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Discussion Forum
On
Assess, Challenge & Demonstrate Quality System
in your Manufacturing Facility
Obaid AliCivil Service Officer, Government of Pakistan
11 Feb 2017, Hotel PC, Karachi
Thanks for invitation
&
Opportunity to participate in discussion
Wish to have a Good Day of Knowledge Sharing
DISCLAIMER
Not the view of DRAP
Current judgment
No obligation on DRAP
Regulatory experience
Warm up exercise
Fundamental Scenarios of Manufacturing of
Healthcare Products
1
Thalidomide Tragedy
DiethyleneGlycol
Contamination
Heparin Catastrophe
Pyrimetamine MixupMedication
ErrorsCutter Incidence
Kellse
Quality Safety Efficacy Identity Purity Strength
0 50 100
Agree
Agree
0 50 100
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?
Case Studies
Direct Questions & Discussion
2
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
Typically Consumer Can not
see Quality
Out of sight
Out of reach
May often look
like
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 Tramadolcontaminated with
Metoprolol HCl (19 Feb 2008)
Tablet Metoprololcontaminated 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
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 rife with contamination for years
GSK, Peurto Rico
Good Manufacturing Practices
Elements and their Role in Quality
3
Because
Drugs are public good and not simply just another commodity:
first for their high social value, and then because consumers and
prescribers are unable to assess their quality, safety and efficacy.
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
Trust on Safety, Efficacy & Quality
is not simple but so complex
What is cGMP & What it does?
Defined
Regulatory
Methodology to manufacture the
drugs
Protects
Integrity &
Quality of manufactured
product intended
for human use
Intent of GMP
• Identity, quality, and strength of pharmaceuticals.Provide assurance of
• Correct procedures are followed.Assure that
• Documentation, traceability.Provide
• Quality is “built in” to the approach.Overall Intent:
To assure
Pure
Consistent
Zero Mix Up
Drug Batches
1 2 3
Batch after Batch
Within Batch
Time after Time
GMP Elements
Premises Equipment Personnel Materials
DocumentationQualification &
ValidationEtc.
GMP Systems
Quality System
Production System
Lab Control System
Facilities & Equipment
System
Materials System
Packaging &
Labeling System
GMP System Indicators & Attributes
Complaints RecallInvestigations
& CAPAInternal Audits
Reviews
Change Management
Supplier Qualification
Risk Management
DeviationsMaster
Maintenance Plan
Master Validation
Plan
Master Training Plan
Calibration
Facility
Ventilation, Segregation of areas, Cleaning
Documents
COA & batch records, deviations
Equipment
Qualification
Product testing
Lack in finished product testing, Shelf-life data unavailable
Personnel
QC/production manager qualification independence of QC
Identify any
pattern of failure to
Control batches before release
Conduct investigation to resolve ….
Discrepancies, failure,
deviation, complaint
Aging Manufacturing Facilities & with Old Approaches
Lets unfold to understand
Uncertainty
Aging (Facility, Process, Analytics) and its Drivers
Due to lack of proactive Improvement Programs
Investment into appropriate Maintenance Plan
Area/
FlowEquipment AnalyticsProcess
Specific Risks of Older Factories
Inefficient Processes
Inappropriate material & personnel flows
Antiquated or obsolete ventilation system
Old equipment no longer meeting current requirements
Major change in facility! Does it worth?
Utilities HVAC (air changes etc), Water, Piping etc.
Systems Quality Policies & Compatibility
Premises Design, construction & maintainability
Flow Material, personnel, trafficking
Ways to keep align with modernization
Time wastage in quality documentation & administrative procedures?
Do you have adequate trained personnel in the maintenance unit?
Are adequate SOPs and maintenance protocols in place?
Analyze your number of defect rates, deviations?
