Patient Centricity: New Paradigm in Quality Management
Contamination Control – Product and
Facility Point of View
HAZARD
QUALITY
CONTROL RISK
Rajendra Kumar Das
AVP-Engineering & Projects
Sun Pharmaceuticals
(25th Feb 2021) 1
Content
Contamination
Consequences of Contamination
Regulatory perspective
Overview- Possible ways of contamination and its preventions
Contamination through Airborne with examples
Contamination through Mechanical transfer with examples
Contamination through retention with examples
Contamination through Mix up with examples
2
Contamination & Cross-contamination
Contamination Cross-contamination
Undesired Introduction of any
Contamination of a material or product with
Unwanted/foreign Physical, Chemical,
another material or product
Biological material into the product
unlike above example, Many times contamination /Cross contaminations are not visible and not
identified during visual inspection as well as during consumption.
3
Consequences of Contamination/Cross-contamination
Risk to patient health:
• Adverse drug reaction, health
complications leads to life
threatening.
• Penicillin contamination may trigger
hypersensitive exaggerated allergic
immune response
Risk to Organisation:
• GMP non-compliance
• Recalls
• Sales Loss 4
• Company Reputation
Regulatory Perspective
EU GMP Chapter-3 21 CFR Part 211: ISPE’s risk map Guide to
(Premises and Subpart C: Buildings managing Risks
equipment) and Facilities Associated with Cross-
211.176 Penicillin Contamination inline
Contamination with Chapter-3 and
EU GMP Chapter-5
Chapter-5 of EU GMP.
(Production)
ICH Q9: Quality risk
management
5
Few Regulatory Observation in India
6
Few Regulatory Observation in India
7
Overview: Possible ways and Management of Cross-contamination
Airborne transfer Mechanical transfer Retention Mix-up
Dirty Clean
1. Facility design 1. Facility design 1. Cleaning 1. Facility design flow
• Containment • Personnel/ Material • Cleaning Methods – • Unidirectional flow
movement Auto/Manual
2. HVAC • Cleaning Validation 2. Labelling Procedure:
• Pressure regimen 2. Gowning/ Gloves
• Labelling of product,
• Filtration • Decontamination 2. Equipment: equipment etc.
• Equipment Design
• Maintenance
8
Airborne Transfer:
Airborne
Transfer
Facility Design HVAC
Filtration and
Containment
Pressure gradient
Transfer of powder aerosol via air movements and deposition on exposed product
surface or equipment surface. 9
Controls to prevent Airborne Transfer
Closed Transfer Containment Facility Design HVAC Micro
• Close transfer of material from one
equipment to other
• No manual interventions during
transferring and unloading.
10
Controls to prevent Airborne Transfer (Continue…)
Closed transfer Containment Facility Design HVAC Micro
• Closed Charging, processing, sampling and discharging of powder/granules.
• Closed cleaning Viz. CIP/WIP
• Decontamination before exposing the product contact area using wet sprinklers within equipment.
Isolator With Sifter Compression M/C With Containment FBE
11 With Containment
Controls to prevent Airborne Transfer (Continue…)
Closed transfer Containment Facility Design HVAC Micro
Smooth surfaces of walls, floor and ceiling- Wall and ceiling with modular partition or PU painted. Flooring with
epoxy coating. Coved corners.
Accessibility for cleaning – Process area including mezzanine and service area with easy accessibility for cleaning
Clean room fitting – Light fixture, HEPA housing, Smoke sensors, grilles, etc. with leak-proof design
Clean & positively pressurized corridor/airlock against process area
BUBBLE AIRLOCK CASCADE AIRLOCK
05 PA 05 PA 05 PA 05 PA
PROCESS AREA PROCESS AREA PROCESS AREA PROCESS AREA
15-PA 15-PA
A/L
15-PA 15-PA
A/L
A/L A/L
VP VP
05 PA 25 PA 12
CORRIDOR CORRIDOR
Controls to prevent Airborne Transfer (Continue…)
Closed transfer Containment Facility Design HVAC Micro
Appropriate filtration level to maintained required
cleanliness gradation
Maintaining adequate differential pressure between
RS
clean and process area
Maintaining Temperature/RH for working comfort of
(+) (-)
personnel and product requirement.
Maintaining maximum ACPH and low level riser for
effective flushing of airborne particles
The HVAC and dust collector ducts cleaning in fixed
frequency
NRV and interlocking with HVAC system to be
considered for dust collector. Easy to clean piping
system installation for dust collector.
13
Controls to prevent Airborne Transfer (Continue…)
Closed transfer Containment Facility Design HVAC Micro
• Ideal Drain Traps
• Cleaning and
Sanitization
14
Controls to prevent Airborne Transfer (Continue…)
Closed transfer Containment Facility Design HVAC Micro
Tank should be pressurized with filtered compressed air which
is controlled through PLC after SIP.
PLC is tested and validated for intended control logic.
Equipment consist of below safety for prevention of
contamination
Barrier filter
Non Return Valve (NRV)
Slow cooling with Filtered compressed air
15
Mechanical transfer
Transfer of contaminant from non-contact surfaces of equipment area, accessories through
routes of movement/transfer.
Mechanical
Transfer
Gowning
Gowning Facility Design
Personnel/Material
Decontamination
Movement
16
Mechanical transfer: Causes and controls
Dirty
Gowning and
Process flow equipment
De-gowning
handling
Unidirectional Procedure for
decontamination
process flow and
covering/wrapping
of equipment/parts
during transfer from Procedure for de-
one area to other gowning, removal of
area/wash area. gloves and other
apparels before
leaving the area.
