Tutorial - 1: Creating & Sustaining a Culture of Quality

Creating a Sustainable Culture of Quality
(Tutorial - 1)
Roohi B. Obaid
07 April 2018, Karachi
[155 slides]

Knowledge Sharing Exercise
To Learn through Debate, Discussion &
Experience of others

Introduction
Name
Qualification
Experience
Designation
Any others ….

Lets have a quick exercise
to create opportunity of
discussion and reduce the
barriers in journey of
learning

0418 RO 2017 PHR
April 2018 RO Experience Subject
Total
Searle
Pharmacy - PHR
Business - BLG
Engineering - ENG
Allied Sciences - AHS
Chemistry - CHM
Microbiology - MCB
0418-RO-2017-PHR

This presentation discusses Regulatory Science,
nothing more & nothing less
Reference: US-FDA Documents / Scientific Articles
Personal point of view & nothing to disclose
Disclaimer

1
2
3
6
5
4
7
8
9
12
11
10
13
14
15
18
17
16
Gp-A
Gp-B
Gp-C
Gp-F
Gp-E
Gp-D

What is GMP?
It is a set of
Regulatory
Methodology
to manufacture the
drugs

What GMP Does?
Protects
Integrity &
Quality
of manufactured
product intended
for human use

What GMP Does?
Ensures that products are
consistently produced &
controlled

What is the Intent of GMP?
Consistency
Contamination/cross-
contamination
Mix up

GMP Provides
Documentation
Traceability
Trust
Predictability

GMP Assures
Identity, quality &
strength of drugs
Correct procedures are
followed
Timely documented
Reviewed before release

If a drug qualifies all test, can it be released or
something else will be required?

Quality cannot be observed by every one and/or by naked eye
Quality cannot be tested in a laboratory but has to be built in to
the product

If a drug is manufactured in GMP environment & qualifies all
tests, is it sufficient for quality or something remains?

Surveillance
Complaints
Recalls
Vigilance

Pure
Consistent
Zero Mix
Up
Drug
1 2 3
Batch after Batch
Within Batch
Time after Time

GMP Elements
Premises Equipment Personnel Materials
Documentation
Qualification &
Validation
Etc.

GMP Systems
Quality
System
Production
System
Lab
Control
System
Facilities &
Equipment
System
Materials
System
Packaging
&
Labeling
System

GMP System Indicators & Attributes
Complaints Recall
Investigations
& CAPA
Internal
Audits
Reviews
Change
Management
Supplier
Qualification
Risk
Management
Deviations
Master
Maintenance
Plan
Master
Validation
Plan
Master
Training Plan
Calibration

Quality Safety Efficacy Identity Purity Strength

Background Concerns that
Develop Foundation for Culture of Quality

…. Lets have a deep breath and see ….
Who we are, What we do, What can go wrong &
Where we have to focus
It’s a matter of human life, it’s a matter of your
own progress & progress of company

What will happen if we don’t have Penicillin?
What Penicillin did
Horrible death & Fear across

What will happen if we don’t have cardiovascular drugs?
E.g. What Captopril did
Life Crisis

What will happen if we don’t have drugs for Diabetes?
E.g. What sulfonylureas did?
Death Penalty

What will happen if we don’t have drugs for Psychiatry?
E.g. What haloperidol did?
Social Crisis

What will happen if we don’t have drugs for Asthma?
E.g. What salbutamol did?
Breath Crisis

PIC Tragedy of Pakistan took about 125 lives ………

149
deaths
Test was
passed
Signals not
responded
Finally
contamination
detected
Its not Pakistan & its 21 Century
Can you recall, what was the case & where it happened?

Over sulfated chondroitin sulfate (OSCS)

If it happened in Pakistan, were me & you able
to catch?
What do you think can it be caught in testing?
Do you think we are capable to catch such level
of contaminant or less?
No
Yes
Don’t
know

What happened in 1930? 107 people died

What happened in 1930? 107 people died
Diethylene glycol … repitition of tragedy
… even in 2017 … found lacking in
corporate companies too

What happened in 1941?
About 300
people died

What happened in 1941?
About 300
people died
When sulphatiazole tablets were
tainted with phenobarbital

What happened in 2015? Several deaths

What happened in 2015? Several deaths
When Ciprofloxacin tablets were
tainted with pesticide

Lets come on the same page
to walk & think together

Safety
Will you allow the use of a drug for yourself or your
loved one which is suspicious in terms of safety?

