QUALITY RISK MANAGEMENT OF STRATEGY

FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 1 of 16

1.0 APPROVAL:
This document has been approved by the following functional heads.

Department Name Signature / date

Quality Assurance

Head of Production

Head of Quality control

Head of Engineering

Head of Warehouse

Head of QA
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 2 of 16

2.0 TABLE OF CONTENTS:

SERIEAL. No. CONTENTS PAGE No.

1.0 APPROVAL 1

2.0 TABLE OF CONTENTS 2

3.0 PURPOSE 3

4.0 SCOPE 3

5.0 BACKGROUND INFORMATION 3

6.0 TEAM INVOLVED FOR EVALUATION OF QUALITY RISK MANAGEMENT 5

7.0 RISK ASSESSMENT 6

8.0 SUMMARY AND CONCLUSION 36

 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 3 of 16

3.0 PURPOSE:
This Risk Assessment is prepared for preventing the risk of cross contamination of products manufactured with the following purpose:

a. Identify and evaluate the risk associated with the cross contamination from process, products, equipment, facility and personnel.
b. Evaluate the technical and organizational measures available to control the risk of cross-contamination.
c. Identify any additional technical and organizational measures for controlling the risk of cross-contamination.

4.0 SCOPE:
This risk analysis is applicable for preventing the risk of contamination of products manufactured in Production area.

5.0 BACKGROUND INFORMATION:

This risk assessment study shall cover all the possible sources of contamination/ cross contamination and the available procedures to mitigate contamination / cross contamination. The risk assessment study shall also identify
all the molecules which are manufactured in plant. A separate consideration shall be given for identifying the controls available for handling of molecules which require technical and organizational measures.

The risk assessment study shall focus on the following possible mechanisms for cross contamination:
a. Surface to Surface:
• Originating from contact with inadequately cleaned shared equipment/ tool surfaces through failures or inadequate design of cleaning process/equipment.
• Originating from contact with contaminated equipment
• Originating from personnel gowning.
b. Airborne to air/surface
• Originating from poorly controlled and unintended release of product into the environment due to inadequate control of powder particles during process after which the contamination settles on the product contact
surface.
• From recirculation in AHU’s between areas where filtration is inadequate.
• From inadequately controlled exhausts or return riser filters or filter integrity check.
c. Direct or indirect contamination from process or equipment failure:
• Back flow from waste or vacuum systems
• Technical failure of equipment.
• Spillage and leaks from equipment or handling during processing.
d. Originating from movement of personnel, materials or equipment or accessories from one location to other using processing area.

Mapping of stages with operations possible of generating particles leading to risk of contamination and cross contamination.

The mapping of stages where there is possible generation of particles with a risk to contamination/cross contamination shall identify the different stages where there is possibility of particles being generated of the active material.

The mapping is carried out based upon the amount of particles generated during a particular process. It is focused on processes which are more prone for generation of particles and processes which are less prone for generation of
particles.

Below table represents the stages of particle generation and possible causes of particle generation.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 4 of 16

GENERATION OF
STAGES POSSIBLE CAUSES FOR GENERATION OF CONTAMINATION
PARTICLES
Receipt of Raw materials Low Damaged containers containing the raw materials.
Sampling of raw material
High Contamination during sampling if proper procedure is not followed.
Dispensing of raw material High Contamination during Weighing of raw materials in case spillage occurs
Bulk Sampling Medium Contamination during sampling
Preparation
(Liquid Stirring Low Stirring/ mixing of raw material ingredients carried out in closed equipment however there can be contamination during charging of material in equipment’s.
Injection/
Filtration Low Filtration of prepared bulk solution carried out in closed filtration assembly and single time used filter for filtration of the product however there can be contamination
Ophthalmic)
during non dedicated filter used in filtration.
Product transfer through Low
Transfer of material through transfer line is carried out in close system.
transfer line
Filling of injection Medium Contamination can be happen during dosing of liquid in ampoule/ Vial due to time out of proxy sensor or not working properly to provide the signal for positioning of
vial/ ampoule at the time of sterile liquid dosing.
Dry Powder Sampling Medium
Contamination during sampling
Injection
Filling Charging of container at Low Filtration of prepared bulk solution carried out in closed filtration assembly and single time used filter for filtration of the product however there can be contamination
Hopper during non dedicated filter used in filtration.
During In process verification Low
of fill weight Contamination during In process verification of fill weight.

Filling of Dry Powder Medium Contamination can be happen during dosing of powder and time out of star wheel, proxy sensor not working to provide the signal for positioning of vial holed by star
injection wheel at the time of sterile powder dosing.
Ladling/ Visual Inspection/ Packing of
Low No any chances of contamination in Ladling/ Visual Inspection/ packing area because product is in packed condition
Injection
Dispatch of Finished goods
Low No any chances as product in packed condition

This Risk Assessment has been initiated for evaluation of Technical and Organizational measures during manufacturing of hazardous as well as non-hazardous product and control measures available to mitigate contamination and cross
contamination. The risk rating as High, medium and low have been assigned based on the risk control measures available.

6.0 TEAM INVOLVED FOR EVALUATION OF QUALITY RISK MANAGEMENT:

Risk Management team comprises of representative from Production, QA, QC, Warehouse and Engineering.

Name Designation Department

Manager Compliance Quality Assurance

Deputy Manager Quality Assurance

Executive Quality Assurance

Deputy Manager Quality Control

Manager Production
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 5 of 16

7.0 RISK ASSESSMENT:

Risk Analysis and Evaluation Current control Risk classification Risk Acceptability
Description of Risk Risk classification measures based on control (Yes/No)
Potential Impact Risk
identified Failure mode based on risk measures
number
identified
Technical measures - Facility

• The processing areas and corridor are having dedicated AHU systems for
containment of air born particles and to prevent risk of cross contamination of
products processing in different areas.

• The corridor adjacent to the processing areas is having most negative as

compared to the processing areas which prevents entry of air born particles to
the processing areas and further to the adjacent areas.

• The pressure zoning (cascade) and AHU zoning diagrams of all the areas at
site has been reviewed and includes the controls are available for confine
potential air born contaminant within processing areas.
There will be
transfer of air
• Additionally, certain areas are having air locks separate for personnel entry
borne contaminant
Failure in facility and material entry
to air /surface to Low Yes
design with respect to
corridor and
Inadequate containment of
adjacent processing
pressure cascade so to • Magnahelic gauges are provided for indicating differential pressure across
product within processing R01 confine potential Medium areas as follows
areas.
areas airborne contaminant ➢ processing area with respect to Corridor
This will result in
within a specified area ➢ Corridor with respect to air lock (In certain areas)
cross ➢ Corridor with respect to material entry (In certain areas)
contamination of ➢ Air lock and material entry with respect to processing area (In certain
areas)
next product
• Pressure differential is verified and documented before start of the critical
activities such as dispensing, manufacturing and packing operations.

• Doors provided for each processing areas are having door closures and ensures
proper closing door so to prevent accidental conveying of air born particles if
remains open.

