Cross Contamination Control

in
Parenteral
&
Solid Orals

By: Amit Sareen

 ‐Disclaimer –

This presentation reflects the personal views and

opinion of the speaker and should not be construed
to represent Lupin Limited’s views or policies.

2
1. DEFINITION

Contamination is the undesired introduction of Cross‐contamination is the contamination of the starting,

• Chemicals (Leftover residue of Previous Process) intermediate products, or finished products with other starting
• Microbes materials or products during production
• Foreign matter (Dust, Glass & rubber particles, Fibers, Oil, Three main types of cross-contamination
Hairs & Skin fragments) into or on to a starting material or • Product – to - Product
intermediate, during production, sampling, packaging or • Equipment - to - Product
repackaging, storage, and transport • Person - to - Product

3
2. BACKGROUND

FDA Drug Recall Statistics Since 2012 Recall Distribution Since 2012
Drug Recalls Per Year
1317
Class I
2500
2,163 Cause serious health problems or death
2052
2000

1500 1,365
1,552
1,405
10168
Class II
1,231
1,078 1,039
Result in short term health issue
1000
459 443
500
1302 Class III
0 Unlikely to cause harm to
someone’s health

Major Contributes for Recall

 Cross Contamination
 Since 2012: There have been 12,787 total drug recalls issued  Mislabeling
 Adverse Reaction
by the FDA  Defective Product
 On Average, 1,279 drugs are recalled every year  Incorrect Potency

References – https://www.maylightfootlaw.com 4
 2. BACKGROUND

PQD – Product Quality Defects

Top Defect Types, PQD Total FY 2016 ‐2020

All Others -6%
 Contamination is one of the
Product Quality
Issues-4%
quality defect, leads to product
Product Quality Labeling Issues-4%
Questioned-27%
OOS & Stability
Testing Issues-4%
recall
Contamination
& Sterility
 A focus area for the industry to
Issues‐6%
improve quality by developing
Physical Issues-7% control strategy on cross
contamination.
Reaction, Illness,
Device Issues -18%
Adverse event – 9%

Packing Issues -18%

5
References – Fiscal year 2020, published by Center for Drug Evaluation and Research office of pharmaceutical quality
2. FEW EXAMPLES OF CROSS CONTAMINATION RECALLS

Sr. Year of
Facility Brief Description Of Recall Observations
No. Observation

Health Canada closed an API plant (XXXXX Pharmaceuticals) in Toronto, due to recall of all
1. April, 2015 API
nonpenicillin APIs which was cross‐contaminated by penicillin.

Due to cross contamination with other products, XXXXX Pharmaceuticals, Voluntary recalled 998
2. Oct , 2018 OSD
bottles of Synjardy (Empagliflozin and Metformin Hydrochloride) tablets, 5 mg/1000 mg.

Consumer complaint was raised for contamination of dangerous metal particles including nickel, iron and
3. May, 2019 Liquid chromium which was introduced during manufacturing process of Infant’s Tylenol at XXXXX
Healthcare’s plant in Fort Washington, Pennsylvania.

XXXXXX Pharmaceuticals U.S.A., had recalled one lot of Lamotrigine Tablets due to cross-
4. Jan , 2020 OSD
contamination with Enalapril Maleate.

XXXXX USA, voluntarily recalled a single lot of Dexmedetomidine HCl in 0.9% Sodium Chloride
5. April, 2020 Sterile
Injection, 200 mcg/50 mL (4 mcg /mL), 50 mL due to presence of lidocaine content in the lot.

