quality and risk management in hospital pharmacies for the ...uuid... · the problem (2/3) to avoid...

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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

1

CONFIDENTIAL| IHS Berne 2013

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AGENDA

April 1, 2013

2


•The problem

•Regulatory guidelines

•Technical solutions / features / monitoring

•Conclusion

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THE PROBLEM

April 1, 2013

3


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

4

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)


5

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


6

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THE TOOLS

April 1, 2013

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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”


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)


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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.


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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

April 1, 2013

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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

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Incre

asin

g R

elia

bili

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f O

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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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THE PARAMETERS: AIRTIGHTNESS

April 1, 2013

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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


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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

20

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


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THE BIODECONTAMINATION PROCESS

4 main phases

24


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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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


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USE AND CHOICE OF GLOVE

28


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AUTOMATIC LEAKTEST OF GLOVE

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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

33


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CONTROL OF LEAKTIGHTNESS OF DPTE® : TLT

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100% LEAKTEST OF DPTE® DISPOSABLE WASTE BAG

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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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• 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


P+++

P++

P+

40

April 1, 2013 CONFIDENTIAL/Name of presentation

LOCAL OVERPRESSURE MONITORING (ALARM

SET @+10Pa)


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CONCLUSION

April 1, 2013

41


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)


42

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April 1, 2013

43 CONFIDENTIAL| IHS Berne 2013

quality and risk management in hospital pharmacies for the ...uuid... · the problem (2/3) to avoid...

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