• In certain areas there are biometric interlocks which prevents simultaneous

opening of doors of two adjacent areas & only authorized person will enter in
processing area.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 6 of 16

7.0 RISK ASSESSMENT:

Risk Analysis and Evaluation Current control Risk classification Risk
Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures -Facility (Contd.)
There will be improper • The surfaces of floor, walls and ceiling in processing areas are smooth
cleaning of surfaces which allows ease of cleaning or decontamination during routine
• Failure to clean
leading to transfer of air product change over and in-between the same product.
surfaces of floor,
borne contamination
walls and ceiling for
(that settles on the
removal of air born • The corners of floor, walls and ceiling are provided with coving so as to
surfaces) to the air / permit ease of cleaning.
particles
surfaces in the area
accumulated during
after product
processing • All the locations in processing areas are easily assessable so as to allow
Improper facility changeover is cleaning and there are no collection points for powder that may be
design with respect completed. Medium difficult to clean. Low Yes
to surfaces of floor, R02 • Failure to reach out
all the location in
walls and ceiling of This could result in
processing areas for • Procedures are available for cleaning of processing areas during routine
processing area cross-contamination of product change over and in-between the same product.
next product cleaning during
routine product
change over and in- • All the personnel in production are trained on the respective procedures.
Product failure
between the same
product.
More Market
complaint observed
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 7 of 16

7.0 RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk
Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures -AHU design
• AHUs of processing areas are having series of filters as follows for air
supplied to processing area so to ensure that airborne contamination is
removed prior to recirculation.
➢ 10µ (Pre-filter) fresh air
➢ fine Filter: 5µ
➢ 0.3 HEPA exhaust filter
➢ Semi HEPA filter 3 µ
➢ Terminal: 0.3µ HEPA
➢ Return riser: 10µ
• The filters are having gaskets at the sides which provides fitment in filter
housing thereby preventing passing of unfiltered air to different filtration
system and finally to the processing areas.

• AHU qualification has been performed for all the AHUs in processing areas
• Failure to design covering parameters which are impacting its performance of air supplied
There will be AHU with respect to meeting Class A, B, C & D.
transfer of air recirculation of air
borne contaminant through inadequate • Air velocity measurement is verified Once in a 6 months ± 30 days
to air / surface controls in place for
In-adequate controls
after product the filtration system
Medium • HEPA filter integrity is verified during revalidation of AHU once in a 12
change over months ± 30 days
on the re circulated R03
air through AHU
cleaning. • Recirculation of Low Yes
untreated or • Pressure Differential reading is recorded at every 4 hrs. Interval on daily
This will result in insufficiently filtered basis.
cross air to processing
contamination of areas • Air flow pattern test (Smoke test) is verified once in a 12 months ± 30 days
next product
• Non-viable particulate counts measurement is verified Once in a 6 months ±
30 days (FOR ISO CLASS 5, 6,7)

• Viable Particle count test is performed on daily basis.

• HEPA filter integrity is verified during revalidation of all the AHUs once in
a year as per SOP no. SOP, SOP titled” Qualification of Air Filtration
System”

• The change rooms are provided for entry and exit to the processing areas
through a gowning procedure

• All the personnel in production,QA and engineering are trained on the

respective procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 8 of 16

• AHUs of processing areas are having more than 20 air changes per hour for
Failure to design AHU processes where there is high risk of air born particles generated as per SOP
with respect to air no. SOP, SOP titled ” Qualification of Air Filtration System”
changes for controlling
R04 Low Yes
the air born particles Medium • The air changes are verified during revalidation of all the AHUs in
generated during processing areas once in a year, and air velocity once in 6 month for RLAF,
processing LAF.

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk
Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures -AHU design(Contd.)
• Magnahelic gauges are provided across fine filters of AHUs so as to indicate
the pressure differential across filter and there by guiding the personnel for
taking decision of any filter that is damaged.
• Terminal HEPA filters of AHUs of processing areas are also having port for
measuring pressure differential across filter for taking decision of any filter
that is damaged.
• The differential pressure indicated on the gauge of 3µ fine filters of AHU is
recorded at AHU switch on time.
Medium • Monthly verification of differential pressure is in place across terminal HEPA
• Damage to filters of filter.
AHU resulting in • The differential pressure data recorded is used for taking decision of filter
recirculation of cleaning or replacement of filter if it does not meet the acceptance criteria as
untreated or defined
insufficiently
Refer following SOPs for differential pressure
filtered air to
SOP No., SOP titled “SOP For Measuring Pressure Drop Across HEPA Yes
In-adequate controls processing areas
Filter”.
on the recalculated
Contd. R05 ➢ SOP no., SOP titled ”SOP for Operation of Air Handling Unit. Low
air through AHU • Blockage of filters
(Contd.) of AHU during
• Filter cleaning procedure is in place to clean the filters (20µ, 10µ, 5µ and 3µ)
routine operation
as per defined frequency in SOP no., titled “SOP for AHU Filter Cleaning”
which can impact
the air changes • Preventive maintenance of AHU is performed every 3 month Refer SOP No.,
supplied to SOP titled “SOP for Annual Preventive Maintenance Plan”
processing areas
• Refer SOP no., SOP titled “SOP for Preparation and implementation of
preventive maintenance plan” for annual preventive maintenance schedule of
HVAC Equipments.
• Documentation details during preventive maintenance is as follows
• Details are recorded in checklist
• Preventive maintenance schedule is updated w.r.t. planed vs. Actual
preventive maintenance date
• History card of respective equipment is updated after completion of
preventive maintenance.
• After preventive maintenance AHU checked for its smooth operation.
Refer SOP, SOP titled “SOP for Preventive Maintenance of HVAC Equipments”
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 9 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk
Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures -AHU design(Contd.)
• Filters of AHU are cleaned during routine operation as per SOP, SOP titled
“SOP for filter cleaning”.

• Filters of AHU are replaced during routine operation if differential pressure

does not meet acceptance criteria or any damage is observed as per SOP,
titled “Procedure for integrity testing & replacement of vent filter of water
system”.
In-adequate controls
• Return risers in processing areas are cleaned during every change over as
on the recirculated
Contd. R05 Contd, Contd, per SOP, SOP titled “SOP for filter cleaning of ahu, return riser & duct Contd Contd
air through AHU
cleaning “
(Contd.)
• Documentation details during filter cleaning is as follows
➢ Details are recorded in the operation logbook of filter cleaning
station
➢ Visual inspection is done after completion of filter cleaning activity.
• All the personnel in production and engineering are trained on the
respective procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 10 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk
Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures -AHU design(Contd.)
• In case of AHU stoppage or power failure, the AHU of processing areas is
• Failure of AHU of restarted first and then corridor, so to prevent accidental conveying of air
corridor or born particles from processing areas to corridor.
processing areas • Procedures are available for handling AHU failure or powder failure.