Enhancing robustness
Improving production reliability
Adoption of new technologies leads to
Managing Values
Take Home Message
Keep an eye on ways
of Improvement
Always stay on the ball
regarding technology
Continuously adapt to
the changes
Implement improvement procedures,
perform risk assessment, analysis, set up
actions & document efforts
Keep abreast of new technologies &
processes. Work with your supplier to try to
improve your machinery on the shop floor
Try to implement a culture of quality and
improvement. The only constant thing is
change
Assessment of Manufacturing Facility
Maintain System & Making Change
Product & process
design with scientific
understanding is
critical
Knowledge Management
Product Development
Technology Transfer
Process Validation
Commercial Manufacturing
Basic Process Design (Process Validation)
CQA
Identification
Appropriate
Manufacturing Process
Suitable Control
Strategy
Impurity levels
Content Uniformity
Dissolution
Reactions
Equipment
Environmental
assessment
In process &
release testing
Proven Acceptable
Range/Normal
Operating Range
Process Qualification (Process Validation)
Building Design & Facilities
Understand &
incorporate
Material
Invariability
Process Performance
Qualification
Appropriateness &
Capability of Equipment
Fully evolved control
strategy for
commercialization
Protocol design, execution
& interpretation
Pre-Approval Inspection
ReadinessConformance to
ApplicationData Integrity
Equipment
Procedures
Quality
Management
Processes
Equipment scale
Process as
proposed
Submitted
information, raw
data & accuracy
Justification for commercial scale & process design not adequate
Commercial scale equipment not qualified, method not validated
Common Observations on Readiness (PAI)
Serious GMP deficiencies
Commercial scale equipment listed not available on-site
Implemented process does not match with the reported one
Common Observations on Conformance to Application (PAI)
Manufacturing process changes not reported
Averaging to hide fail results in data
Common Observations on Data Integrity (PAI)
Unknown
impurities
Retesting till
desired results
Not representative holding
studies
Use of trial
injectionsLack of audit trails
Failing results attributed to
analyst error
Continued Process Verification
Active proof that state of control is
maintained throughout the
process
Understanding of process & risk to develop a strategy
for monitoring
Variability potential in manufacturing & incoming material
properties assessment
Process Performance Qualification batches & reports
Stability & Shelf Life
Component Supplier Qualification
Post-Approval Inspection
Determination of cGMP Compliance & Quality Culture
Investigations to determine root causes & strengthen the quality
Deficiencies, Non-compliance & Violations
Surveillance Inspection
Discussion
on Events & Phenomena
4
Case Studies
1- Facilities & Equipment System
Repackaging of beta-lactams in a multiple packaging facility
Personnel move freely in common place from both ends
Story ended up with recall of the product
Manufacturing facility is ceased
Decontamination and renovation of facility
Publication of
warning letter
on public
domain
Safe level of penicillin ?
Can cleaning substitute?
Analytical method limitation?
Segregation alternatives?
Dedication waiver?
L
E
A
R
N
Case Studies
2- Packaging & Labeling System
Re-packaging of different drugs
Operator changes master labels
Change of master label without SOP
Complaints of low fill volumes
Recalled
Publication of
warning letter on
public domain on
inadequate
manufacturing
control
Repack may change characteristics
Change may impact safety & efficacy
Improper packaging, repackaging can cause ADR
Poor control may end up with disaster
Non-compliance with regulations
L
E
A
R
N
Case Studies
3- Production System
Pre-compressed blend samples … to determine operation parameters for tablet press
Use of different blends without any knowledge
Pre-compression practice observed during inspection
Inadequate release testing
Aware with the process problem
Publication of
warning letter on
public domain on
account of lack of
process validation
Operational parameters should be selected
using risk & science based approach
Process design must be completed and
adequate
Knowledge gained during scale up should be
incorporated in process design
Knowledge gained during scale up should
be incorporated in control strategy
Sampling plan for batch release should be
scientifically sound
L
E
A
R
N
Case Studies
4- Laboratory System
Multiple tarns dermal patches manufacturing for many years
Developed new drugs, utilized same adhesion matrix
5000 complaints received in 1st
year for efficacy and using difficulty
Up to 25% of drug was sticking to the liner
Drug adhesive interaction problem found
Caution
Firm argued, no specification for peel force
Did not recall and continued distribution
Ended up with recall
Peel force adhesion has to be established
Publication of
warning letter on
public domain on
account of lack of
specifications and
failure to assure
proper strength
L
E
A
R
N
Do not assume what worked before, will work
under different conditions
Don’t think, if it not happened, it will not
happen in future
Don’t think if inspection has been done, everything
will be good
Evaluate data to determine need for change
in specifications
Keep eyes open always
Case Studies
5- Materials System
Multiple adverse events and complaints that indicated presence of endotoxins in injectable drugs
Firm did not took serious and not identified a root cause
Regulatory inspection
Firm found in testing of endotoxinprior to terminal sterilization
Some tests were OOS but released on the basis of compliance of finished product
Keep thinking
Reason of high level of endotoxin in in-process testing?