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3. BASIC PRINCIPLES (ETHICS TO AVOID CROSS‐CONTAMINATION)

• Cross-contamination is a major concern within the pharma manufacturing industry, particularly for
products produced at multi-product or shared facilities
• Cross contamination can compromise patient or environmental safety and can have impact on the
business

Three Basic Principles to avoid Cross‐Contamination

Conversation with Employees regarding cross-contamination

Follow a robust & disciplined process

Develop a Quality Culture that empowers everyone to act on any issues they encounter during day-to-day
activity

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4. ROUTES OF CROSS CONTAMINATION & IT’S CONTROLS

4.1.1 Facility Design 4.1.2 Procedural Control

 Man & Material Flow  Labelling Process
 Automation  Line Clearance Process
 Warehouse Management Process

4.1 Mix ‐ up
4.4.1 HVAC, LAF and other 4.2.1 Facility Cleaning
relevant System • General Housekeeping
(Air Filtration ) • Cleaning method design

4.4 Airborne Cross

Transfer Contamination 4.2 Cleaning
4.2.2 Equipment Cleaning
4.4.2 Facility Design  Cleaning Procedure Design
(Pressure Gradient)  Setting of Cleaning limit
4.3 Mechanical  Maintenance
Transfer
4.3.2 Facility Design
• Personal
4.3.1 Gowning • Material Movement
• Air Lock System
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4. ROUTES OF CROSS CONTAMINATION & IT’S CONTROLS

4.1.1 Facility Design 4.1.2 Procedural Control

 Man & Material Flow  Labelling Process
 Automation  Line Clearance Process
 Warehouse Management Process

4.1 Mix ‐ up
4.4.1 HVAC, LAF and other 4.2.1 Facility Cleaning
relevant System • General Housekeeping
(Air Filtration ) • Cleaning method design

4.4 Airborne Cross

Transfer Contamination 4.2 Cleaning
4.2.2 Equipment Cleaning
4.4.2 Facility Design  Cleaning Procedure Design
(Pressure Gradient)  Setting of Cleaning limit
4.3 Mechanical  Maintenance
Transfer
4.3.2 Facility Design
• Personal
4.3.1 Gowning • Material Movement
• Air Lock System
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4.1 MIX‐UP CONTROL
4.1.1 APPROACHES RELATED TO FACILITY DESIGN (MAN‐ MATERIAL FLOW & AUTOMATION)

1 3 5

Uni-Directional Material & Warehouse Management Designated Storage Area for Cleaned
Personnel Flow System Equipment’s
2 4 6

Product Dedicated Facility

(e.g. Penicillin, Oncology & Designated Storage Area for
Material Identification System Contraceptive etc.) Uncleaned Equipment’s
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4.1 MIX‐UP CONTROL
4.1.2 APPROACHES RELATED TO PROCEDURAL CONTROL

1 2 • To avoid errors with respect to

Restrict & Control the entry of correct name, description,

unauthorized persons (those stage of material along with its

who are involved in other storage

product processing) • In process labels with

different color
Authorized Personnel Movement & Access
Control Labelling Practice

3 4
To control cross contamination
of different products due to
personnel movement in high To avoid carryover of
potent product facility(common previous product
corridor or /during product
processing )

Air Shower for De‐dusting Product Dedicated Equipment Change Parts

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4.1 MIX‐UP CONTROL
4.1.2 APPROACHES RELATED TO PROCEDURAL CONTROL

5 6
• Evaluating hard to clean
To ensure equipment /line is
area
free from previous product
• Emphasizing on checking
traces to avoid mix-up/Cross
during line clearance
contamination

Visual Verification Process In Line Clearance Hard to Clean Area

7 8
Rinse/Swab sampling
Assuring/confirmation/cross
method to be established for
checking of correct
verification of traces of
processing/cleaning
previous product

Doer & Checker Mechanism Periodic Cleaning Verification

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4.1 MIX‐UP CONTROL
4.1.2 APPROACH IN WAREHOUSE FROM MATERIALS RECEIPT TO DISPENSING
(SAP ENABLED WAREHOUSE)

Receipt of Materials Sampling / Testing/

Storage of Materials

Verification of material
container and vehicle Sampling performed under
condition before unloading RLAF

Picking right materials

Batch wise Segregation of API Dedicated accessories used for Dispensing by
materials at receipt area during
unloading
for sampling using handheld
scanner.

