1.

PURPOSE
The purpose of this document is to perform a high-level risk evaluation of the cleaning
processes’ impact on product quality in order to determine the frequency of routine
cleaning monitoring for the manufacturing equipment. The output of this assessment (i.e.
routine monitoring frequency) will be included in 242192, Cleaning Validation Inventory
List (Appendix 1 for 242191). Application of this Risk Assessment process will
contribute to a sustained focus on product quality throughout the product and process
lifecycle.

A review of this assessment should be performed at least once every 12 months (tracked
through work order in Maximo), and revisions should be made whenever there is a
change to a risk factor of any system within the scope of this document, or when new
systems come in place. During this review, a query of deviations (DR) and an
assessment of all DRs impacting cleaning validation will be performed to assess any
cleaning failures and determine any effect in the risk score for the monitoring frequency
impacted by section 3.4.3, Impact Factor C of this Risk Assessment.

2. SCOPE
This risk assessment applies to all product-contacting equipment used in GMP
manufacturing of immunodiagnostic products on the Emeryville site. For a complete list
of validated systems for cleaning process, refer to Document 242192. These systems have
been grouped in cleaning families based on the similarities of cleaning method and use in
the manufacturing process. Throughout this document, the terms “system” and
“equipment” are used interchangeably. QC labware, cleaned in Technical Services has
been identified as being within the scope of VMP 242191, Validation Master Plan:
Cleaning Process Validation. However, this labware is not used for manufacturing
processes, and are only used for QC raw material testing and QC product testing. The
QC methods are validated and have assay acceptance criteria and/or system suitability
criteria as assay controls. Therefore, since the use of this labware is not for
manufacturing product and there are assay controls in place, they will be removed from
the scope of VMP 242191 and from this assessment. This assessment is performed for
each manufacturing equipment family described below:

 CEPA Centrifuges
 Disk-Stack Centrifuges
 Dynomills
 Fermenters
 Holding Tanks
  Upstream UF Systems
 14 cm Column (CO-0321)
 Process Lines
 Pressure Cans and Misc. Fittings
 Tri-Flo Pumps
 Bulk Fill Process Vessels
 Filling Nozzles
 Labware Cleaned in Glasswashers
 Manually Cleaned Labware
 Impellers and Tube-end Weights
 Omni-mixer Blades
 Sonicators
 UV Monitoring Flow Cells (UVis-920)
 Fraction Collector Racks
 Stirred Concentrators
 AKTA chromatography systems
 Filtration Parts

3. DESCRIPTION OF PROCESS
This risk assessment consists of the evaluation of potential cleaning failures based on
different risk factors, and its potential impact to product quality associated with exposure
to those potential failures. This risk assessment process focuses on different risk factors:

 Cleaning Method
 Usability of Equipment (Usability Factor)
 Manufacturing Process Stage
 Impact Factor
3.1. Cleaning Method
This risk factor evaluates the risk associated with the type of cleaning that is applied to
product-contacting equipment. There are three (3) cleaning methods that have been
evaluated for cleaning failure risk: manual, semi-automated, and automated. Refer to
Table 1.
 Table 1: Score Assessment for Cleaning Method Risk Factor
Cleaning
Risk Evaluation Score
Method
Cleaning process that involves human action of hand-scrubbing and
hand-rinsing a surface area to remove of residues and contaminants.
Manual cleaning can also involve disassembly and re-assembly of the
parts of equipment to be cleaned in order to clean, and to reassemble
Manual the parts that were cleaned. Due to the reasons described above, 3
manual cleaning may result in operator to operator variability for a
given action. With manual procedures one must rely on the operator
skill and through performance training of the operator is necessary to
reduce variability in performance.
Cleaning process that includes both manual and automated cleaning
Semi- steps (see definitions for “Manual” and “Automated”) that together
2
Automated will remove residues and contaminants. Variability may occur during
the manual steps due to reasons described above.
Cleaning process that is supported by a system that can be
programmed to produce repeatable steps (e.g. pump setup with a
defined flow rate, automated CIP system, etc.). The operator does not
Automated directly contact the product contact surfaces in order to clean the 1
system. Automated cleaning may include manual steps like
connecting process lines, hoses, and pumps to the system being
cleaned.

3.2. Usability of Equipment (Usability Factor)

Some manufacturing systems can be used for the production of more than one product,
while others are dedicated to one specific product. Equipment that is shared between
different products has a higher risk of product carry over causing cross-contamination.
See Table 2 for scoring evaluation between shared and dedicated equipment.

