QUALITY AND RISK MANAGEMENT IN HOSPITAL PHARMACIES FOR THE PREPARATION OF INJECTABLE ANTICANCER DRUGS EUROPAEISCHE KONFERENZ FUER KRANKENHAUSTECHNIK BERN APRIL 11/13 , 2013 DAVID BARBAULT & DIDIER MEYER April 1, 2013 1 CONFIDENTIAL| IHS Berne 2013
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QUALITY AND RISK MANAGEMENT IN HOSPITAL PHARMACIES FOR THE PREPARATION OF INJECTABLE ANTICANCER DRUGS EUROPAEISCHE KONFERENZ FUER KRANKENHAUSTECHNIK BERN APRIL 11/13 , 2013 DAVID BARBAULT & DIDIER MEYER
April 1, 2013
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CONFIDENTIAL| IHS Berne 2013
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AGENDA
April 1, 2013
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CONFIDENTIAL| IHS Berne 2013
•The problem
•Regulatory guidelines
•Technical solutions / features / monitoring
•Conclusion
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THE PROBLEM
April 1, 2013
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CONFIDENTIAL| IHS Berne 2013
THE PROBLEM (1/3)
• Preparation of injectable anticancer drugs is a
compounding including 3 sterile components:
The drug itself (liquid or powder, freeze dried
drug in vial)
The solvent (mainly bag of LVP’s)
The administrative set (eg. syringe, pump cassette….)
• Evidence for worker exposure and health effects: Health care workers who work with
or near hazardous drugs may suffer from:
Skin rashes
Infertility
Miscarriage
Birth defects
Leukemia or other cancers
CONFIDENTIAL| IHS Berne 2013 April 1, 2013
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THE PROBLEM (2/3)
TO AVOID THIS RISK, THESE PREPARATIONS ARE CENTRALIZED AND
PERFORMED IN HOSPITAL PHARMACIES AND DISTRIBUTED READY TO
ADMINISTRATE, THUS BECOMING A CONTINUITY OF THE PHARMACEUTICAL
PRODUCTION WITH :
Protection of the personnel versus the drug with an appropriate barrier
Working in controlled area for keeping the original Sterility Assurance Level (SAL)
of the 3 components (10-3 to 10-6)
CONFIDENTIAL| IHS Berne 2013 April 1, 2013
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THE PROBLEM (3/3)
• Average delivery time from prescription to administration to the patient must not
exceed 90 minutes
• No Pharmacopea sterility testing possible (14 days of incubation)
HOW TO KEEP THE STERILE QUALITY IN PROCESS
WITH NO RISK
HOW TO COMBINE A REAL TIME RELEASE AND A FULL PROTECTION OF
THE OPERATOR
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THE TOOLS
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CONFIDENTIAL| IHS Berne 2013
FDA Regulatory Drivers
• Pharmaceutical cGMPs for the 21st
Century – A Risk Based Approach
• Guidance for Industry, Process
Analytical Technology -
Framework for Innovative
Pharmaceutical Development,
Manufacturing and Quality
Assurance
Source: Pfizer
PROCESS ANALYTICAL TECHNOLOGY
(PAT)
“a system for designing, analyzing, and controlling manufacturing
through timely measurements (i.e. during processing) of critical
quality and performance attributes of raw and in-process materials
and processes with the goal of ensuring final product quality”
• ‘analytical’ not restricted to measurement but includes chemical,
physical, microbiological, mathematical, and risk analysis conducted in
an integrated approach
Source: Pfizer
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QUALITY RISK MANAGEMENT: ICH Q9
10
April 1, 2013
“…protection of the patient by managing the risk to quality should be considered of prime importance”
CONFIDENTIAL| IHS Berne 2013
CLOSED BSC BSC & CLEANROOM
ROBOT
ISOLATOR
BED-SIDE RECONSTITUTION
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RISK FROM ICH Q9
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April 1, 2013
• Risk: Combination of the probability of occurrence of harm and the severity of that
harm
• Quality Risk Management: A systematic process for the assessment, control,
communication and review of risks to the quality of the drug (medicinal) product
across the product lifecycle
• Risk Assessment: A systematic process of organizing information to support a risk
decision to be made within a risk management process. It consists of the
identification of hazards and the analysis and evaluation of risks associated with
exposure to those hazards
• Risk Analysis: The estimation of the risk associated with the identified hazards
• Tools for Risk Analysis: FMEA (Failure Mode and Effects Analysis), HACCP (Hazard
Analysis and Critical Control Points), FTA (Fault Tree Analysis), HAZOP, (HAZard
and OPerability study), PHA (Preliminary Hazard Analysis)
CONFIDENTIAL| IHS Berne 2013
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Real Time Release
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April 1, 2013
• Real Time Release (former Parametric Release) is the ability to evaluate and
ensure acceptable quality of in-process and/or final product based on process
analytical data.