Dedusting of received material Materials ok

containers QC Materials transferred to
Discrepancy Testing unrestricted location.
If any discrepancy observed Note
Bar coded “Material Status Initiated
Label” pasted on all material Materials Not ok
containers
Physical segregation of
material container
Material shifted to respective Materials transferred to
storage area as per the Restricted location
required storage condition

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4.1 MIX‐UP CONTROL
4.1.2 APPROACH IN WAREHOUSE FROM MATERIALS RECEIPT TO DISPENSING

Cross Contamination Controls at Material Dispensing

Line Clearance • Usage of PPEs (Gloves/Goggles/

Dedicated dispensing
Hand held Scanner for procedure of Over gown/Booties)
accessories Used
material Picking Dispensing Booth • Changing of gloves & gown
during change of API & Colored
materials

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4.1 MIX‐UP CONTROL
4.1.2 APPROACH IN WAREHOUSE FROM MATERIALS RECEIPT TO DISPENSING

Cross Contamination Controls at Material Dispensing

• Dispensing under RLAF

Dispensing of high Incase of high potent
• Cleaning of return riser
potent drugs in Isolator product dedicated SS
filter during product
container with lid shall
changeover
be used

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4. ROUTES OF CROSS CONTAMINATION & IT’S CONTROLS

4.1.1 Facility Design 4.1.2 Procedural Control

 Man & Material Flow  Labelling Process
 Automation  Line Clearance Process
 Warehouse Management Process

4.1 Mix ‐ up
4.4.1 HVAC, LAF and other 4.2.1 Facility Cleaning
relevant System • General Housekeeping
(Air Filtration ) • Cleaning method design

Cross
4.4 Airborne 4.2 Cleaning
Contamination
Transfer
4.2.2 Equipment Cleaning
4.4.2 Facility Design  Cleaning Procedure Design
(Pressure Gradient)  Setting of Cleaning limit
4.3 Mechanical
 Maintenance
Transfer
4.3.2 Facility Design
• Personal
4.3.1 Gowning • Material Movement
• Air Lock System
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4.2 CLEANING CONTROL
4.2.1 METHODOLOGY FOR HOUSEKEEPING ACTIVITIES

Trained Person for Housekeeping Application Methods Wet Contact Time & Use ‐ Dilution

Disinfectant Efficacy (DE) Study Recovery Control Selection and Rotation of Cleaning Agents

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4.2 CLEANING CONTROL
4.2.2 METHODOLOGY FOR INTERMITTENT /BATCH TO BATCH CLEANING

Intermittent Cleaning of Dusty Operations

Isolator Decontamination

Sifting Operation Roll Compacting Operation

Cleaning of Dust collector tubing & bags

Tablet Counter Tablet Compression

Filter Cleaning
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4.2 CLEANING CONTROL
4.2.2 METHODOLOGY ON EQUIPMENT CLEANING

Stage 1 Worst case product evaluation addressing patient safety, typically

Cleaning Process
Design expressed as either Acceptable daily exposure (ADE)/Permitted
1 MACO (Maximum daily exposure (PDE)/Health based exposure limit (HBEL)
confirm

allowable carry over limit )

/ARL (Acceptable residue
Changes

Stage 2 limit) Manual Cleaning process with

Cleaning Process
Performance reduced variables
Qualification
confirm

Stage 3
Continued Cleaning
3 2 • Water Temperature, Time & pressure
Process Verification Cleaning Validation Life Cleaning Procedure
Control Visual cleaning acceptance criteria
Cycle Development
Recipe Based (Auto)Cleaning
Process

Hard-to-clean substances (Polymer, sticky) to

be identified and the difficulty of cleaning will
be rated according to the three categories Easy,
Medium, Difficult Cleanability Assessment
Recipe Based Cleaning of Equipment’s

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4.2 CLEANING CONTROL
4.2.2 METHODOLOGY ON EQUIPMENT CLEANING

 Reproducibility of the cleaning process can be proved by

validating the following cleaning process variables
 Manufacturing of different batches & different products
 Manufacturing of campaign batches
 Using different operators for different batches
 Using Non-dedicated equipment

 Development of Dirty Equipment /Cleaned Equipment

/Campaign Run , Hold Time Study.