Table 2: Score Assessment for Usability of Equipment Risk Factor

Usability Factor Risk Evaluation Score
Equipment that can be used with different products. Product quality
Shared 2
may be impacted with potential product carryover.
Dedicated Equipment that is intended to be used with only one product. 1

3.3. Manufacturing Process Stage

The step at which equipment is used in the manufacturing process has an impact on the
risk to product quality. Product manufactured with equipment used during upstream
stage of manufacturing process will undergo additional processing steps designed to
selectively purify and recover the target protein while removing impurities. These steps
include detection and in-process controls that minimize the risk of product quality impact
(See table 3). Recombinant antigens that are manufactured using E. coli and Yeast
fermentation methods (upstream stage), are provided to our customers as non-sterile,
non-parenteral, non-human use, critical bulk raw materials for further processing. After
processing, the proteins are coated into microtiter plates, micro beads, or other
proprietary processes by our customers for their in vitro Inmuno Diagnostic test kits.
These kits are tested and released per their specifications and are routinely used for the
screening of blood donations for HCV, HBV, and HIV. For scoring rationale on the
process stage factors, refer to Table 3.

Table 3: Score Assessment for Process Stage Risk Factor

Process Stage Risk Evaluation Score
Equipment that supports the isolation and filling of product. This
Downstream process occurs after fermentation and starts with the first 2
chromatography step.
Equipment that is part of the entire process from early cell isolation
and cultivation, through cell expansion until final harvest (termination
of the culture and collection of the live cell batch). This process
usually occurs prior to the first chromatography step. The purification
processes for all antigens are designed to selectively enrich the target
Upstream 1
protein while removing the host cell impurities. Therefore, any
residual host cell proteins that could potentially get transferred to
another batch would be removed through the purification process. For
recombinant antigens manufactured using E. coli and Yeast, testing
controls are performed by our customers before use.

3.4. Impact Factor

There are different factors that can influence the probability of having an ineffective
cleaning. Each factor that could potentially impact the cleanability of a system is scored
as two (2) to acknowledge that there is potential risk. A score of two (2) is used to
provide better differentiation of risk based on scoring. Each cleaning equipment family is
scored by the sum of these impact factors. If it is determined that there is no risk for a
determined impact factor, then such factor will not be considered for the sum of the
applicable factors. Refer to Table 4 for a list of factors that are considered to potentially
impact the cleaning process of a system.

3.4.1. Equipment Requires Disassembly for cleaning

Equipment disassembly can increase the cleaning surface area and cleaning
extensiveness. There is a higher risk of cleaning failure when there are more
surfaces to clean, more steps to perform, and more parts to handle.
3.4.2. Complex Equipment Design
Systems with complex designs usually have areas that are difficult to reach for
cleaning. Additionally, complex equipment can have components or areas that
are difficult to handle during cleaning due to their form, material, weight,
function, or location within the system.
3.4.3. Historical Data of Cleaning Failure
Historical data of cleaning failure is identified by performing a query of closed
DRs associated with cleaning failures. These cleaning failures are assessed to
determine impact in routine monitoring frequency scoring. The assessment is
performed by evaluating the DR root-cause and its impact to validation. The
assessment is documented in Section 5 of this risk assessment document. A DR
assessment must be performed every year to determine if new cleaning failures
will impact the cleaning monitoring frequency or sampling method of system in
the scope of this risk assessment document. If during a year time frame there
were no cleaning failures observed for a determined piece of equipment or
system, the risk score should be blank (none applicable). If there was one (1) or
more cleaning failures observed the risk score should be two (2). The DR query
time frame must start from the last date of the previous query performed and
must be documented in this section.
DR query is performed per SOP 400349, Managing Deviations and CAPAs in
SAP.
Note: A DR assessment was performed to obtain historical data of cleaning
failure for all systems from their initial cleaning development/validation until
31AUG15 during initial implementation of routine monitoring frequency per
this risk assessment.
3.4.4. Complex or Extensive Cleaning Procedure
The amount of time and number of steps that a cleaning procedure takes to
complete can increase the probability of ineffective cleaning. This factor refers
to the complexity of a cleaning process. There are more chances for error during
an extensive and complex procedure.
3.4.5. Detection of Product Residue via Visual Inspection
For shared manufacturing equipment, the potential protein carry over limit to a
subsequent batch has been established as 50, 5, and 2μg/in2 for Upstream,
Downstream, and shared labware, respectively. Refer to document 400746,
Evaluation of BCA Swab Limits for Shared Equipment.
The detection of the potential protein carry over is made by using either the
surface swab method or the visual inspection method. The surface swab method
is validated to detect as low as 2µg/in2 per 402229, Validation Report for Test
Method 402051, BCA Assay for Detecting Residual Protein during Cleaning
Validation. The personnel visual inspection method is qualified to detect a
standard value of protein residue 5μg/in2 per SOP 218774, Visual Inspection
Qualification and Performing Visual Inspection of Product Contact Surfaces.
 Thus, the risk of detecting surface residues below 5μg/in2 in Labware is higher
in upstream and downstream equipment.

