

treatment items (i.e., risk reducing actions) and a

reassessment of the risk priority numbers (RPNs).

This approach essentially leaves out the third and fourth

elements: risk communication and risk review. Despite this

limitation, many companies still rely on FMEA as their overall

approach to QRM.


COMMUNICATION - THE WEAK LINK WHEN IT COMES

TO RISK

Communication is a key issue in all of science and

engineering. The best scientific argument may fail to convince

if it cannot be communicated cogently to the stakeholders.

This is especially true of Risk Acceptability Criteria.

Make sure you have internal communications and external

communication policies and procedures

SOURCE: https://store.pda.org/ProductCatalog/Product.aspx?ID=3447

https://store.pda.org/ProductCatalog/Product.aspx?ID=3447


FIVE REASONS WHY COMPANIES DEVELOP A “QUALITY CULTURE PROBLEM” - #3

An organization’s culture can limit how QRM is applied proactively

Misapplying a specific risk-assessment tool as a QRM process

Using rating scales that are neither specific nor appropriate to a given

situation

Not acknowledging when uncertainty (or the lack of important information) is

present

0Neglecting to keep risk assessments current with changes that could affect

underlying assumptions and key decisions

.

2

3

4

5

6

7

Using QRM to justify an action instead of as a tool for truly assessing and

exploring risks

Issues with using Quality Risk Management incorrectly:

1 Using formal QRM tools in situations where they are not actually needed

SOURCE: James Vesper and Keven O’Donnell in Pharmaceutical Engineering Nov - Dec 2016


THE VALUE OF DATA FOR QUALITY METRICS

“In the inspection realm, we find too many, disturbing

examples of firms providing us with false information, and

doing so deliberately.

In order for those of us at FDA to do our jobs, we must

receive accurate information from firms. Quality metrics based

on false data are meaningless. An NDA or ANDA based on

false information can be a danger to the public.

Fundamentally, data integrity is a corporate responsibility.

There are other examples of corporate responsibility that our

Office of Criminal Investigations has emphasized.”

SOURCE: Howard Sklamberg, Deputy Commissioner, Global Regulatory Operations and Policy, U.S.


A FEW DEFINITIONS TO START WITH

Metric:

A measure against a standard (standards of measurement by

which efficiency, performance, progress, or quality of a plan,

process, or product can be assessed)

Indicator:

Provides indication of performance (qualitative or quantitative),

e.g., to evaluate success of an organisation or activity

Key Performance Indicator (KPI):

Target critical areas of performance (not all indicators are key)


MEASURABLE COMPLIANCE - METRICS


QUALITY METRICS - MEASURE WHAT?

FDA Submission of Quality Metrics Data Guidance for Industry,

Revision 1, November 2016

FDA Quality Metrics Technical Conformance Guide Technical

Specifications Document, Version 1.0, June 2016


WHY THIS PROGRAM?

The proposed guidance is designed to drive manufacturing modernization

and also reduce the compliance burden.

Companies that have standardized processes and are able to maintain the

required quality standards would be subject to less frequent inspections,

giving them a strong incentive to focus on process improvement.

It is part of FDA’s Pharmaceutical cGMPs for the 21st Century - A Risk-

Based Approach initiative


HOW TO PREPARE?

People:

Senior management buy-in

Allocation of resources and organizational adjustments to

implement and run the processes required

Awareness creation and training

Technology:

Automation of data collection and reporting

Interfaces for multiple systems

Data calculation and trending algorithms

Data dashboards


Verification that all required data are collated

HOW TO PREPARE CONT.

Standardization of data and of the processes for reporting

the data

Validation of the processing systems

Identification of the quality metrics2

3

4

5

Processes:

Identification of the processes that manage the quality

metrics data 1


HOW TO PREPARE - SUMMARY

Courtesy of Steve Mendivil PDA Quality Metrics Task Force lead


QUALITY INDICATORS - FDA VIEW 1

Accepted lots/Total number of lots started.Metric

RationaleThis rate is an indicator of manufacturing process

performance, and is proposing it in terms of accepted

lots.

Measurement“The number of accepted lots in a timeframe divided by

the number of lots started by the same covered

establishment in the current reporting timeframe.”



Product quality complaints received / Total dosage units

distributed.Metric

Rationale

This rate is an indicator of patient or customer feedback and

is proposing it in terms of complaints per distributed dosage

units, which will remove lot size as a variable in the complaint

equation

Measurement“The number of product quality complaints received for the

product divided by the total number of dosage units

distributed in the current reporting timeframe.”