• Failure to restart • Processing of product is stopped and intimated to Engineering

the AHU of • Procedures are defined to evaluate an impact on the processing conditions
corridor or during power failure or AHU stoppage.
R06 processing areas
after any AHU Medium • Assessment of the time needed to return to a clean status once power is
There will be transfer switched ON after power OFF is performed as a part of AHU qualification
stoppage (fault) or Low Yes
of air borne particles to and same is followed routinely in-case of any failure.
the adjacent areas such switch off of AHU
Restart of AHU of as corridor and other during out of hours
and power failure, • Recovery test has been performed as per AHU qualification Schedule.
corridor and processing areas due to
processing area disturbance in pressure in a predefined
• Magnahelic gauge indicates pressure differential outside the acceptance
cascade resulting in sequence
criteria and same is used for identifying any failure of AHU.
cross contamination
• The temperature / humidity monitoring devises are provided in processing
areas to monitor conditions as the product requirement.
• Failure in
controlling
• Processing of product is stopped in-case of any failure of conditions and
temperature / Medium Low Yes
intimated to Engineering.
R07 humidity supplied
to area based on • Daily monitoring RH,Temperature and differential pressure from Radix as
product per SOP. SOP titled “OPERATION OF AIR HANDLING UNIT”
requirement.
• All the personnel in production, QA and engineering are trained on the
respective procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 11 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design
Equipment Design Controls
• The product contact surfaces of equipment’s are having smooth surfaces
which facilitate ease of cleaning and assure confirmation of cleanliness
to a predefined limit for left over residue of previous product.
• Equipments are cleaned during every change over as per respective SOP
of cleaning.

• Based on review of product contact parts of equipment’s following parts

There will be inadequate can be easily cleaned and confirm cleanliness through visual inspection
cleaning of surfaces of swabbing and rinse.
shared equipment/ tool
through inadequate design Failure in equipment ➢ SS 316 L
In adequate of equipment impacting design with respect to Medium ➢ Silicon
R08
equipment design cleaning process and ease of cleaning
resulting in surface to • Following product parts of equipment’s has been identified as product Low Yes
surface cross dedicated
contamination of next
product ➢ Dispensing tools
➢ Manifold
➢ Piston
➢ Cartridge Filter Integrity
➢ Filling Nozzle
➢ Silicone tubing’s used for spraying of solution
• All the personnel in production & QA are trained on the respective
procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 12 of 16

7.0 RISK ASSESSMENT(CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)
• Types of processes used during manufacturing of Tablet products have
been reviewed with respect to release of powder to the environment during
processing. These process have been grouped under following categories
➢ High risk processes includes:
Dispensing, Sampling of raw materials, Sifting, Milling/ Grading of
material, Racking of material during drying, Loading/unloading of
There will power
material or granules or tablet, etc.
generation in processing
➢ Medium risk processes includes:
areas resulting in
Mixing/Granulation in Rapid Mixer Granulator, Blending,
blockage of return risers
Compression, Coating, Packing of uncoated products (Blister
in area. • Failure to control the Packing) etc.
spread of powder ➢ Low risk processes include:
This will in turn result in generated at source Inspection and packing of coated products (Blister Packing)
disturbance in pressure during processes such as
Inadequate
cascade and AHU ➢ Sifting
containment of • Certain parts of equipment’s are having dust extraction so as to control the
performance with respect ➢ Mixing
powder powder generated at source and prevents in release to environment in
to Air changes thus ➢ Granulation
generated at R09 processing areas
resulting in cross ➢ Drying
source from ➢ Compression zone at turret of compression Machine
contamination ➢ Milling/grading
different Medium ➢ Feeding parts and Vibrator of Blister Packing Machine. Low Yes
➢ Tablet inspection
processes ➢ Deduster of Compression Machine
The personnel working in ➢ Compression
area will be exposed to ➢ Capsule filling
the air born particles ➢ Blister Packing • Certain machines are having lifter type of arrangement for hopper which
conveys granules to certain height and then feed it to the hopper of
The air born particles equipment.
will be transferred to the
gowns worned by the • In this case Bin Blender is used for transfer of dried granules to the hopper
personnel. of equipment.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 13 of 16

7.0RISK ASSESSMENT(CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)

• Gaskets are provided for certain parts such as lid of Mixing Tank, Holding
Tank & Buffer vessel. This type of arrangement will provide air tight
sealing.

• Processes such have Dispensing and samplings are having Reverse Laminar
Air Flow equipment’s for controlling the powder generation in areas.

Inadequate • Enclosures are provided to certain parts of following equipment’s to prevent

containment of release of powder to the environment in processing areas.
powder Failure to control the ➢ Compression machine
generated at R09 spread of powder ➢ Blister Packing Machine Low Yes
Contd.
source from (Contd.) generated at source
different (Contd.) • In-case of following equipment’s charging ports are provided for feeding of
processes powder or granules to the equipment which prevents entire opening of lid of
(Contd.) Medium equipment. This type of arrangement minimises the release of powder to
environment in processing areas.
➢ Rapid Mixer Granulator
➢ Coating Machine
➢ Bin

• Certain process which involves charging of powder / granules /tablets which

involves powder generation, precautionary measures such as slow addition,
direct charging from container or immediate closing of lid of hopper /
equipment are followed by operating personnel.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 14 of 16

7.0 RISK ASSESSMENT(CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)
• In following equipment’s, precautionary measures are taken with respect time
Inadequate allowed for powder to settle in the equipment before opening
containment of ➢ After mixing in Rapid Mixer Granulator
powder Failure to control the ➢ After Mixing in Bin Blender
generated at R09 spread of powder ➢ After drying in Fluid Bed Dryer
Contd.
source from (Contd.) generated at source Medium ➢ After completion of milling process/sifting process etc. Low Yes
different (Contd.) • During milling / sifting process,/ polybags are connected to the discharge which
processes feeds the material/granules to bin.
(Contd.)
• All the personnel in production are trained on the respective procedures.
• In following instruments, precautionary measures are taken with respect time
• Failure to control the allowed for PW & WFI Genration.
spread of water
generated at source ➢ Passivation are completed after installation
➢ sanitization are performed on Monthly basis.
• Passivation Medium ➢ Conductivity meter is installed in return loop line
sanitization was not ➢ Automatic Actuated Valve
Inadequate ➢ valve & zero dedleg valve installed.
peformed during
containment of ➢ pH meter installed.
qualication activity
purified water & ➢
• PW & WFI Sampling sampling plan available
water for ➢ operation of PW & WFI process available.
R09 plan is not prepared
injection Contd. Yes
generated at
(Contd.) • PW & WFI sampling Low
source from not performed
according to sampling After completion of DQ, IQ & OQ of water system (PW & WFI), PQ was
different successfully performed. No any deviation has been observed & continue monitoring
processes plan.
is running according to sampling plan.
• Conductivity failure
Refer SOP, SOP titled “Operation of Purified Water System”
• Circulation of water is SOP titled “Operation of Purified Water Circulation Loop”
not proper in loop line. SOP titled “Cleaning & Sanitization of Purified Water System”
SOP titled “Qualification of Water system”
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 15 of 16

• The pipelines connected to dust collectors and equipment’s are having valves
which prevent possibility of back flow of powder thereby controlling risk of
cross-contamination.
• Backflow of powder
will result in cross- • The powder collected in the dust collectors is regularly cleaned which can affect
contamination of its performance.
next product if not
cleaned or • The filters of dust collector are cleaned as per the procedure.
controlled
• The joints of pipelines of dust collectors are sealed so as to prevent release of
• The leakage of powder in the area though which it is passed till the collection point.
Backflow or powder though the Failure to exercise
leakage of Low Yes
powders through
pipelines will result control back flow of • Preventive maintenance of duct work or transfer line is performed which
in contamination of R10 powder from utilities Medium includes verification of any issues related to leaks which could contaminate
the dust service areas such as pipe lines of dust other areas.
collector
collectors
pipelines
• Documentation details during preventive maintenance follow & details are
recorded in checklist

• All the personnel in production are trained on the respective procedures.