Table 4: Score for each Cleaning Impact Factor

Impact Factor Score

A Equipment requires disassembly for cleaning 2
B Complex equipment design 2
C Historical data of cleaning failure 2
D Complex or extensive cleaning procedure 2
E Detection of Product Residue via Visual Inspection 2

3.5. Risk Levels and Sampling Monitoring Frequency

Risk levels are the result of a combination of different risk factors based on the
multiplication of a predetermined score for each factor. There are three different risk
levels that determine cleaning monitoring frequency: low, medium, and high. Each level
defines a sampling monitoring frequency. See table 5 for the score ranges that assign the
routine monitoring frequency of each risk level.

Monitoring in Table 5 is determined based on different risk factors of the cleaning

processes’ impact on product quality with input from cross functional team members.
Change to the current risk ranking and frequency requires a formal re-assessment of the
risk factors and scoring methodology. In some instance, temporary increase to
monitoring frequency of a specific cleaning process may be occur when triggered by a
quality system such as a DR or CAPA. For example, increase in frequency may apply to
an aging system to allow more detectability of equipment issues related to wear or tear.
Such exception in frequency increase needs to be justified in Table 6.

Within each equipment family defined in Table 6 (Risk Scoring and Sampling
Monitoring Results), the sampling for each independent system will be scheduled
following manufacturing operations. Monitoring frequency will be dependent and applied
if manufacturing operations schedules allows such frequency. In the case a system is used
with less frequency than assigned in this risk assessment, monitoring for such system will
take place within the closest time frame available. If a specific system is not used in
operations within the frequency time scheduled, a justification should be documented in
the routine monitoring program summary report.

Routine monitoring will be scheduled in the Cleaning Validation Inventory List 242192.
Monitoring sampling should not occur within a timeframe of 6 months with each other
for the same system (e.g. a system sampled for cleaning monitoring in October of
calendar year 2016 cannot be monitored again in February of year 2017, but after April of
2017). See table 6 for routine monitoring frequency for each equipment family.
There are two types of sampling sets that will be taken depending on the risk level
assigned for each system: rinse samples and BCA swab samples.

Rinse samples will be collected per SOP 218773, Procedure for Collecting Rinse Water
Samples to Support Cleaning Validations or Verifications; and BCA swab samples (total
protein assay) will be collected per SOP 239935, Validation Surface Swabbing
Procedure. Swab sample locations are determined per the cleaning validation protocol of
the system being monitored. Samples will be tested as follows-BCA Rinse and BCA
Swabs (Test Method, 402051 BCA Assay for Detecting Residual Protein during Cleaning
Validation) Bioburden (SOP 217087, Bioburden Testing by Membrane Filtration
Method), and Conductivity SOP 222229, Conductivity Testing for Cleaning Validation
Rinse Samples). Additionally to each sample set, visual inspection will be performed by
qualified personnel per SOP 218774, Visual Inspection Qualification and Performing
Visual Inspection of Product Contact Surfaces. Per Cleaning Validation Report 400746,
Evaluation of BCA swab Limits for Shared Equipment, Visual Inspection will support
the detection of product residue of at least 5µg/in2 of protein. Swab limit for upstream
equipment is ≤50µg/in2, ≤5µg/in2 for downstream equipment, and ≤2µg/in2 for labware.