 Product Dedicated FBE Filter Bag / RMG Venting Bags

 API dedicated Silicone tubes/Product transfer Hose pipe

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4.2 CLEANING CONTROL
4.2.2 METHODOLOGY AT STERILE FACILITY FOR MACHINE/CHANGE PARTS USED
IN MULTI PRODUCT FILLING LINE/S

Critical product contact surfaces (i.e., product tanks, stopper bowls, filling needles) are
covered to prevent cross contamination.

Filling Needles

Aseptic connections and manipulations should be minimized or performed in a way to

prevent contamination/ cross contamination (e.g., microbial, particulate, etc.)

Manifold

Cleaned equipment and parts should be dry and covered to avoid contamination/ cross
contamination

Cleaned Parts

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4.2 CLEANING CONTROL
4.2.2 METHODOLOGY AT STERILE FACILITY FOR MACHINE/CHANGE PARTS USED
IN MULTI PRODUCT FILLING LINE/S

• For Filtration of product, “single use” filter shall be used in every batch
• For Product transfer during filtration, dedicated single use Silicone tubes shall
be used in every batch
Filters Silicone Tubes

• In liquid injectable, Dedicated tubing’s, filters shall be used to avoid Cross

contamination
• For Change parts bowl, manifolds, connectors, needle, piston shall be cleaned
using Auto process and rinse sample verification shall be evaluated to confirm
traces of previous product
Liquid Filling Line

• Powder filling shall be done in preferably in a closed RAB.

• Vacuum pipelines shall have NRV’s
• Removal of powder traces by applying vacuum
• Cleaning of Return risers/ pre filter to remove previous product traces
• Cleaning of powder collector to remove traces of Previous product
• Verification of previous product removal by assuring swab/ rinse analysis.
Powder Filling Line

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4.2 CLEANING CONTROL
4.2.2 MAINTENANCE APPROACHES OF AGED EQUIPMENT

Equipment

Design Maintenance

Aged Equipment
Easy to Clean Inert Non Reactive Non Additive &
Non Absorptive (Interior surface imperfections and scratches on product contact surfaces)

 Material Selection :‐
SS316L/Non-oxidizing
 Periodic
Maintenance :‐
Electrolytic/Anodized
polishing

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4.2 CLEANING CONTROL
4.2.2 MAINTENANCE APPROACHES OF AGED EQUIPMENT

Identification of rough/scratch's/dents surface area

Roughness tester RA value RA Value <0.8

measurement No action required
RA Value >0.8
“Mechanical Polishing” shall be performed to those Area and ensure the smooth
surface & finishing. As like OEM

Equipment/Part should be cleaned with starch after “Mechanical Polishing”

Molybdenum kit
Not complying Surface MOC
Component/part verification
shall be replaced (SS316L)
Complying
Roughness verification.
Not complying Limit
Roughness
tester
Equipment cleaning to be done as per procedure.

Batch execution as per the commercial plan.

Cleaning verification if required. Evaluation completed

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 Example of Cross Contamination source
&
Recipe based cleaning approach for Equipment / Contact
Parts

25
4.2 CLEANING CONTROL
4.2.2 EXAMPLE OF CROSS CONTAMINATION SOURCE FROM EQUIPMENT

•In 2012, FDA conducted an inspection of a US

Generic drug manufacturer based on field alert
reports (FARs) submitted regarding an issue
discovered by the firm during maintenance.
Firm manufactured multiple drugs on fluid bed
dryers (including hormones) which leads to Cross
contamination from one drug to another
occurring via fluid bed ductwork.
Previous Product Residue

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4.2 CLEANING CONTROL
EXAMPLE OF RECIPE BASED AUTOMATIC DUCT WASHING SYSTEM IN FBE/TABLET COATER

27
4.2 CLEANING CONTROL
EXAMPLE OF RECIPE BASED AUTOMATIC CLEANING OF VESSELS AT STERILE FACILITY

Recirculation Line CIP SEQUENCE

Flushing & Drain

Cleaning Cycle 1

Cleaning Cycle 2

Cleaning Cycle 3

Collection
Vessel
Air Purging

Conductivity

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4.2 CLEANING CONTROL
EXAMPLE OF RECIPE BASED AUTOMATIC CLEANING OF CONTACT PARTS USING
AUTO WASHER MODULE IN A STERILE FACILITY

