Saturday, October the 10, 2015

Quality Metrics & Science

Habib University, Karachi

Obaid Ali & Roohi B. ObaidCivil Service Officers at Drugs Regulatory Authority of Pakistan

1 Math, Statistics and Computer in Quality Science

2Cultural Scores and Site Performance for key Quality Metrics

5 Quality is everyone's responsibility

6Closing words - Simple, clear and loud

3 Essential Attributes for Culture of Quality

4Roots and Principle of Quality Culture

Where everyone willingly takes responsibility for patient protection and

quality of product

Where patient is centre of everything

Econometrics

Pharmacometrics

Chemometrics

Science

Rational

Data Integrity – Deviant Behaviors

Not recording activities

contemporaneously

Backdating Fabricating data

Copying existing data as

new data

Re-running samples

Discarding data

Alicia M. Mozzachio, July 2014, FDLI, Washington DC

Trends help indeed to understand and predict

Lets have a visit to some slides of US-FDA

Time

Proc

ess P

aram

eter

Lower Specification Limit (LSL)

Upper Specification Limit (USL)

today

Uncertainty

RISK: For a given severity of risk event, what are the chances (probability) of exceeding the USL in the next period of time?

G. Claycamp, FDA, Sept. 2005

Tomorrow ?

Proc

ess P

aram

eter

Lower Specification Limit (LSL)

Upper Specification Limit (USL)

Uncertainty

Tomorrow ?

G. Claycamp, FDA, Sept. 2005

RISK: Control options are scenarios for risk management. Note that this scenario shows the best estimate is below the USL.Time today

Time

Proc

ess P

aram

eter

Lower Specification Limit (LSL)

Upper Specification Limit (USL)

today

Uncertainty

Take a cut at a moment in time: Risk has a distribution.

Tomorrow ?

G. Claycamp, FDA, Sept. 2005

Quality Metrics

Indicator of operational reliability Quality Culture

Quality Metrics

Lot Acceptanc

e Rate Product Quality

Complaint Rate

Right first time Rate

Invalidated OOS Rate

APR or PQR on

time Rate

CAPA Rate

Ability to initiate

voluntary CAPA

Lots rejected/total lots in a year

Lot Acceptance Rate

Lot Acceptance Rate

4/355=

Deviated lots/ total lots in a year

Right First Time Rate

38/355=

Right First Time Rate

APR triggered CAPA/ total number of APRs

Corrective & Preventive Action (CAPA) Rate

Corrective & Preventive Action (CAPA) Rate

3/30=

Process capability or performance index for each critical quality attribute that

triggers a CAPA

Ability to initiate voluntary CAPA

Ability to initiate voluntary CAPA

Cp value

The number of batches for which complaint received/ total number of

batches (very specific to the product)

Product Quality Complaint Rate

Product Quality Complaint Rate

6/30=

Invalidated initial OOS tests / total number of tests in a year

Invalidated OOS Rate

Invalidated OOS Rate

200/9900=

The number of APRS within 30 days of annual due date / the total number of products

produced during the year

APR or PQR on time Rate

APR or PQR on time Rate

05/40=

Cultural Scores & Site Performance Key Quality Metrics

Pharmaceutical OnlineKen Congdon, 26 May 2015

Stronger culture is correlated with fewer action limit excursions in steriles

1/4 ISPE

Cultural Scores & Site Performance Key Quality Metrics

Pharmaceutical OnlineKen Congdon, 26 May 2015

Stronger culture scores are associated with higher lot acceptance

2/4 ISPE

Cultural Scores & Site Performance Key Quality Metrics

Pharmaceutical OnlineKen Congdon, 26 May 2015

Sites with higher quality culture scores have lower deviations recurrence

3/4 ISPE

Cultural Scores & Site Performance Key Quality Metrics

Pharmaceutical OnlineKen Congdon, 26 May 2015

Sites with higher quality culture scores have higher CAPA effectiveness

4/4 ISPE

Identified Essential Attributes for Culture of Quality

Harvard Business ReviewSurvey April 2014

Leadership Emphasis

Message Credibility

Peer Involvement

Employee Ownership

Identified Essential Attributes for Culture of Quality

Harvard Business ReviewSurvey April 2014

Maintaining a leadership emphasis on quality

What they say & What they do

1/4

Even when executives have the best intentions, there are often gaps b/w

What they say & What they doAs a result, employees get mixed messages about

whether quality is truly important. Company leaders must first buy into quality improvement initiatives and clearly demonstrate their own personal commitment to this effort

to employees

Identified Essential Attributes for Culture of Quality

Harvard Business ReviewSurvey April 2014

Ensuring Message Credibility

One Message

2/4

Quality messaging should be tailored in such a way that it resonates with every employee.

Different messages may need to be developed to resonate appropriately with employees at

different sites.

The key is to regularly test these messages with employees, solicit their feedback, and refresh

these messages over time if necessary

Identified Essential Attributes for Culture of Quality

Harvard Business ReviewSurvey April 2014

Encouraging Peer Involvement

Participation

3/4

A variety of different tactics can be used to create positive social pressure that encourages employees to participate in (& even generate) quality initiatives. These can include friendly

“quality competitions”.The key is to test these tactics and solicit

feedback to see which are most effective with employees.

Identified Essential Attributes for Culture of Quality

Harvard Business ReviewSurvey April 2014

Increasing Ownership & Empowerment

Engage in Decisions

4/4

Employees should be free to apply their own judgment to situations that fall outside the

common directive. Providing the right level of guidance is crucial to this effort

but they must know how to act when they encounter specific quality issues.