• The combined process analytical measurements and other test data gathered
during the manufacturing process can serve the basis for Real Time Release of the
final product and would demonstrate that each individual batch conforms to
established regulatory quality attributes.
CONFIDENTIAL| IHS Berne 2013
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Continuous Quality Assurance AFTER the Initial Validation
(IQ, OQ & PQ)
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April 1, 2013
By Process Understanding & Real-Time Control:
• The desired QUALITY ATTRIBUTES are ensured through continuous assessment
& control during manufacture
• DATA from production validates the process
• Reflecting the total system DESIGN CONCEPT (Quality by Design QbD)
• Supports validation with EACH manufacturing batch
• Periodical media fill test for each operator
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THE SOLUTION
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OPTIONS FOR A SEGREGATIVE ATMOSPHERE
ISO 14644-7 & PDA TR 34
Aseptic
Isolators
Ase
ptic C
yto
toxic
Clo
se
d
Ase
ptic O
pe
n
Cyto
toxic
Clo
sed
Bio
sa
fety
Ca
bin
et
La
min
ar
Flo
w H
oo
d
Cla
ssifie
d R
oo
m
Cla
ssifie
d R
oo
m
- U
n-c
lassifie
d R
oo
m
Un-c
lassifie
d R
oo
m
Incre
asin
g R
elia
bili
ty o
f O
pe
ratio
n
Positive Pressure Negative Pressure
Increased sterility assurance Increased worker protection
Ase
ptic C
lose
d
Containment
Barr
ier
Syste
m (
RA
BS
)
April 1, 2013
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COMPOUNDING ASEPTIC CONTAINMENT ISOLATOR (CACI)
(USP<797>)
MANIPULATION
TRANSFER
VENTILATION & FILTRATION
Half-suit Glove / sleeve DPTE® suit
• Positive pressure
• Negative pressure
• Turbulent flow (ETF)
• Unidirectional flow (UDF)
Batch
CONTAINMENT (isolator)
Continous
• Flexible wall
• Rigid wall
Dynamic output Sterilization
tunnel DPTE® transfer
Chemical airlock Oven - Autoclave
BIO DECONTAMINATION
April 1, 2013
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CACI EXAMPLE: ISOCYT FREJA
5. Transfer system
6. Bio-decontamination airlock
7. Dynamic Output Port
8. Steritrace II - Integrated H2O2 sterilizer
1. Containment enclosure
2. Ventilation / filtration
3. Control system
4. Manipulation system
April 1, 2013
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CONFIDENTIAL| IHS Berne 2013
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THE PARAMETERS: AIRTIGHTNESS
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ISO 10648-2
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April 1, 2013
• Classification of enclosures according to their leaktightness
• Intended for « sensitive products requiring a special atmosphere and/or a sterile
medium » i.e. applicable for the isolators (0,1 to 0,5% of the volume/h of leak -Class 2
& 3-)
• When to perform (automatic) leaktest:
• Factory Acceptance Test
• Site Acceptance Test
• Operational Qualification Test
• Before and after the production
CONFIDENTIAL| IHS Berne 2013
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COMPARISON OF LEAKRATES BETWEEN ISOLATOR,
GLOVE AND DPTE®
Test pressure (Pa)
Specifications Equivalent leak rate
(Std cm3/sec) Flow rate at pressure use -50 Pa
(cm3/sec)
Isol.