 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 16 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Risk measures based on control Acceptability
Description of
Potential Impact Risk classification measures (Yes/No)
Risk identified Failure mode
number based on risk
identified
Technical measures - Equipment Design(Contd.)
• Processes such as Dispensing and Sampling are having RLAF for controlling the
powder generation in areas.

• RLAFs are having series of filters as follows for air supplied to processing area so
• Failure to exercise to ensure that airborne contamination is removed prior to recirculation.
controls in areas on ➢ AHU plenum: 10µ and 5µ
area where materials ➢ Supply: 0.3 µ HEPA
are sampled or ➢ Return riser: 3µ
dispensed with respect
to cleaning between • The filters are having gaskets at the sides which provides fitment in filter housing
different products to thereby preventing passing of unfiltered air to different filtration system and
There will be transfer prevent the spread of finally to the material handling areas.
of air borne powder generated at
Inadequate
contaminant to air / source and cross Medium • RLAF qualification has been performed covering parameters which are impacting Low Yes
containment
surfaces of adjacent contamination such as its performance of supply air
within the
areas. ➢ Sampling
dispensing and
➢ Dispensing
sampling area • Air velocity measurement is verified Once in a 6 months ± 30 days
There will be transfer R11
and
of air borne • Failure to design
In-adequate • HEPA filter integrity is verified during revalidation of RLAF once in a 12 months
contaminant to air / Reverse Laminar Air
controls on the ± 30 days
surface after product Flow (RLAF) with
recirculated air
change over cleaning. respect to recirculation
through RLAF
of air through • Pressure Differential reading is recorded at every 4 hrs. Interval on daily basis.
This will result in inadequate controls in
cross contamination of place for the filtration • Air flow pattern test (Smoke test) is verified once in a 12 months ± 30 days
next product system
• Non-viable particulate counts measurement is verified Once in a 6 months ± 30
• Recirculation of days (FOR ISO CLASS 5, 6,7)
untreated or
insufficiently filtered • Viable Particle count test is performed on daily basis.
air to processing areas.
• All the personnel in production, QA and engineering are trained on the respective
procedures

Refer SOP, SOP titled” Qualification of Air Filtration System”

 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 17 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Risk measures based on control Acceptability
Description of
Potential Impact Risk classification measures (Yes/No)
Risk identified Failure mode
number based on risk
identified
Technical measures - Equipment Design(Contd.)
• Magnahelic gauges are provided for following filters of RLAF so as to indicate the
pressure differential across filter and there by guiding the personnel for taking
decision of any filter that is damaged.

• The differential pressure indicated on the gauge of filters of RLAF is recorded as per
SOP

• Damage to filters of • The differential pressure data recorded is used for taking decision of filter cleaning or
Inadequate RLAF resulting in replacement of filter if it does not meet the acceptance criteria as defined and same is
containment recirculation of intimated to production area.
within the untreated or
dispensing and insufficiently filtered Medium • Preventive maintenance of RLAF is performed as per SOP which includes
sampling area air verification of filters for any damage.
and Contd. R12
In-adequate • Blockage of filters of • Documentation details during preventive maintenance is as follows
controls on the re RLAF during routine ➢ Details are recorded in checklist
circulated air operation which can ➢ Proper tightening of filter is verified after completion.
through impact the air ➢ Any damage to filter is verified Low Yes
RLAF(Contd.) supplied to areas • Return risers of RLAF are cleaned during every change over as per SOP titled” SOP
for Dispensing Booth Filter Cleaning”

• Documentation details during filter cleaning is as follows

➢ Details are recorded in the checklist
➢ Proper tightening of filter is verified after completion.

• All the personnel in production, QA and engineering are trained on the respective
procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 18 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)

• Procedures are available for handling of powder failure

• Dispensing / sampling of material is stopped and intimated to Engineering as per

SOP titled “Intimation, necessary action and documentation in-case of
Breakdown of Machine and Systems”.
There will transfer of
air born particles to • Procedures are defined to evaluate an impact on the processing conditions
Failure to exercise control
the containers in during power failure or RLAF stoppage.
Restart of RLAF during any stoppage of
which materials are R13
during failure RLAF
stored and materials • Assessment of the time needed to return to a clean status once power is switched Low Yes
that are dispensed / Medium ON after power OFF is performed as a part of RLAF qualification and same is
sampled followed routinely in-case of any failure.

• Magnahelic gauge indicates pressure differential outside the acceptance criteria

and same is used for identifying any failure of RLAF.

• All the personnel in production, QA and engineering are trained on the

respective procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 19 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)
• In certain areas High pressure jet machines which are used for cleaning of
There will failure to equipment’s/parts are qualified with respect to assurance of cleaning procedures
Inadequate
clean the equipment Failure to design cleaning
monitoring of
surfaces as per process with respect to • Monitoring devices such as pressure gauges are available for indicating the
process Medium Low Yes
simulation during R14 monitoring of critical pressure during cleaning process.
parameters which
cleaning validation parameters during cleaning
controls cleaning
process
process • The High pressure jet machines are verified for its operation and shall be covered
as a part of routine preventive maintenance.

• Calibration of measuring instruments is performed as per the schedule mentioned

in the SOPs. SOP titled “calibration Policy” discontinue
There will be failure to
clean the equipment
Malfunctioning • The measuring instruments associated with processing equipment’s and areas
surfaces as per
of measuring routinely checked for proper functioning.
simulation during Failure to exercise controls Medium
instruments of
cleaning validation R15 to identify malfunctioning
AHU , RLAF
of measuring instruments • The measuring instruments associated with equipment used for cleaning are Low Yes
and equipment’s checked for its proper functioning prior to start of cleaning process.
There will impact on the
used for cleaning
performance on
AHU/RLAF etc. • There is procedure available for handling any calibration failure or
malfunctioning of measuring instruments which involves evaluation of potential
impact on cross contamination and cleaning validation.
• The difficult to clean parts of equipment has been identified for each equipment
with appropriate justification based on the following
➢ Material of construction of product contact parts
➢ Level of dismantling for cleaning
There will be
➢ Ease of access for cleaning
inadequate cleaning of
➢ Cleaning agent used for equipments cleaning.
surfaces of shared Medium ➢ Check the light intensity. Low Yes
Identification and equipment product Failure to identify difficult
➢ Time taking for cleaning
cleaning of contact parts to clean parts for
➢ Water pressure
difficult to clean R16 confirming cleanliness
➢ Water quantity
locations of Improper cleaning will after product change over
equipment’s result in surface to cleaning
• The difficult to clean parts are verified for visual cleanliness as a part of lines
surface cross
clearance during product change over.
contamination of next
product
• The difficult to clean parts are covered for swab sampling or rinse sample during
cleaning validation/ cleaning verification
Refer SOP.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 20 of 16

