Manufacturing of Sterile Products
Session 3
Risk based Progressive Model to Assess
Facility & Operation
Presentation Focus
1. What is Risk
2. Risk Calculator
3. Risk Model for Aseptic Sterile Operations
4. Risk Model for Terminally sterilized Products
Closing Message
Right Tool for Right Work
Guenther Gapp & Peter Holzknecht
Risk Analysis of Sterile Production Plants: A New & Simple Workable Approach
PDA J Pharm Sci and Tech 2011
Process Understanding
Control what is critical
Process understanding as input to Risk Management
Identify Critical to Quality parameters
Improved Process Knowledge to Identify and Remove Sources of Variability
Detectable and controlled lionLess detectable & free small
snack
Which is Dangerous
ICH Q9, Quality Risk Management
ICH Q9, Quality Risk Management
Fall less frequently (1 time in a month)
Fall more frequently (10 times in a month)
Which is Dangerous
ICH Q9, Quality Risk Management
Combination of the probability of occurrence of
harm and the severity of that harm
Managing Risk is a Behavior
The
investigation of
risks
is at once a
scientific activity
and an
expression of
culture
Parameters for “calculating” Risk
• Past Probability
• Today Detectability
• FutureSeverity
T
I
M
E
Risk Priority Number
Risk Assessment Matrix
Severity
Probability
Frequent Likely Occasional Not often Unlikely
Catastrophic E E H H M
Critical E H H M L
Marginal H M M L L
Negligible M L L L L
Raw Materials
Raw
Materials/
Component
Received Contaminated
Contaminated during sampling
Contaminated during storage
Personnel
Personnel
Inadequate hand sanitization
Poor personnel hygiene
Inadequate face, hair, cloth etc.
Personnel-Training
Training
Operators
ineffectively
trained
Evidence of training
Review of training proficiency
Proficiency not demonstrated
Training program not in place
Facilities
Facilities
Appropriateness of
constructions
materials
Difficult to sanitize
Particulate generation
Air Quality
compromised
Lack of Air Quality Control
HVAC-HEPA compromised
Facilities
Fa
cili
ties
Water quality
compromised
Generation sys compromised
Delivery hoses compromised
Source compromised
Dead Legs
Reverse inclines
Cleaning/ Sanitization
Cle
an
ing
/ S
an
itiz
ati
on
Inadequate pest control
Ineffective sanitization agents Compatibility of agents
Lot to lot cleaning effectiveness
Carry over
Residual
Bio-burden
Contamination of cleaning implements
Resistant pattern against cleaning
Inadequate removal of visible debris
Process
Pro
cess
Transfer/
sampling issue
Sample hold compromised
Sampling error
Transportation compromised
Inadequate
separation betweenClean and dirty operations
Process
Pro
cess
Hold time is not
validated
Process hold time
Clean hold time
Dirty hold time
Inadequate protection uncontrolled environment
Raw Materials (Non-Sterile)
Supplier audited by
others
Supplier approved
through your own audit
Batch wise incoming microbial count and endotoxin testing
• Appropriate frequency
• Lower frequency
• No testing
History and trends of incoming material
compiled and reviewed
Raw Materials (Non-Sterile)
Preparation of antibiotic/ micro-static material in Class D or lower room classification
Preparation of growth promoting material in Class C or lower room classification
Nature of material
Antibiotic Micro static Growth promoting
Filling/Sterilization Operations
Product undergoes a microbial filtration before filling
Clean room design and zoning concept
Filling in Class A or Class B or Class C
Unidirectional air flow above and/ or at critical locations (e.g. turntables, interventions..) or not
(turbulences or shadowing)
Optical impression of house keeping
Filling/Sterilization Operations
Clean room
parameters appropriate
Non-viable particulate
count
Pressure
Air exchange rate
Humidity
Temperature
Filling/Sterilization Operations
Alarm response for clean room parameters in place
Good alarm system for clean room parameters in place
Visual signal system in place
Filling/Sterilization Operations
Smoke study video during
filling operations
demonstrate
Uniform air flow
Non-adequate air flow
No studies
Filling/Sterilization Operations
Closed transport under controlled conditions through surrounding area
All interventions are documented
Transfer of material from surrounding area into filling area controlled
All heat stable equipment and material heat sterilized
Filling/Sterilization Operations
Appropriate gowning concept
Personal airlock: the final stage should be the same as the surrounding filling area
Defined sanitization step while approaching of material to Class C and D from lower area
Filling/Sterilization Operations
Validation of disinfection
Via carrier testSuspension
testingNone
Documentation of cleaning and disinfection procedures
Good Not good None
Filling/Sterilization Operations
Non-viable particulate (NVP)measurements
according to respective clean room requirements
Periodical use of sporocidal disinfectants
for clean room and filling cabinet
Micro EM trends
Well-designed rationale micro environmental monitoring (EM)
system based on risk analysis
Trend of NVP
Filling/Sterilization Operations
Placement of investigation procedure in case of EM failure
Verification of EM results of production or engineering by
Quality Department
Oversight of QA and QC on EM performed by production or
engineering
Characterization of isolates
Placement of corrective action procedure in case
of EM failure
Filling/Sterilization Operations
Verification of EM results of production or
engineering by Quality Department
Oversight of QA and QC on EM performed by
production or engineering
Characterization of isolates
Placement of corrective action procedure in case of
EM failure
Placement of investigation procedure in case of EM
failure
Filling/Sterilization Operations
Qualification or disqualification criteria for
personnel defined
Qualification of maintenance personnel and others
Rationale of the location of sampling point for NVP
monitoring
Continuous training program for operators
involved in sterile filling
Monitoring program of qualified operators by
QA during filling
Filling/Sterilization Operations
Looping temperature in water for injection (WFI) system
Endotoxin level of primary packaging material
Assessment of the impact on sterility in case of change in
change control procedure
Filling
Validation of WFI testing methods
Point of sampling of WFI
Filling/Sterilization Operations
Endotoxin level of primary packaging
material
Assessment of the impact on sterility in
case of change in change control procedure
Validation of WFI testing methods
Point of sampling of WFI
Looping temperature in water for injection (WFI) system
Filling/Sterilization Operations
Investigation ability for excursions in water
system
Qualification of water system (12 month study)
On-line monitoring of WFI
Monitoring of Bio-burden prior to
sterilization process
Qualification of autoclave
Filling/Sterilization Operations
Use of Biological Indicator and Temperature Mapping in
Requalification of Autoclave
Annual requalification of Steam Sterilization process for
specific product
Bio-burden testing of Micro Lab
Product Specific D Value determination for
qualification process
Qualification and Requalification of
Loading plan
Filling/Sterilization Operations
Periodical Audit of Service Provider of Autoclave
Control of Cool Down Phase by WFI
Steam Sterilization effect study and Over Kill approach
Container Closure Integrity performance at
different air pressure
Validation of Sterility Test
Filling/Sterilization Operations
Holding, line Clearance and possibility of mixing
Visual Inspection programme of Sterilized Product