OOS test results invalidated / Total OOS test resultsMetric

RationaleThis is an indicator of the operation of a laboratory. It includes

stability testing and only focuses on cases where measurement

aberrations led to the invalidation of OOS results.

Measurement

“The number of OOS test results for lot release and long-term

stability testing invalidated by the covered establishment due to

an aberration of the measurement process divided by the total

number of lot release and long-term stability OOS test results in

the current reporting timeframe.”


IT’S STILL IN THE DESIGN PHASE

FDA is planning to open an electronic portal in January 2018

for voluntary submission of quality metrics data, which the

agency is encouraging companies to submit on a quarterly

basis.

But, the clock is ticking


QUALITY INDICATORS - WHAT YOU SHOULD MEASURE

ANYWAY

Inspection Preparation Effort - known?

Remedial Action Effort - measured?

% Right First Time - where are you?

Percentage GMP Systems validated - tracked?

Compliance level with key regulations - red, amber or

green?

Time to respond to medical queries


HOW TO PREPARE CONT.

Identification of the quality metrics2

3

4

5

Processes:

Identification of the processes that manage the quality

metrics data 1

6

Verification that all required data are collated

Standardization of data and of the processes for reporting

the data




THE ANNUAL QUALITY PRODUCT REVIEW (APR) OR

PRODUCT QUALITY REVIEW (PQR)

The FDA “Annual product review” is intended to confirm that

every batch of product released during the review period

complied with the registered process and specification.

The EU PQR concentrates on the quality system and process

to show that they continue to produce consistently good

quality product.

SOURCE: http://tinyurl.com/zyrzesd

http://tinyurl.com/zyrzesd


THE ANNUAL QUALITY

PRODUCT REVIEW (APR)

OR PRODUCT QUALITY

REVIEW (PQR)

From the stone age to the 21st

century:

• From manual transcription to

interlinked computerized

systems.

• From manual entry into

spreadsheets to real-time

trending data, providing an

immediate snapshot of the

quality and compliance status of

the company.


QUALITY INDICATORS?

Some not so sensible ones:

Number of 483 observations in a FDA inspection

All deviations closed out in 30 days

All audit trails reviewed

Incentive systems and their influence on corporate culture:

• “What gets measured gets done” (an old maxim from the

Management by Objectives approach, attributed to several

people)

• What gets tangibly incentivised gets done first!

• Systems that incentivise “pushing product out the door” or which

have unbalanced objectives that fail to consider quality and

compliance can quickly drive behaviours in the wrong direction


INTERACTIVE EXERCISE• Please split up in groups

• Then select one of these topics

(preferably all topics should be

covered by a team):

o Defining an objective

o Managing risks

o Reporting quality metrics

• Please provide solutions and/or

strategies for how to achieve the

desired outcomes

• Prepare to share your findings

with the rest of the audience


INTERACTIVE EXERCISE - DEFINING AN OBJECTIVE

Your company is planning to launch a new product 3 years from now

Your operations, marketing, quality and other teams need a common

objective (preferably no more than one or two sentences)

Define this objective:


INTERACTIVE EXERCISE - MANAGING RISKS

Your company is planning to launch a new product 3 years from now.

Your operations, marketing, quality and other teams need to work out the

risks associated with this launch.

Define the approach:


INTERACTIVE EXERCISE - REPORTING QUALITY

METRICS

Your company is planning to launch a new product 3 years from now.

Your operations, marketing, quality and other teams need to define and

report quality metrics to senior management and the authorities.

Define the quality metrics:


FDA ON QUALITY METRICS - NEWS TICKER

+++ Latest News +++ Latest News +++


FDA ON QUALITY METRICS - TIMELINE

SOURCESteve Mendivil, from the Opening Presentation


FDA ON QUALITY METRICS - NEWS TICKER

To be completed at the conference


QUALITY METRICS - A FEW OPEN QUESTIONS

Open questions:

• Does FDA have the legal authority to

request quality metrics?

• How should FDA implement the program?

• Product segmented by site or Site

segmented by product?

• Optional Metrics?

• Should FDA share peer ranking?

• Metric reporting leading to more drug

shortages?


THE COMPLIANCE PYRAMID - VALUE GENERATION


CURRENT VERSUS DESIRED COMPLIANCE STATE


COMPLIANCE FRAMEWORK


YOUR PRESENTER

Siegfried Schmitt, Ph.D., FRSC

CChem CSci

Principal Consultant

PAREXEL International

+44 7824 592401

[email protected]

[email protected]


THANK YOU