Ceased materials and in-process testing
Recall
Thorough investigation
Eventually confirmed it came from raw material
Publication of
warning letter on
public domain
L
E
A
R
N
Testing is not the answer
Quality should be built in by design
Quality should be monitored
Quality should be controlled
Be vigilant, do needful, don’t assume and
leave unattended
Case Studies
6- Quality System
Contract giving to multiple sites
Contract services had several GMP problems
COA was the tool to review the materials
Found not reviewed versus specifications
Stability failures and complaints inadequately investigated
Publication of
warning letter on
public domain on
account of lack of
oversight by the
Quality Unit
L
E
A
R
N
Marketer (contract giver) is responsible
No matter who manufactured them
No matter who tested them
Don’t lose your reliability
Don’t put your name on thin ice
Lets demonstrate
Quality Management System
5
If something has not happened yet, it will likely not happen
Design may be flawed, but there is no evidence that there is a problem
If something has not been identified by inspector, it is ok
Passing the media fill assures process control
Lets correct, it is misconception
Sterility test has not yet failed but reason of pass is not defendable
We are complying and it is enough, no matter what you are referring
Traditional approach is a good approach
Insulin was filled in an area under exhaust fans in history
Lets correct, it is misconception
When calculated risk is the only option
Each and every caution is indispensible
GMP Elements
Premises Equipment Personnel Materials
DocumentationQualification &
ValidationEtc.
GMP Systems
Quality System
Production System
Lab Control System
Facilities & Equipment
System
Materials System
Packaging &
Labeling System
GMP System Indicators & Attributes
Complaints RecallInvestigations
& CAPAInternal Audits
Reviews
Change Management
Supplier Qualification
Risk Management
DeviationsMaster
Maintenance Plan
Master Validation
Plan
Master Training Plan
Calibration
Identify and Understand factors that impact product quality
Information is not knowledge
Let us not confuse the two
W. Edwards Deming
We are drowning in information
but starved for knowledge
John Naisbitt
Variations
Batch SizeMaster
FormulationManufacturing
SiteManufacturing
ProcessEtc.
Types of Contamination
Particulates
Micro-organisms
Cross-contamination
PA
RT
ICU
LA
TE
S
Dust
Dirt
Paper
Metal
Fiber
Etc.
MIC
RO
OR
GA
NIS
MS
Bacteria
Yeast
Moulds
CR
OS
S-
CO
NT
AM
INA
TIO
N Drug
Materials
Types of Cross-contamination
Source of contamination
Air
Water
Surface People
Pest
Weighing room…….
• Entry point …….to manufacturing
• Transit point …. For materials coming from warehouse and entering into the process area
Careful attention is indispensible
• Design…
• Layout….
• Operation
Principle derives the design of weighing room
(raw material staging, dispensing weighing, working process staging)
Unidirectional flow of
Materials
Personnel
Segregation between
Hazardous
Non-hazardous
Separation of
Storage … processed/intermediate
materials
Manufacturing items
Designated space
Remember Please …. To comply with GMP…establishment has to provide for every operation
Sufficient spacePhysical
separation
Adequate
• lighting
• Ventilation
• Utensils
• Equipment
• Facilities
Types of Human Error
Organizational/
systemic
Procedural (SOPs)
Careless work
Voluntary/
intentional
Involuntary
Material transfer
between unit process
with inadequate
assurance of integrity
and contamination risk
Dust extraction and
containment
Holding of process materials without study
Most common observations of US-FDA
No or inadequate procedures or not followed (production, cleaning, QC)
No management review of procedures
No Management oversight / QA oversight
No internal audits performed
Inadequate employee training
Inadequate validation (process mainly)
Inadequate laboratory controls
Incomplete laboratory notebooks
Lack of scientifically established specifications, sampling plans
Raw data not reviewed / maintained
Inappropriate investigation:
OOS, Recurring Deviations
Microbial contamination, Environmental monitoring excursions
Complaints, Temperature excursions during shipping
No procedures for corrective and preventive actions (CAPA)
Batch review inappropriate
Validation records
Second check not done for raw material additions & critical steps
Reprocessing not validated
Most common observations of US-FDA
10
Equipment Cleaning and Maintenance
7.1 %
7
Testing and Release
8.6.9 %
8
Personnel Qualifications/
Training
8.2 %
9
Batch Record Preparation/
Review
8.1 %
4
Laboratory Controls
9.9 %
5
Written Procedures
for Production
9.3 %
6
Investigations
9.1 %
Top 3
Most Common Observations
6
1
QCU Responsabilités
15.9 %
2
Adherence to Production Procedures
12.7 %
3
Production Procedures(Validation)
11.1 %
Regulatory world is
touching sky and getting so
complex
Requires interpretation and
somehow leniency to
promote evolution of science
such as off-label use by
physicians
Learn
De-learn
Re-learn
New
Tools
Approaches
Sta
nd
ards
E
Q
P
S
R
E
G
U
L
A
T
O
R
Y
S
C
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N
C
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