WFI IN Contact Part Washer Operation

Process Air IN

Purified Water IN
Sequence
Flushing & Drain
Heat
Exchanger

Pre Washing PW

TOC &
Conductivity
Washing 1 WFI
Circulating
Pump
Drain Washing 2 WFI
Sampling
Valve

 WFI wash phase shall be repeated till TOC and Conductivity Conductivity & TOC
parameters are achieved as per set parameters in Contact Part
Washer
 After achieving TOC & Conductivity, contact part washer shall Drying Carriage for Contact
automatically proceed for drying phase
 Visual inspection for presence of particulate matter
Part Washer
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4. ROUTES OF CROSS CONTAMINATION & IT’S CONTROLS

4.1.1 Facility Design 4.1.2 Procedural Control

 Man & Material Flow  Labelling Process
 Automation  Line Clearance Process
 Warehouse Management Process

4.1 Mix ‐ up
4.2.1 Facility Cleaning
4.4.1 HVAC, LAF and other • General Housekeeping
relevant System • Cleaning method design
(Air Filtration )

4.4 Airborne Cross

4.2 Cleaning
Transfer Contamination
4.2.2 Equipment Cleaning
4.4.2 Facility Design  Cleaning Procedure Design
(Pressure Gradient)  Setting of Cleaning limit
4.3 Mechanical  Maintenance
Transfer
4.3.2 Facility Design
• Personal
4.3.1 Gowning • Material Movement
• Air Lock System
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4.3 MECHANICAL TRANSFER CONTROL
4.3.1 THROUGH EFFECTIVE GOWNING PRACTICE

 Area Dedicated
 Color coded for specific identification
Over gown  Single use /disposable
 Non-Particle shedding

 Single use hand gloves

 Intactness checking of hand gloves prior to use
Hand gloves  Powder free hand gloves
 For sterile operation, double hand gloves shall be
used

 Product dedicated Laundry (e.g., high potent

Garment Laundry Products)
 Validated Cleaning Cycle

 Visual inspection of cleaned garments includes

Garment Inspection Stains, Torn, stitched fiber defects, Ink mark etc.

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4.3 MECHANICAL TRANSFER CONTROL
4.3.1 THROUGH EFFECTIVE GOWNING PRACTICE

Multi Product operational Suites at Solid Oral Facility

• Additional over gowning procedure to be followed for entry and exit from one process
cubicle to another process cubicle.

Multi Product operational Suites at Sterile Facility

• Each Filling line have dedicated Entry & Exit change rooms
• Sterile disposable gown.
• Separate Laundry for washing and inspection of used garments

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4.3 MECHANICAL TRANSFER CONTROL
4.3.2 FACILITY DESIGN THROUGH AIR LOCK SYSTEMS

Air Locks
Interlocking airlocks between entry points for classified
areas of different grades (e.g., between ISO 8 and ISO 7).

Restricted Entry
Restricted and controlled access to aseptic processing
areas engaged in manufacturing of different products (e.g.,
card readers, biometric access).

Pass Through Procedure

• One Product material ,shall pass through at a time
• Dedicated pass box

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4.3 MECHANICAL TRANSFER CONTROL
4.3.2 DIFFERENT TYPES OF AIRLOCK DESIGN

Bubble Airlock Sink Airlock

Bubble Airlock: These types of airlocks have a higher pressure Sink Airlock:‐ These type of airlocks have a lower pressure inside
inside the airlock and lower pressure on both adjacent areas. the airlock and higher pressure on both adjacent areas.

