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Miranda - Risk Assessment For Routine Monitoring Frequency PDF
Miranda - Risk Assessment For Routine Monitoring Frequency PDF
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.
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.
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.
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.
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.
(B) Complex Equipment Design No changes to existing system design or introduction of new complex equipment design. NA NA
Impact Factor
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”
(C) Historical data of cleaning 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
failure 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