7.0 RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)
• Processes such has Fluid Bed Dryer and Coating Machine are having filtration
system with series of filters as follows for air supplied to equipment so to ensure
that contamination is removed
• Failure to design ➢ 20µ & 5µ or 10 µ (As per equipment suppliers design)
adequate filtration system ➢ 3 µ (As per equipment suppliers design)
which supplies filtered ➢ 0.3 µ HEPA
air to equipment that is
There will be
Inadequate coming in direct contact
contamination of • The filters are having gaskets at the sides which provides fitment in filter
control on air with product in-case of
product due to housing thereby preventing passing of unfiltered air equipment.
supplied for R17 following equipment’s Medium Low Yes
improper filtration of
processing of ➢ Fluid Bed Dryer
air supplied to • Qualification has been performed covering parameters which are impacting its
equipment’s ➢ Coating machine
equipment performance of supply air
• Supply of untreated or
• HEPA filter integrity is verified during revalidation as per SOP, SOP titled”
insufficiently filtered air
Qualification of HVAC, LAF, RLAF, APU and Vacuum cleaning System”
to equipment.
• All the personnel in production, QA and engineering are trained on the
respective procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 21 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)
• HEPA filter integrity is verified during revalidation as per SOP titled”
Qualification of HVAC, LAF, RLAF, APU and Vacuum cleaning System”

• Preventive maintenance of filtration system of equipment is performed every

• Damage to filters of month as per SOP titled “SOP for Preventive Maintenance of FBD, and
filtration system for SOP titled “SOP for Preventive Maintenance of Coating machine’ as Per
equipment resulting in Schedules and Its Documentation” which includes verification of pre-filters
supply of untreated or for any damage.
insufficiently filtered
Inadequate control on • Documentation details during preventive maintenance is as follows
air
air supplied for
Contd. R17 • Details are recorded in checklist
processing of
equipment’s(Contd.) • Blockage of filters • Proper tightening of filter is verified after completion.
during routine • Any damage to filter is verified
operation which can
impact the air supplied
Medium Low Yes
to equipment • Documentation details during filter cleaning is as follows
➢ Details are recorded in the checklist
➢ Proper tightening of filter is verified after completion.
➢ Any damage to filter is verified before starting for routine operation.

• All the personnel in production and engineering are trained on the respective
procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 22 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Technical measures - Equipment Design(Contd.)
• Processes such has Fluid Bed Dryer and Coating machine are having HEPA
filters for filtration system of air that is exhausted out from equipments to ensure
• Failure to design adequate that contamination is removed
filtration system for air
that is exhausted out in-
• The filters are having gaskets at the sides which provides proper fitment in filter
case of following Medium housing thereby preventing passing of unfiltered air that is exhausted from
R18 equipment’s Low Yes
equipment.
➢ Fluid Bed Dryer
➢ Coating machine
• HEPA filter integrity is verified during revalidation of once in a year.

• All the personnel in production and engineering are trained on the respective
procedures.
Inadequate There will be • Filter cleaning procedure is in place to clean the filter as per cleaning frequency.
control on air contamination of
that is exhausted environment in which • The differential pressure indicated on the gauge of filter is recorded
out from the the air is exhausted • Damage to HEPA filters
equipment’s out. of filtration system which • Preventive maintenance of filtration system of is performed as per SOP, titled
will exhaust out untreated “SOP for Filter cleaning, Replacement and Destruction of filters” which
or insufficiently filtered includes verification of filters for any damage as per SOP ‘Replacement of Low Yes
air from equipment Medium Filter’.
R19
• Blockage of HEPA filters • Documentation details during preventive maintenance is as follows
of during routine
• Details are recorded in checklist
operation which can
• Proper tightening of filter is verified after completion.
impact the air that is
exhausted out from • Any damage to filter is verified
equipment • Differential pressure is verified before releasing for routine operation.

• All the personnel in production and engineering are trained on the respective
procedures.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 23 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Organizational Measures

• The movement of Manifold, Nozzle filter housing & transfer line (silicon &
SS) within the processing areas is controlled as follows to prevent risks of
cross contamination of others products processed in adjacent areas.
Movement of dirty The contaminant of ➢ The external surfaces of like Manifold, Nozzle filter housing &
mobile equipment’s product from dirty Failure to design procedure transfer line (silicon & SS) are cleaned prior to movement to other
like Manifold, equipment will fall into and routinely follow during areas.
Nozzle filter the corridor during movement of dirty Manifold, ➢ The equipment’s like Manifold, Nozzle filter housing & transfer line Low Yes
R20 Medium
housing & transfer movement. Nozzle, filter housing & (silicon & SS) are transferred in closed condition rapped with poly
line (silicon & SS) transfer line (silicon & SS) beg prior to movement to washing & sterilization area.
within the within the processing areas
The product particles
processing areas. • All the personnel in production, QA are trained on the respective procedures.
fallen could be
conveyed to the
Refer, SOP titled “Cleaning and storage of stainless steel container,
adjacent areas resulting
scoops, mugs and other accessories used in manufacturing.’
in cross contamination
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 24 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk Risk classification measures based on control Acceptability
Potential Impact Risk
identified Failure mode based on risk measures (Yes/No)
number
identified
Organizational Measures (Contd.)
• The movement of cleaned Manifold, Nozzle filter housing & transfer
The air borne
Failure to design line (Located in different rooms) to the processing areas is controlled as
contamination will be
procedure and routinely follows to prevent risks of cross contamination of others products
settled on the surfaces
Movement/ transfer follow during the processed in adjacent areas.
of cleaned equipment’s
of cleaned movement/ transfer of
if not closed.
equipment’s from cleaned mobile ➢ Open parts of equipment’s are covered with poly bags prior to
R21
storage areas to equipment’s Manifold, Medium movement to other areas.
The contaminant settled Low Yes
required Nozzle filter housing &
on the surfaces will
processing areas
result in cross
transfer line (silicon & • All the personnel in production are trained on the respective procedures
SS) from storage areas
contamination of next
product
to the processing areas Refer SOP no., SOP titled “Cleaning and storage of stainless steel
container, scoops, mugs and other accessories used in manufacturing.’
• The wash rooms are designed in such a way that the residue of the
previous product being cleaning from equipment’s and accessories can
be cleaned and removed through a drain provided

• The AHU system is having return risers which allows control of air born
particles release in area from the equipment being cleaned.
The air borne
In adequate controls • The washing is controlled in such a way that cleaned items are prevented
contamination Failure to design
on the equipment for recontamination.
generated in wash area procedure and routinely
that is un cleaned
during cleaning along follow the control in
and cleaned in • The cleaning of wash room is performed to ensure that there is no risk of
with improper R22 wash rooms with
washing area cross-contamination or recontamination.
segregation respect to risk of cross- Medium Low Yes
identification and contamination or
Inadequate design of
protection will results recontamination • The status labels are affixed to equipment’s and accessories for clear
wash area
cross– contamination identification of cleared and cleaned items as per SOP titled ” Status
Labeling”

• The cleaned equipment’s and accessories are transferred to cleaned

controlled area from washing & sterilization room after covering with
polybag.

• All the personnel in production are trained on the respective procedures.