Application‐ Research facility, where substances that are

Application‐ Used in areas where the product needs protection
experimented on are highly potent products and it is essential to
and the people external to the clean rooms require protection
keep them from being exposed. In few types of production
from the product to reduce the possibility of particulate from
processes, in a clean room, air from contaminated area has to be
entering the lesser pressure clean area
contained in one place

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4.3 MECHANICAL TRANSFER CONTROL
4.3.2 DIFFERENT TYPES OF AIRLOCK DESIGN

Cascade Airlock
Cascade Airlock:‐ Airlocks having a higher pressure on
one side and lower pressure on another side. This
prevents entry dust and contamination from outside to
airlock and from air lock to inner side

-Application-
Any manufacturing facility where the product requires
protection from particulate matter but the people
outside the clean room don’t need protection from the
product in the clean room

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4. ROUTES OF CROSS CONTAMINATION & IT’S CONTROLS

4.1.1 Facility Design 4.1.2 Procedural Control

 Man & Material Flow  Labelling Process
 Automation  Line Clearance Process
 Warehouse Management Process

4.1 Mix ‐ up
4.2.1 Facility Cleaning
4.4.1 HVAC, LAF and other
• General Housekeeping
relevant System
• Cleaning method design
(Air Filtration )
Cross
4.4 Airborne 4.2 Cleaning
Contamination
Transfer
4.2.2 Equipment Cleaning
4.4.2 Facility Design  Cleaning Procedure Design
(Pressure Gradient)  Setting of Cleaning limit
4.3 Mechanical
 Maintenance
Transfer
4.3.2 Facility Design
• Personal
4.3.1 Gowning • Material Movement
• Air Lock System
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4.4 AIRBORNE TRANSFER CONTROL
4.4.1 CONTROL VIA HEPA IN RETURN FOR HIGH POTENT MOLECULE FACILITY

SUPPLY

37
4.4 AIRBORNE TRANSFER CONTROL
4.4.1 ISOLATORS

• Pharmaceutical Isolator provides for both barrier protection

from cross-contamination as well as a clean air system.

• RABS and cRABS aim is to provide a controlled environment

with high level of protection to transfer and process materials

or devices through small openings (called “mouse holes”)

38
4.4 AIRBORNE TRANSFER CONTROL
4.4.1 DEDICATED AIR HANDLING UNIT FOR UNIT OPERATION IN MULTI
PRODUCT PROCESS FACILITY

• Preferably area dedicated

AHU’s for a unit operation
in multi product processing
facility.

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4.4 AIRBORNE TRANSFER CONTROL
4.4.1 DEDICATED AIR HANDLING UNIT FOR UNIT OPERATION IN MULTI
PRODUCT PROCESS FACILITY
Sterile Facility Oral Solid Dosage Facility

40
4.4 AIRBORNE TRANSFER CONTROL
4.4.2 PRESSURE ZONING IN FACILITY DESIGN

Sterile Facility Oral Solid Dosage Facility

Legends:-
• Pressure differential between same class NLT 6 Pascal
+ Pressure symbol
Air flow • Pressure differential between different class NLT 12 Pascal

41
4.4 AIRBORNE TRANSFER CONTROL
4.4.2 THROUGH AHU OPERATION SEQUENCE AT STERILE FACILITY

 Cascading AHU ON / OFF sequence

In Dynamic Condition

Non‐Process Corridor(Undefined )
Manufacturing Area(ISO‐8 )
Change Room(ISO‐8 )
Aseptic Corridor(ISO‐7 )
AHU ON Staging Area (ISO‐7 )
Filling & Sealing (ISO‐5 )
AHU OFF

 AHU interlocking System

 UPS supply available to AHUs during power failure

42
CONTROLS ON MULTI PRODUCT OPERATIONAL LINE IN STERILE FACILITY

 For multi product operations, dedicated vessels, filling lines, filters, S2S
connectors, tubing's with coding and identification.

 Gown coding (with different colors).

 Each filling line must have dedicated exit change rooms

 Separate laundry facility for washing the dresses

 Demarcation for dedicated transfer lines

 Disposable gowns/gloves

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5.0 CONCLUSION

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THANK YOU

Registered Office

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3rd Floor, Kalpataru Inspire, Off. Western Expressway Highway, Santacruz (East), Mumbai 400 055, India.
Phone: +91 22 6640 2323 | Fax: +91 22 6640 2051 | www.lupin.com

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