Safety
Can you catch presence of any toxic substance by testing

Efficacy
The drug is overheated in the dryer. What do you think?
Should it go to the market

Cleaning
An equipment is cleaned but not properly cleaned after
manufacturing of a male hormone. Time is not available
and you have to manufacture female hormone in the
same equipment.
What decision you think appropriate?

Consistency
Can you catch the variation in consistency
by product testing?

HVAC
Can you list what is harm, if we do not supply HVAC in
a manufacturing facility?

Documentation
Why do we rely on document only and do not rely on a
trustworthy person?

Validation
Instrument is not a human being. Why do we require
exercise to develop trust on equipment performance?

Process Parameters
…….. Dry at 15 to 20 minutes.
Why do not write dry up to 2% moisture level in batch
instructions?

Quality Attributes
What would be the harm if a tablet is cracked?
Why it is not acceptable?

Typically Consumer Can not
see Quality

Roohi B. Obaid, DDC, DRAP, Jan 2015

Plastic
container
Bulk oral drug
product
Washing in
b/w use
No document
to prove
It is cleaned
Residues
removed
Its re-use
contamination
S, I, S, Q, P
under question
Case study ….

Adequate
assessment ?
Cross-
contamination
risk
Manufacturing of
several
hazardous
compounds
High powder
generation
operation
Documented
justification
lacking
Well designed
contamination
prevention
strategy lacking
Absence of
sound design &
control approach
w/o proper
separation ….
Lacks assurance
That drug does
not contaminate
another drug
Teva Pharmaceutical Industry, Israel

Inadequate
cleaning
procedure
Incomplete
dis-assembly
Preventive maintenance not
robust to detect potential
contamination
Study of placebo
batches instead of
product for
cleaning
Inadequate study
Cleaning procedure should be
robust to ensure that no or
reasonable residue from
previous batch remains
Apotex Incorporation Canada

Beta-lactam &
cephalosporin
Personnel can freely move
for collecting samples and
engaging in other
activities
Failed to monitor
surface sampling for
residual traces
Ranbaxy Laboratories Ltd, India

Tab Tramadol
contaminated with
Metoprolol HCl (19
Feb 2008)
Tablet Metoprolol
contaminated with
Metformin (25 Feb
2008)
The investigation
was limited to
Tramadol tab after 2
months
Investigation was
not extended to
closely related …
confirm incident
Other potential
impact was not given
priority
Source of
contamination was
neither isolated nor
confirmed
Continued releasing
of drug product at
the same time
……..
Story ended up with
regulatory actions
Caraco Pharmaceutical Laboratories, USA

Material contaminated with
tank (a waste tank of API,
Intermediates & Solvents)
Aware in Jan
2012
Complete risk
assessment in
April 2013
In b/w assessment
you distributed
the batches
Some batches
were rejected
Assessment
approaches used
were different
Ended up with
warning
letters
GSK, Cork, Ireland

2001-2005
750m $ Mix up Too much or too
little API
Contamination
A number of products, tablet, cream,
control release etc.

GMP failures,
Establishment of
contamination
A number of products were
questionable
Matter expanded to
criminal investigation
Story ended up in payment
of $750 million for bad
products manufactured in a
plant that was live with
contamination for years
GSK, Peurto Rico

Regulations
EnforcementCompliance
Guarantee
?

Safe, efficacious & have correct
identity
Deliver the same performance as
claimed
Perform consistently over shelf
life
Made in a manner that ensure
quality
Will be available when needed
Patient and
Doctor
assume that
Drugs are

Me, my kids &
parents use same
drug which I
manufacture
No batch has ever
failed

Sky scrapping
challenges ahead
Data Integrity
Integrated
Regulations
Quality
Metrics

Temperature Control lost for sometime
during supply chain?
Situation

Situation
Non-sterile Initially Fail
Pass after 2
weeks
Its not only fail but Quality System is now under
microscopic examination

No
Anti-microbial effectiveness test
Preservative must not be used as a substitute to GMP
Appropriate procedure to prevent objectionable
microorganisms in non-sterile products
Preservative is to reduce the viable microbial
population

No
Preservative may not be used to reduce initial OOS
result
Failure to meet established conditions must be
rejected
Preservative is used to reduce bio-burden of a multi-
dose formulation
Rejection is not an option but obligation

No
… to reduce microorganisms introduced during
manufacturing by addition of preservative
It is an opportunity to see & review manufacturing
process & identify the weakest area
Holding for 2 weeks is a great question that provides
opportunity …
Look back & see desensitization of Quality
Management System

Lets discuss what is culture & how it
influences on quality

Defined as the
shared beliefs, values,
attitudes, and behavior
patterns that characterize
the members of an
organization.
CULTURE