Visible Signals of Quality Culture

Right tone at the top

Focus on the right value

Constant display of putting patient

above everything

Constant display of concern for quality

Consistently walks the talk

With great people skill

& strong value

More than financial rewards

Roots of Strong Quality Culture

Introduction of Improvement & Innovation for quality driven productivity

Adaptation & Investment in Technology to ensure state of control over system

Promotion of change & continuous improvement in Quality System

Roots of Strong Quality Culture

Prompt adaptation of best practice, low staff rotation

Proactive & transparent behavior

Strong relationship based on dialogue, science & mutual respect

Principle of Quality Culture

Product & Process Understanding Sensible Business Management

Sufficient depth of science to explain why deviations have not impacted on quality of

product

Too fast growth & operating at limit of capacity triggers often

issues & non-compliance

How mature is your quality system

1 2 3 4

Level

Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA

Small problems ultimately snowball into larger ones, and management becomes aware only when there is a crisis

How mature is your quality system

1 2 3 4

Level

Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA

Nearly always reactive, but there is willingness to change. Patchwork corrections are the norm

How mature is your quality system

1 2 3 4

Level

Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA

More proactive. Increasingly detects emerging adverse trends, surfaces major issues, and makes lasting manufacturing and

system improvements

How mature is your quality system

1 2 3 4Level

Richard L. Friedman, FDLI Workshop Washington DC, July 2014US-FDA

Routinely acts preventively as described in level 3. Fully institutionalizes and reinforces (rewards) a vigilant culture that makes meaningful manufacturing and systemic improvements

Systems Thinking

System is the product of interacting parts

Improving the parts taken separately will not improve the system

Quality is everyone’s responsibility

Selected Quotes, W. Edwards Deming

Lack of knowledge …

that is the problem

If you do not know how to ask

the right question, you

discover nothing

If you can’t describe what you are doing as a process, you don’t know what you are

doing

Rational behavior requires theory.

Reactive behavior requires only reflex

action

Whenever there is fear, you will

get wrong figures

Learning is not compulsory … neither is survival

Strong Quality Culture Efficient Quality System Consistent manufacturing

It’s the culture that decides the path

Poor Quality Culture Unreliable Quality System Defects and Recall

Soft gelatin capsule Paracetamol tablet

Pyrimethamine tragedy Metronidazole label

Dis

inte

grat

ion

failu

re

Dis

solu

tion

failu

re

Mat

eria

l mix

up

Labe

l Mix

up

One of the important Hormonal Product

Contract manufacturing

Changed in color

Stability was not done

Quality Agreement

Batch of 1 million tablets 22 batches Underweight

Caught after 2 weeks

System ???or culture ???

Antibiotic & steroid cream

Analytical method

unable to quantify

Manipulated method used

for years

Ended up with

withdrawal of product

from market

Lets Look Around …

09 Oct, 2015, Tab Paracetamol - USA

Tablet Paracetamol

Wrongly labeled

325 mg instead of 500 mg

175 mg additional than claimed

What do you think what should be the action?

End up with recall

Aug 2015Puerto Rico &

Taiwan

Wood fragments found in

toothpaste

3.9 M tubes recalled

Attix Canada April 2015

Attix Canada April 2015

Health Canada …. FDA closed an API

repackager in Toronto

recall hundreds of bulk APIs … cross-

contaminated by penicillin

failed to use separate facilities, or

equipment like hoods and air handlers

cross-contamination … employees move

freely b/w the different areas

Attix stance: We have carefully cleaned

everything before use

Regulatory Stance: Cleaning is not a

substitute for segregating products

Cross-contamination with sensitizing agents

can initiate life-threatening allergic

reactions

No safe level of penicillin

contamination has been determined to be

a tolerable risk

Attix Canada April 2015

Philippines-Aug 2014

GMP non-compliance in

ItalyTetrahydrozoli

ne HCl RM

Used in manufacturing of ophthalmic

solution in China

Phillippinesinstructed

discontinuation of

distribution, sale & use

Many lots recalled

Do you calculate a cost of poor quality

at your site?

ISPE/PDA Survey Sep 2011

Have you evaluated the cost of improving quality

vs. the cost of failure (recalls, rejections, low yield, downtime etc)?

ISPE/PDA Survey Sep 2011

Lets make it simple, clear & loud

Me, my kids & parents use same

drug which I manufacture

No batch has ever failed

Drug manufactured in non-cGMPenvironment

It does not mean that there is necessarily something wrong with the drug

But “intention in question”

Please remember

Lack of adverse event reports, or “something is wrong” is NOT the same

as evidence of no harm….

Closing words

Innocence

• Quality mainly outsourced to regulators

Awareness

• Quality unit will identify the issue

Understanding

• Quality system & Metrics reveals reality & drives action

Competence

• Quality mind set in all functions. Design quality in & anticipate issues

Excellence

• Competitive advantage through prevention of quality issues

Journey of uncertainty to certainty matters

Link

age Science &

compliance

Cha

lleng

e Traditional validation & continuous verification Mai

ntai

n Process robustness & drives reliability

Product & Process Criticality

Culture of Quality beyond complianceNew technology

Even a great quality system will fail, if the

Quality Cultureis not equal standard

The question isn’t whether we will have standards …

The question is how useful can we make standards