Table 5: Risk Levels and Sampling Monitoring Frequency

Frequency (in years)

Rinse and Swab
Rinse Samples and
Risk Priority Samples, and Visual Risk Levels
Visual Inspection
Inspection
1
2
3
1 N/A Low
4
6
8
12
16
18 1 2 Medium
24
32
36
48
64 0.5 1 High
72
96
4. RESPONSIBILITIES
The following responsibilities are in addition to the ones stated in VMP 242191:
4.1 Cleaning Validation
 Serve as subject matter expert (SME) for cleaning validation procedures and
facilitates risk assessment analysis.
 Reviews the risk assessment at least once every year and revise whenever
there is a change to any risk factor or equipment family.
 Updates the Cleaning Validation Inventory List based on the frequency
assigned to each system in this risk assessment.
4.2 Manufacturing
 Supports cleaning validation risk assessment for routine monitoring by
communicating production schedule updates.
 Supports the risk assessment effort when there is a change to any risk factor
or equipment family.
4.3 Quality Assurance
 Approves the Monitoring Frequency Risk Assessment and supports
necessary revisions assessment.
 Table 6: Risk Scoring and Sampling Monitoring Results

Cleaning Usability Process Monitoring Frequency

Impact Factor Risk Priority
Method Factor Stage (in years)
System Families
for Cleaning Rinse Rinse and Comments
Total (IF)
Validation Sample Swab
(CM) (1- (UF) (1- (2-8) (PS) (1- (CMxUFxIF
A B C D E and Sample,
3) 2) (A+B+C+D 2) xPS)
Visual and Visual
+E)
Inspection Inspection
DR #200012652. Frequency has
been temporarily increased to
1/4 1/4 quarterly [year 2018 monitoring
CEPA Centrifuges 3 2 2 2 2 6 1 36
(quarterly) (quarterly) period] per DR CAPA
#000200013092 instead of 0.5/1
year per Table 5.
Disc-Stack Centrifuges 2 2 2 2 2 6 1 24 1 2
No DR for year 2017 as such Impact
Factor ‘C’ updated from ‘2’ to
Dynomills 3 2 2 2 4 1 24 1 2 ‘blank’. Risk Priority changed from
‘36’ to ‘24’ as well as monitoring
frequency from 0.5 / 1 to 2.
Fermenters 2 2 2 2 2 6 1 32 1 2
1The system is cleaned with a shared
Holding Tanks 2 2 1 4 1 21 CIP skid that is also used with disc-
stack centrifuge and fermenters.
Upstream UF Systems 2 2 2 2 2 6 1 24 1 2
14 cm Column
2 1 2 2 2 8 1 0
(CO-0321)
1The system is cleaned with a shared
Process Lines 2 2 1 4 1 21 CIP skid that is also used with disc-
stack centrifuge and fermenters.
Pressure Cans
3 2 2 2 1 12 1 2
and Misc. Fittings
1The system is cleaned with a shared
Tri-Flo Pumps 3 2 2 2 1 12 1 21 CIP skid that is also used with disc-
stack centrifuge and fermenters.
 Table 6: Risk Scoring and Sampling Monitoring Results

Cleaning Usability Process Monitoring Frequency

Impact Factor Risk Priority
Method Factor Stage (in years)
System Families
for Cleaning Rinse Rinse and Comments
Total (IF)
Validation Sample Swab
(CM) (1- (UF) (1- (2-8) (PS) (1- (CMxUFxIF
A B C D E and Sample,
3) 2) (A+B+C+D 2) xPS)
Visual and Visual
+E)
Inspection Inspection
1No
Bulk Fill Process swabs and BCA rinse are
3 1 2 2 2 12 1 01
Vessels necessary for dedicated equipment.
Filling Nozzles 2 1 2 2 2 8 1 0
Labware Cleaned
1 2 2 2 2 6 2 24 1 2 DR 200012106
in Glasswashers
Manually Cleaned
3 2 2 2 4 2 44 0.5 1 DR 200011530
Labware
1This is a shared system; however, it
is used only with buffer solutions
Impellers and Tube-
3 11 N/A 2 6 1 0 and is considered with same risk
end Weights
level as dedicated equipment.

Omni-mixer Blades 3 2 2 2 1 12 1 2
1No swabs and BCA rinse are
Sonicators 3 1 2 6 1 01
necessary for dedicated equipment.
UV Monitoring Flow
2 1 2 2 2 8 1 0
Cells
Fraction Collector
3 1 N/A 2 6 1 0
Racks
1No swabs and BCA rinse are
Stirred Concentrators 3 1 2 2 2 12 1 01
necessary for dedicated equipment.
AKTA 1 2 2 2 2 8 1 0
1No swabs and BCA rinse are
Filtration Parts 3 1 2 2 2 12 1 01
necessary for dedicated equipment.
 5. PERIODIC REVIEW OF RISK ASSESSMENT
The table below documents periodic reviews of this risk assessment document to determine potential impact to
Routine Monitoring frequency by assessing each Risk Factor for every piece of equipment under the scope of this
document, listed in Table 6.
Also, per section 3.4.3, if during the review time frame there were no cleaning failures observed for the piece of
equipment or system then the risk score has to be updated to “blank” (none applicable). Impact Factor C
(historical data of cleaning failure) for Dynomills has been updated to blank which has impacted the Risk Priority
from High ‘36’ to Medium ‘24’ as well as monitoring frequency from every 0.5 (rinse/visual) and 1 year
(rinse/visual/swab) to every 1 and 2 years, respectively.