Quality Culture
It starts with leadership that
understands that human behavior and
motivations are critical to meeting
ongoing quality requirements, and
naturally emphasizes continuous
improvement of processes

1
2 3
4
Let’s identify attribute of culture

Let’s identify correct relationship
Girl and Mehndi
Boys and Mehndi
Girl and Tattos

Mehndi &
Bangles
Boys and Bangles
Girl and Bangles

Eid
Exam day
Fun

Quality
Metrics
Indicator of
operational reliability Quality Culture

What is Metrics?
Objective or quantitative
measurement of any parameter
Provides a meaningful
interpretation

Quality Metrics in Pharmaceuticals
Objective measure of state of quality at the
Additional tool in
surveillance tool box
Product Site System

Quality
Metrics
Lot
Acceptanc
e Rate
Product
Quality
Complaint
Rate
Right first
time Rate
Invalidate
d 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

Deviated lots/ total lots
in a year
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=

Expectation of Regulatory Agency from Manufacturer
Extensive
knowledge of
Critical products
Process parameters
Quality attributes

Be clear about ….. Role of Regulatory Agency
Verification & audit to
Keep
manufacturing
supplements /
variations
minimum

Recap: Why Quality Metrics?
Improves process performance
Continuous improvement in PQS
Improves product quality
Increased operational excellence
Important element of oversight

Quality Metrics ultimately leads to
QM
leads to
Patient access to
reliable therapies
Fewer drug shortageFewer recalls

Key Focus of Regulatory Agency
Robustness of
Manufacturing
process
Lot
Acceptance
Rate Robustness of
Lab
Operations
Invalidated
OOS Rate
Voice of
customer/
patient
Product
Quality
Complaint
Rate

Further Emphasis of Regulatory Agency
Process capability
& performance
Quality culture
CAPA
effectiveness
Meeting PQS
timeframes
Senior
management
commitment to
quality

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

Stronger culture scores are associated
with higher lot acceptance
2/4 ISPE

Sites with higher quality culture scores
have lower deviations recurrence
3/4 ISPE

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

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 do
As 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

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

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.

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 but within frame of approved
procedure & authority. Providing the right level of
guidance & training is crucial to this effort
Remember, 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

1 2 3 4
Level
Nearly always reactive, but there is willingness to change.
Patchwork corrections are the norm

1 2 3 4
Level
More proactive. Increasingly detects emerging adverse trends,
surfaces major issues, and makes lasting manufacturing and
system improvements

1 2 3 4
Level
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

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

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

Drug manufactured in non-cGMP
environment
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….

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

Linkage
Science &
compliance
Challenge
Traditional
validation &
continuous
verification
Maintain
Process
robustness &
drives
reliability
Product & Process
Criticality
Culture of Quality
beyond complianceNew technology

Even a great quality system will fail, if the
Quality Culture
is not equal standard

The question isn’t whether we are honest or not…
The question is how strong your culture of quality is…

Lets see our Culture
Capabilities Governance Leadership
Mindset Integrity

Give your Opinion
1
Strongly
agree
2
Agree
3
Disagree
4
Strongly
disagree

C
A
P
A
B
I
L
I
T
I
E
S
Patient
Focus
I know which parameters of our products are
particularly important for patients
The training I have received clearly helps me to
ensure quality in the end product
Training
Problem
solving
All line workers are regularly involved in problem
solving, trouble shooting & investigations

G
O
V
E
R
N
A
N
C
E
Recognition
We recognize and celebrate both individual &
group achievements in quality
Up-to-date quality metrics (defects, rejects,
complaints) are posted & easily visible in line
We are regularly tracking variations in process
parameters & using them to improve the processes
Metrics
Knowledge
Continuous
Improvement
Each worker can explain what line quality
information is tracked & why

L
E
A
D
E
R
S
H
I
P
Coaching
Supervisors provide regular & sufficient support &
coaching to line workers to help them improve quality
We have daily quality metrics reviews & quality
issues discussions on the shop floor
Dialogue
Gemba
Management is on the floor several times a day both
for planned meetings & also to observe & contribute
to the daily activities

M
I
N
D
S
E
T
Awareness
Every line worker is aware of the biggest quality
issue on their line & what is being done about
them
All employees see quality & compliance as
their personal responsibility
Responsibility

I
N
T
E
G
R
I
T
Y
Openness
I am not afraid to bring quality issues to the
management’s attention
People I work with do not exploit to their advantage
inconsistencies or “grey areas” in procedures
Ethics
Motivation
All employees care about doing good job & go the
extra mile to ensure quality

Tutorial - 1: Creating & Sustaining a Culture of Quality

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