MAL and PAL
Mist showers
17
GOWNING DEGOWNING
Retention:
Retention
Cleaning Equipment
Equipment Design and
Cleaning Cleaning Methods Maintenance
Validation – Auto /Manual
18
Controls to prevent cross contamination due to Retention:
Automatic Equipment and duct cleaning system
SB SPRAY BALL
CF CONTROL FLAP
VG VIEW GLASS
PIPE
DN DRAIN VALVE
PROCESS DUCT
QASV
CF SB VG
SV
CF BYPASS
BLOWER DRY FOR DN SB
SCRUBBER
SCRUBBER VG
SB
FBE
WASHING
SKID
PROCESS AHU
CF
SB SV
SB
VG PROCESS 19ROOM
SB SB SB SB
Controls to prevent cross contamination due to Retention (Continues):
Automatic Equipment and duct cleaning system
• Fine dust particles escape the filters and get deposited in exhaust duct
• Continuous deposition leads to accumulation and hardening of materials.
Automatic bin wash Automatic cleaning After cleaning by
Before Cleaning
system system automatic system
20
Retention : Equipment design and selection
Sanitary Surface Finish
Piping Design
Design and MOC
• Dent free surfaces • No/Minimum dead leg • MOC - Stainless steel
(Less than 2D) (SS304, SS316,
SS316L), FDA
• Accessible for • Slopes for drain ability approved plastics and
inspection and rubber
maintenance • Leak free valves and
accessories • Non-reactive, Non-
• Hermetically sealed porous, corrosion
resistant, smooth, non-
hollow areas • Inert gas and Orbital absorbent, non
welding followed by releasing and
boroscopy
• Difficult to clean cleanable surface
locations shall be
minimum
21
Retention : Equipment Maintenance
Periodic inspection
of equipment
Equipment surfaces shall
Life cycle evaluation
Periodic replacement be checked for of equipment
of gaskets scratches, dents, cracks Equipment shall be
and finishes evaluated periodically
Gaskets of tri-clover
Periodic maintenance of frequent breakdown,
joints, view glasses, Lids,
equipment. Scheduling, damages in equipment
filters shall be checked
execution and recording should be considered
and replaced periodically
through electronic ERP for life cycle
means like SAP evaluation
Data trending and
review
22
Retention: Material (residue) evaluation
Criteria for Residues with great risk to the next product.
High Toxicity
High potency
Sensitivity/Allergic reaction
Criteria for worst case product selection
Solubility
Clean ability
Toxicity
23
Mix-Up: Prevention of Cross-contamination
Mix up is the contamination of one product with another product by human
error or inadequate process or plant design.
MIX UPS Unidirectional flow of
man and material
Procedure and
Facility Design
controls
Labelling and SOPs
Unidirectional flow of
Man & Material /
Labelling and SOPs
Electronic Process
controls
Mix-Up: Causes & Controls to prevent Cross-contamination
Probable causes for Mix Ups- Wrong API used in process /Accidental use of dirty
equipment/The wrong dedicated part used/The wrong label placed on container
Technical Facility & Administrative Procedural
SOP
Engineering Controls Dedicated Facility
SOP
• Linear Layout Design
• Electronic verification of materials through • Dedidated facility of high potent • Labeling and identification procedure
Bar coding/AGV /ASRS molecules • Man and material movement procedure and
• Electronic verification through Camera • Dedicated Suites for manufacturing of layout
systems specific products • Procedures for segregation of
• Access control for authorized entry • Dedicated storage areas for Dispensed, equipment/material during storage and
• Acess Control System In-process material, clean and Dirty process
• Dust collectors – Swan neck and NRV at equipment • Room status labelling
point of use and interlocking with AHU • Physical separation of high risk products
Consequences of Cross-contamination
Penicillin can be a sensitizing agent that triggers a hypersensitive exaggerated allergic immune
response in some people. Differences in the 6-aminopenicillanic acid side chain can generate
allergic reactions ranging from skin rashes to life-threatening anaphylaxis.
All penicillin finished pharmaceutical manufacturers, including re-packers, are required by the
CGMP regulations to establish a comprehensive control strategy designed to prevent cross-
contamination of other drugs with penicillin.
These requirements include:
• 21 CFR 211.42(d): Separation of facility and equipment
• 21 CFR 211.46(d): Separate air handling systems (HVAC)
• 21 CFR 211.176: Test for traces of penicillin where possible exposure exists.
26
QRM for prevention of cross contamination
Product profile review of products manufactured in shared facility
• High risk products
• High vulnerability products
• Potent products
Current containment approach review
• Process flows
• Equipment/room matrix
• HVAC evaluation (AHU matrix)
Required Primary/minimum Controls (FMEA)
• Challenging controls for 4 probable pathways of
cross contamination
27
QRM for prevention of cross contamination
Review the risk profile:
• Change/Modification in the Facility & HVAC design.
• Change/Modification in equipment or utilities catering the process area.
• Change/Modification in Limit for pressure differential in process area.
• Change in procedure.
• Introduction of new Equipment/HVAC/New manufacturing process.
• Corrective action effectiveness check.
Thank you
Rajendra Kumar Das
AVP-Engineering & Projects
Sun Pharmaceuticals
29
Q&A