 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 25 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of Risk classification measures based on control Acceptability
Potential Impact Risk
Risk identified Failure mode based on risk measures (Yes/No)
number
identified
Organizational Measures(Contd.)
• The equipment log books are used for documentation and identification for
There will be cross which the equipment was used for processing.
Inadequate contamination of next Failure to identify
identification of product processed on equipment’s / product
Medium • Status labeling is affixed on the movable or fixed equipment/ accessories/ Low Yes
previous product the equipment if R23 contact parts of equipment’s
product contact parts which provide identification for which the equipment was
processed on the identification of for the product for which it
used for processing. to prevent mix up/ cross contamination.
equipment product processed is was used for processing
improper
Refer SOP titled ” Status Labeling”
• Procedure is available for identification and controlling of dedicated
equipment/parts.
Inadequate There will be cross • The equipment log books are used for documentation and identification for
identification of contamination of next Failure to identify dedicated Medium which the equipment was used for processing. Low Yes
dedicated product processed on equipment’s / dedicated
R24
product contact the equipment if product contact parts of • The dedicated equipment/parts are having status label or engraving or marking,
part / dedicated identification is equipment’s so as to prevent accidental use of parts for processing of different product other
equipment’s improper than for which it has been dedicated.

Refer SOP titled ” Status Labeling”

• The status labels are affixed on the polybag or container used for storage of
material/ product to prevent cross-contamination and / or mix-up from the
material/ products having hazards.
Medium Low Yes
Inadequate • The products / materials are handled with precautionary measures such as
identification of There will be mix-up Failure to identify and wearing gloves.
products / of products /materials follow measures for
R25
materials stored due to improper handling of products / • Rack wise product segregate & numbering system are allotted.
in the storage identification material during storage
area • Approved materials are having under the green line with status labeled.
• Under testing material are having under the yellow line with status labeled
• Rejected materials are having under the red line with status labeled.

Refer SOP titled ” Status Labeling”

Failure to control cross • The containers / poly bags are sealed and closed until used for processing.
There will be cross
contamination from the
Contamination of contamination of
surfaces of containers /
products stored product if it is not • The external surfaces of containers / polybag (e.g. after sampling or dispensing
R26 polybag after sampling or Medium
in polybag/ properly sealed to due or unloading of processed product in containers / vessel) are cleaned before
dispensing or unloading of Low Yes
container’s transfer of air borne transfer to storage location for preventing risk from cross-contamination.
processed product in
particles
containers / vessel
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 26 of 16

7.0 RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based on measures based on control Acceptability
Risk identified Failure mode
number risk identified measures (Yes/No)
Organizational Measures(Contd.)
• The scoop used during sampling and dispensing are cleaned as per the
Inadequate There will be respective cleaning procedures.
cleaning of inadequate cleaning
• In-case of certain products dedicated scoops fare used for sampling /
Scoops used in of surfaces of
Failure to control dispensing
sampling and sampling tools/
contamination for Scoop • Scoops used for sampling and dispensing are covered during cleaning
dispensing dispensing tools
used for sampling / validation.
R27
dispensing and sampling
Inadequate Improper cleaning
equipment’s used during • Status labels are affixed on the tools to identify the details of product for
cleaning of will result in surface which it is used. Low Yes
processing Medium
sampling tools to surface cross
used during contamination of next
processing product Refer following SOPs
➢ SOP titled “Cleaning and Storage of Dispensing Equipments”
• There is a requirement to remove spillages observed during processing and
There will be transfer clean area.
of air borne • The personnel involved in clearing the spillage and cleaning of area are
contaminant to air / trained with respect to procedure that needs to be followed for products
surfaces of adjacent along with precautions based on hazards involved with the material/product.
areas such as corridor
• Impact assessment is performed if there is situation of spillages or other Low Yes
and other processing
Spillage of unusual events that could lead to cross-contamination of following in the
areas resulting in
product/ Failure to exercise Medium close vicinity of area where incident occurred
cross contamination
material in Store R28 controls on the spillages ➢ During clearing the spillages material proper covered the face, hand
& Processing during routine operation & other body part to prevent the any hazards.
The personnel in the
Area
processing areas will ➢ Equipment’s/ parts of equipment’ stored
be exposed to the ➢ Containers / polybag of materials/ products stored.
hazards of API due to
Refer following SOPs
air borne particles.
SOP titled “Handling of Spillage in Store ”
SOP titled “Spillage Handling”
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 27 of 16

7.0 RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based on measures based on control Acceptability
Risk identified Failure mode
number risk identified measures (Yes/No)
Organizational Measures(Contd.)
• Only authorized personnel are allowed to enter into the aseptic area.
The personnel in the
processing areas will • The entry and exit to Grade C Area is though a change rooms after Remove
be exposed to the slippers / shoes in Air lock-I and keep them systematically in SS Rack.
hazards of product Enter into the Air lock-II, by pushing the door with elbow. After that
Entry / Exit Failure to follow entry enter in garment room for wearing the cleaned cleaned garment.
due to air borne
procedure to and exit procedure and
Grade C Area
particles.
R29 precautionary measures as • The entry and exit to Aseptic processing areas is though a change rooms
& Aseptic per hazards associated after removing the factory garment & enter to air lock I II & III in sequence.
The air born particles
processing areas with the product Medium • The gowns are disposed for cleaning after exit from processing areas Low Yes
on the gowns will
lead to cross- • Refer following SOPs
contamination
➢ SOP titled “Entry and Exit Procedure in Grade C Area”
➢ SOP titled “Entry and Exit Procedure in Aseptic Area”
Organizational measures - Control through Campaign Manufacture
• The products which requires manufacturing are identified based on
toxicological assessment and PDE value so as to prevent cross contamination
• There is requirement of reducing the contamination of equipment’s in the area
There will be where products having certain hazards are processed through following
inadequate cleaning measures
of surfaces of shared
➢ Removal of equipment from the area that is not required during campaign
equipment through
manufacturing of the product. These equipment’s are transferred with clean
inadequate cleaning
status.
procedures resulting Failure to control
Product change in surface to surface carryover of product ➢ Equipment’s that are not required for production but cannot be removed from
over cleaning cross contamination R30 residues of previous Medium the area are covered. There equipment’s are also re-cleaned during product Low Yes
procedures of next product products based on the change over cleaning.
hazards • The controls are exercised for the movement of ancillary equipment (e.g. IPC
There will be transfer test equipment) and materials between campaigns (of different products).
of air borne • The procedure for campaign change over includes requirement of cleaning of
contaminant to air / product contact equipment, cleaning of non-product surfaces (Such as chairs,
surfaces from fire extinguishers, computer systems of equipment’s, return risers of AHU,
processing areas exterior of equipment, walls, floors etc.