150 0,5% vol/h 1,38 0,8
100 0,1% vol/h 2,7 10-1 0,2
100 0,1% vol/h 2,7 10-1 0,09
Glove -3000 500 PPM 5,8 10-2 7,75 10-3
DPTE® -4000 10-4 to 5 10-4 Pa.m3/sec
4,9 10-3 to 9,8 10-4 1,58 10-3 to 3,2 10-3
Leak rate given for a 1 m3 volume isolator
Leak rate given for the DPTE® transfer system 105 & 350
1 cm3/sec = 2,12 10-3 Ft3/min
1 Pa.m3/sec = 9,87 Std cm3/sec
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
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THE PARAMETERS: BIODECONTAMINATION
April 1, 2013
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STERILIZATION TECHNIQUES
Overview
23
CORE STERILIZATION CONTACT STERILIZATION
Autoclave Oven Steam
Vaccuum
Dry heat
Sterilant
Isolator
RESULTS :
S.L.R. 106 spores
S.L.R. = Spore Log Reduction
April 1, 2013 CONFIDENTIAL| IHS Berne 2013
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THE BIODECONTAMINATION PROCESS
4 main phases
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CONFIDENTIAL| IHS Berne 2013
1. Condition (dehumidification using compressed air)
2. Injection (high rate of injection)
3. Stabilization (low rate of injection)
4. Aeration (room air + compressed air)
700 ppm
H2O2 concentration
100%
Relative Humidity
0%
Time
1
2
3
4
April 1, 2013
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CONFIDENTIAL| IHS Berne 2013
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April 1, 2013
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THE PARAMETERS: MANIPULATION
April 1, 2013
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GOWNING ACCORDING ISO 14 644-5
AND cGMP
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April 1, 2013
• Class D (ISO 8) : 3 minutes (CACI)
Hat
Gown
Shoes or Overshoes
Class C (ISO 6) : 10 minutes
« bunny suit »
Hat or overhead
Shoes or Overshoes
Class B or A (ISO 5) : 15/20 minutes
« bunny suit »
Overhead
Mask
Gloves
Shoes or Overshoes
Dedicated factory underwear
CONFIDENTIAL| IHS Berne 2013
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USE AND CHOICE OF GLOVE
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
AUTOMATIC LEAKTEST OF GLOVE
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
EXAMPLE OF IN-SITU TEST
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THE PARAMETERS: DPTE® TRANSFER
April 1, 2013
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DPTE® ALPHA AND BETA
PRINCIPLE
1. Container
approach
2. Rotation (60º)
3. Double door
opening
Alpha part Beta part
2 assemblies
Alpha
Bêta
2 lip seals
Meeting at a point
4 elements
mutually shielding each other’s
faces, locked together by rotation
of the Beta part
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
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CONTROL OF LEAKTIGHTNESS OF DPTE® : TLT
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
100% LEAKTEST OF DPTE® DISPOSABLE WASTE BAG
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
THE STERILE MANAGEMENT USING DPTE®
Waste using
DPTE-BetaBag®
Heat and light
sensitive residual
using DPTE®
container
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THE PARAMETERS:
DYNAMIC OUTPUT PORT
April 1, 2013
37 CONFIDENTIAL| IHS Berne 2013
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DYNAMIC OUTPUT PORT
© G
etinge-L
a C
alh
ène •
2008
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April 1, 2013 CONFIDENTIAL| IHS Berne 2013
• Dual flow protection system
• Protection of both the operator and the
product
HEPA filter
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Dynamic Output Port : Example with positive
pressure regulation
Exhaust blower
Zone
barrier
Opening of the door: the dual airflow generates
a local overpressure so assumes a barrier
function
P++
P+
P+++
Pressure
Inlet blower
39
April 1, 2013 CONFIDENTIAL| IHS Berne 2013
P+++
P++
P+
40
April 1, 2013 CONFIDENTIAL/Name of presentation
LOCAL OVERPRESSURE MONITORING (ALARM
SET @+10Pa)
CONFIDENTIAL| IHS Berne 2013
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CONCLUSION
April 1, 2013
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CONFIDENTIAL| IHS Berne 2013
CONCLUSION
• Such a CACI can only be successfully operated for injectable anticancer drugs with
Real Time Release following these features:
Trained operators (media fill test)
Validated equipment
Defined protocol
Key parameters monitoring
• Some new technology development
could reduce the remaining human
risk factor and increase traceability
(such as new Drugcam video /
software solution for operator
assistance, real-time control and
record)
CONFIDENTIAL| IHS Berne 2013 April 1, 2013
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ANY QUESTIONS?
April 1, 2013
43 CONFIDENTIAL| IHS Berne 2013