Table 7: Periodic Review of Risk Assessment Document

Assessment Year: August 2016– December 2017
Maximo Work Order #773430
Risk Factors Impact to Risk Scoring
Assessment Result and Monitoring Result Rational
(Yes/No/NA)
No change to Cleaning Methods of systems. Cleaning Methods type remains manual,
Cleaning Method NA NA
automated, or semi-automated for the systems.
No change to Usability Factor of systems in the scope of this risk assessment. Systems remain
Usability Factor NA NA
in use either for the production of more than one product or dedicated to one specific product.
(A) Equipment Requires No change to equipment requiring disassembly for cleaning. No NA
Disassembly for Cleaning

(B) Complex Equipment Design No changes to existing system design or introduction of new complex equipment design. NA NA
Impact Factor

(C) Historical data of cleaning
failure
DR 200011530 [13Feb17] due to swab limit failure of Labware item 8x8” Pyrex swab during
Routine Cleaning Monitoring. The result obtained was 2.5 µg/swab and the Acceptance
Criterion is ≤ 2 µg/swab. DR investigation was not able to determine the root cause of the OOS As a result of this DR, score for Impact factor
(Out Of Specification). Thirteen (13) swab samples taken on the same day from other “C” has been updated from blank to “2”
representative worst case labware item swab sites had a swab reading of < 2.0 µg/swab and the according to Table 4 in this document. Change
No
one swab that failed exceeded the acceptance criteria only by 0.5 µg. The post-cleaning swab to Impact Factor “C” has not impacted the
sampling portion of the routine monitoring was repeated and swab samples met the acceptance overall Risk Priority therefore the monitoring
criteria of ≤ 2 µg/swab Based on the deviation conclusion and cleaning re-execution results, the frequency will remain the same.
manual cleaning procedure for the labware remains in a validated state and no impact to
cleaning validation.
 Table 7: Periodic Review of Risk Assessment Document, continued
Assessment Year: August 2016– December2017
Maximo Work Order #773430
Risk Factors Impact to Risk Scoring
Assessment Result and Monitoring Result Rational
(Yes/No/NA)
As a result of this DR, score for Impact factor
“C” has been updated from blank to “2”
DR 200012106 [22May17] due to Bioburden failure of Rack 1009 used for Glasswasher GW-
according to Table 4 in this document. Change
0027 and GW-0028. The root cause could not be determined. The failure deemed to pose a No
to Impact Factor “C” has not impacted the
low risk to impacted manufacturing departments.
overall Risk Priority therefore the monitoring
frequency will remain the same.
As a result of this DR, score for Impact factor
“C” has been updated from blank to “2”
Impact Factor

DR 200012652 [07Aug17] due to Bioburden failure of Westfalia SA-1 Centrifuge (CT-0034)

according to Table 4 in this document.
during Routine Cleaning Monitoring. The final rinse sample exceeded the bioburden acceptance
Although, the new Risk Priority calculation of
criterion. The result was 152 CFU/mL and the acceptance criterion is <100 CFU/mL.
24 remains “medium” (refer to table 5 in this
Equipment was deemed to be the probable cause due to expected wear and tear. Surface finish
Yes document) which therefore does not impact the
conditions and the solid chute gap have an impact on cleanability of CT-0034. CT-0034 repairs
current Monitoring Frequency per the DR
or replacement of parts due to observed surface finish and chute issues were completed per
CAPA #000200013092 the frequency has been
work orders WO994367, WO994364 and WO1034528. DR CAPA #000200013092 The
temporally updated to quarterly for the year of
increase in frequency will allow more detectability of equipment issues related to wear or tear.
2018.

(D) Complex or Extensive

No modification the complexity of a cleaning process of existing systems. NA NA
Cleaning Procedure
(E) Detection of Product Residue
No change to existing swab limits of manufacturing equipment. NA NA
via Visual Inspection
No change to the equipment used in the manufacturing process stage. Equipment use remains
Manufacturing Process Stage NA NA
in either Upstream or Downstream.