\\
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 28 of 16

7.0 RISK ASSESSMENT(CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based on measures based on control Acceptability
Risk identified Failure mode
number risk identified measures (Yes/No)
Organizational measures - Equipment Cleaning and Inspection Controls
There will be • The cleaning procedures of equipment’s in different areas has been
inadequate cleaning evaluated and covers the requirements of cleaning for all the products
of surfaces of shared currently included in product matrix / equipment matrix that is maintained
equipment through Failure to design cleaning as a part of Cleaning Validation Master Plan. Refer SOP titled “Cleaning
inadequate cleaning R31 procedures based on Validation”
Product change
procedures resulting product requirement Medium • The suitability of cleaning procedures for any new product introduced at site Low Yes
in surface to surface assessed as a part of cleaning validation evaluation as per respective CVMP.
over cleaning
cross contamination
procedures of
of next product.
equipment
Failure to exercise control During product changeover of the product there is coordination cleaning of area
There will be transfer on preventing along with equipment cleaning so as to prevent re-contamination.
of air borne re-contamination if Medium
contaminant to air / R32 cleaning of area is not Low Yes
surfaces from performed in coordination
processing areas with cleaning of
equipment
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 29 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based measures based on control Acceptability
Risk identified Failure mode
number on risk identified measures (Yes/No)
Organizational measures - Equipment Cleaning and Inspection Controls (Contd.)
• Cleaning procedures of equipment’s in different areas has been evaluated
and includes following as a part of routine cleaning procedure which
needs to be followed during product change over cleaning
➢ Cleaning instructions are provided in cleaning procedures so as to
control the hazard level
➢ Cleaning instructions are outlined based on design and complexity of
equipment.
➢ Instructions for dismantling of different parts of equipment for assuring
consistent cleaning process has been defined in the procedures
There will be ➢ Cleaning procedures includes instructions related to,
inadequate cleaning of ❖ Details of hard to clean areas which needs additional
Product change surfaces of shared precautions during cleaning
Failure to design cleaning Low Yes
over cleaning equipment through ❖ Requirement of scrubbing of parts,
procedures of Medium
procedures of inadequate cleaning ❖ Details of LUX intensity of light for visual inspection.
R33 equipment’s covering
equipment procedures resulting in ❖ Details of volume of water
detailed instruction that
(Contd.) surface to surface ❖ Details of pressure of water which needs to applied.
needs to be followed
cross contamination of ❖ Details of cleaning agent which are used for cleaning.
next product ❖ Details of equipments cleaning time.
➢ There is requirement defined for cleaning of equipment within the dirty
hold time established based on dirty equipment hold time study.
➢ There is requirement defined for use of equipment’s within cleaned
hold time established.

• Cleaning procedures of equipment’s includes checklist covering above

requirements. These checklists are used for documentation of cleaning
process.

• The details documented in the checklist are reviewed as a part of line

clearance.
There will be • Procedures are available for cleaning of vacuum transfer system to prevent
inadequate cleaning of such items from being a potential source of contamination. Refer SOP titled
Product change surfaces of shared
Failure to exercise as ‘Operation and Cleaning of Vacuum Cleaner.
over cleaning accessories through
control contamination
procedures of inadequate cleaning Low Yes
R34 from Vacuum cleaning
vacuum transfer procedures of vacuum Medium
system used during
system cleaning system
cleaning
resulting cross
contamination of next
product
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 30 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk
Description of
Potential Impact Risk Risk classification based measures based on control Acceptability
Risk identified Failure mode
number on risk identified measures (Yes/No)
Organizational measures - Equipment Cleaning and Inspection Controls (Contd.)

Adequate justification is provided for selection of closed process

equipment and transfer pipelines as a part of sampling for testing of left
There will be over carryover from product residue during cleaning validation where
Product change inadequate cleaning of Failure to design a Medium visual inspection is not possible.
Low Yes
over cleaning surfaces of shared procedure for assuring • In-case of certain closed process equipment and transfer pipelines where
procedures of equipment through cleanliness of closed visual inspection is not conducted, there is a requirement defined for
closed equipment inadequate cleaning R35 process equipment and witnessing the cleaning. Equipment
and transfer procedures resulting in transfer pipelines where
• After cleaning of closed process equipment & transfer pipeline where
pipelines surface to surface cross visual inspection is not
cleaning is not verified by visually. Cleaning can be justified by rinse
contamination of next possible
sampling.
product
• Refer following SOPs
SOP titled “Procedure for Sampling of Rinse Water / Swab”
• Cleaning procedures of equipment’s in different areas has been
evaluated and includes following visual inspection requirements as a
part of routine procedure which needs to be followed during line
clearance of product change over.
➢ There is requirement for verification of cleanliness of equipment though
visual inspection
➢ Visual inspection process defines requirement of inspection of difficult
There will be failure to to clean product contact parts to assure detection of potential
identify left over contaminants
Line clearance Failure to design a line
residues of previous ➢ In-case of certain equipment’s there is requirement of visual inspection
procedure during clearance procedure for
product resulting in R36
product change equipment’s during product of parts after cleaning and before reassembly
surface to surface cross
over cleaning
contamination of next
change over cleaning ➢ There is procedural requirement of use of SS mirror and/or torch to help
product for detection of residues on cleaned surfaces by visual inspection
• The final visual inspection is independently performed by QA personnel
Medium as a part of line clearance during product change over cleaning. Low Yes
• During line clearance procedure any potential cross-
contamination sources are identified prior to release of equipment
• The personnel who perform the visual inspection are involved during
cleaning validation and are trained by senior personnel through On Job
training for assuring inspection in a consistent manner.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 31 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based measures based on control Acceptability
Risk identified Failure mode
number on risk identified measures (Yes/No)
Organizational measures - Equipment Cleaning and Inspection Controls (Contd.)
• The personnel who conducts visual inspection are also trained on the
requirements defined in SOP
Refer following SOPs
SOP titled “Procedure for Qualification of Visual Inspector
Line clearance Failure to design a line
procedure during clearance procedure for Medium Low Yes
• There is requirement for verify results of residual testing prior to release
product change Contd. R37 equipment’s during product of equipment for next product after cleaning of equipment.
over cleaning change over
(Contd.) cleaning(Contd.) Refer following SOPs
SOP titled “Procedure for Sampling of Rinse Water / Swab”

• There is a requirement to investigate the failure results for swab/rinse

sample obtained during residual testing.
Organizational measures - Cleaning Validation and Cleaning Verification
• The products handled at site are identified for cleaning validation based
on following
➢ Evaluation of toxicological assessment and PDE value
➢ Product characteristics such as solubility, lowest therapeutic
There will be dose and difficult to clean nature of product -
inadequate cleaning of
Failure to exercise controls
surfaces of shared • Identification of worst case product for cleaning is covered as a part of
related to cleaning validation
equipment through Cleaning Validation Master Plan and document title “Strategy for
Assurance of and verification of
inadequate cleaning
cleaning R38 equipment’s so as to prevent Managing Risks associated with Cross Contamination of Products in
procedures resulting in Shared Manufacturing Facility”.
procedures cross-contamination from
surface to surface cross Medium
the material/ products having
contamination of next
certain hazards • Product matrix and equipment matrix are maintained at site which Low Yes
product
indicates worst case product for cleaning validation.

• Certain products having hazards which needs controls has been

identified and cleaning verification is performed during every product
changeover.
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 32 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based on measures based on control Acceptability
Risk identified Failure mode
number risk identified measures (Yes/No)
Organizational measures - Cleaning Validation and Cleaning Verification(Contd.)
• The MACO limits for the carryover of product residues are calculated
based on PDE value, dose criteria & also visual inspection. The least
value is considered for cleaning validation.

• The swab and rinse sampling techniques are used for assurance of
cleaning to an established MACO level.

• In certain equipment where visual inspection of equipment or certain

parts of equipment (e.g. closed systems or pipeline) is not possible, then
rinse sampling technique is for assuring cleanliness.

• The number and location (Such as difficult to clean locations) for swab
samples during cleaning validation/ cleaning verification are identified
based on evaluation of equipment design and hazard level of product,

• The cleaning processes of all the equipment’s are covered during

cleaning validation so as to demonstrate that the cleaning process can be Low Yes
Assurance of
cleaning Contd. R38 Contd. consistently followed by personnel. In certain cases, equipment’s are
Medium grouped together based on identical design, cleaning procedures etc.
procedures

• The cleaning procedures of equipment include checks covering all

variables and opportunities that will represent the failure of manual
cleaning.

• Certain products identified as worst case based on evaluation of product

characteristics as considered for periodic verification at a frequency of
every three years.

• There is procedure available for verification of equipment surfaces

routinely, for ease of cleaning or any wear and tear after repeated use
over a time since its installation and its potential impact on the validated
cleaning procedures

Refer Cleaning Validation Master Plan of respective areas and SOP

titled “Cleaning Validation”
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 33 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based measures based on control Acceptability
Risk identified Failure mode
number on risk identified measures (Yes/No)
Organizational measures - Cleaning Validation and Cleaning Verification(Contd.)
• The changes to any cleaning processes are evaluated through change
control along with its impact on cleaning validation/verification.
• The following changes are considered for evaluation of impact on
There will be impact cleaning validation
on validated cleaning ➢ Introduction of new product
procedures resulting in ➢ Change in formulation of existing product
Changes to inadequate cleaning of ➢ Introduction of new equipment in the train
Failure to exercise controls Medium ➢ Shift of product to another equipment train Low Yes
validated surfaces of shared
R39 on changes to validated ➢ Modification of product contact parts of equipment
cleaning equipment and thus
procedures ➢ Revision of cleaning procedure
procedures resulting in surface to
surface cross • Revision in minimum batch size and maximum daily dose of next
contamination of next product which impact the MACO value of worst case product.
product AMV to be updated according to MACO value, If required.

Refer Cleaning Validation Master Plan of respective areas and SOP

titled “Cleaning Validation”
• There is procedural requirement of initiating deviation to record failures
Failure to identify observed during cleaning with respect to following:
Deviations procedures which can lead to ➢ Any defined cleaning instructions in procedure that has failed to
observed during There will be repeated potential failures or that render the equipment clean
routine cleaning, failures resulting in needs improvement based on Medium ➢ Any equipment or its product contact part is found to be not
R40 cleaned during visual inspection by the independent person. Low Yes
line clearance cross contamination of review of deviations
and cleaning next products observed during routine • Failure in results for swab/rinse sample
validation cleaning, line clearance and
cleaning validation Refer SOP No. Cleaning Validation Master Plan of respective areas and
SOP titled “Cleaning Validation”
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 34 of 16

7.0RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based measures based on control Acceptability
Risk identified Failure mode
number on risk identified measures (Yes/No)
Organizational measures - Cleaning Validation and Cleaning Verification(Contd.)
Inadequate
There will be failure to • The personnel involved in collection of swab samples are trained in
training to accordance with the procedure defined in cleaning validation protocol
collect the samples as
personnel Failure to provide training and details are documented in respective protocols.
per the validated
involved in to personnel involved in Medium Low Yes
procedures there by R41
sampling of sampling of cleaning
resulting in cross
product contact validation
contamination of next
parts of
products
equipment
• Analytical method validation is performed with respect to identification
of Limit of Detection (LOD) and Limit of Quantification (LOQ) so that
There will be failure to method can quantify the residue that is established with accuracy and
estimate left over precision.
residues from the Failure to demonstrate
Analytical swab/ rinse samples accuracy and precision of • Recover of residue from the product contact parts of equipment’s is
procedures used with accuracy and analytical procedures used Medium performed for all the MOC’s through use of swab and rinse sampling Low Yes
R42 technique.
testing of precision. for testing of samples
samples collected for assurance of
This will result in cleaning. • The results of testing are calculated taking into account of recovery
cross contamination of value obtained during analytical method validation.
next products
Refer Cleaning Validation Master Plan of respective area Analytical
Method Validation/ Verification
Organizational measures - Personnel involved during processing
There will be • All the personnel (New recruit and existing) are provided training on the
non-uniformity and no new procedures or retrained on the revised procedures related to
reproducibility in cleaning and processing of products.
following the
procedures related to
Failure to follow the • The operating personnel are communicated about the precautions related
Inadequate cleaning and to gowning or respirators to be used during handling of any APIs that
defined procedures during
training of processing of products R43 Medium involves certain hazards. Low Yes
cleaning and processing
personnel during routine
during routine operation
operation.

This will result in

cross contamination of
next products
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 35 of 16

7.0 RISK ASSESSMENT (CONTD.):

Risk Analysis and Evaluation Current control Risk classification Risk

Description of
Potential Impact Risk Risk classification based measures based on control Acceptability
Risk identified Failure mode
number on risk identified measures (Yes/No)
Organizational measures - Personnel involved during processing (Contd.)
There will be no • The routine operations (Processing and Cleaning) performed by
identification and operating personnel is supervised by Production Supervisor to ensure
assurance that that the personnel follow the procedures defined along with their
operation personnel behaviours
Inadequate Failure to follow the
always follow the Medium
supervision of defined procedures during
processes and
procedures related to R44
cleaning and processing • There is also oversight from In-process Quality Assurance Personnel Low Yes
cleaning and (IPQA) in processing areas
procedures during routine operation
processing of products
during routine
operation.

• There is procedure available for Entry and Exit in manufacturing areas

There will safety for all personnel though change rooms and following the clothing
hazard to personnel requirements adequate to prevent cross-contamination.
operating in processing Low Yes
Entry and Exit in areas Failure to follow the Medium • Precautions are followed by personnel after existing from processing
manufacturing R45 defined procedures, areas to prevent cross contamination from gowning to other areas.
areas There will be surface movement and behaviours
to surface transfer of
• There are controls on movement of personnel (Production personnel and
particles from
Support personnel such as QA,, QC, maintenance, engineers and
personnel gowning
contractors) between different processing areas
 QUALITY RISK MANAGEMENT OF STRATEGY
FOR
MANAGING RISK ASSOCIATED WITH CROSS CONTAMINATION OF PRODUCT IN SHARED MANUFACTURING FACILITY PAGE No.: 36 of 16

8.0 SUMMARY AND CONCLUSION:

Based on the above risk assessment carried out it can be summarised that all the control measures are available preventing the risks of cross contamination from the identified risks.

During the QRM assessment following additional control measures have been identified for up gradation of procedures To verify the pressure differential across HEPA Filter of FBD and Coating Inlet.

a. Inclusion of requirements for following points in respective

• Scale of CIP tank should be marked
• Risers should be fitted properly with the duct, all bolt of riser duct should be tight.
• Cleaning check list to be incorporate in all SOP of equipment cleaning
• Product should be manufactured/ packed in a closed system, required to cover the packing and compression machine for implementation

Thus based on the above risk assessment and associated measures identified there is low risk with respect to contamination and cross contamination.