Maintaining Good Cleaning Maintaining Good Cleaning
Practices Practices
Kathleen Kendrick
Validation Technology Manager
NEPDA Meeting on PDA TR29
November 12, 2008
http://pdachapters.org/newengland
The Cleaning Program Life Cycle
Validation
Cleaning Program Lifecycle
Design
Development
Commissioning
Operations
MaintenanceValidation
Cleaning Program Lifecycle
Design
Development
Commissioning
Operations
Maintenance
Cleaning Regulations
n FDA CFR Title 21 parts 210 and 211
n EMEA Annex 15
n EMEA Annex 18
n “ (a) Equipment and utensils shall be cleaned, maintained, and, as
appropriate for the nature of the drug, sanitized and/or sterilized
at appropriate intervals to prevent malfunctions or contamination
that would alter the safety, identity, strength, quality, or purity of
the drug product beyond the official or other established
requirements. (b) Protection of the clean equipment from
contamination before use.” 21CFR Part 211.67
Major Elements to Maintaining the Cleaning
Process
n Compliance with Standard Operating Procedures (SOP)
�Visual inspection of internal equipment surfaces prior to use
�Conductivity verification
n Maintenance Program for Equipment
�Preventative Maintenance Program (PM)
�General upkeep of equipment
n A Cleaning Monitoring Program
�Sampling
�Critical parameters
n A Revalidation Program
�Some or all elements of the original validation
n A Revalidation Assessment Program
�Assessment of equipment to verify it is still in a validated state
Standard Operating Procedures
n Effective Training of Operators
�The SOPs must be robust and ensure that equipment is used in the
manner it was validated.
�Operators must comply and perform the cleaning procedures as validated
�Eye exams
�Verification of training at a specified time increment
�Competency training to ensure operators understand the importance of
maintaining the validated state
Visual Inspection
n Visual inspection can allow detection of gross
contamination concentrated in small areas that could
otherwise go undetected by sampling and/or analysis.
�EU Guidelines to GMP Volume 4
n No residue to be visible on the equipment after
cleaning procedures are performed
�Spiking studies to demonstrate level of visibility
�Visual inspections conducted per SOP
�Basically is it clean or not
Cleaning Process Record Keeping
n Records must be kept showing the equipment
numbers, the date of cleaning, who cleaned it and who
inspected/tested it.
n Operators are Important
�They verify that it passes other analytical testing such as conductivity
�They verify the equipment is visually clean
�They should be the ones to notice a change in the internal surfaces.
�They can recommend changes to the procedure
�They have the most contact with the equipment
Failure Example
n Failure to clean and maintain equipment and utensils
used in the production of drug products in order to
prevent contamination [21 CFR § 211.67(a)].
n For example, deteriorating equipment was observed,
including: tape flaking off filling equipment directly
above an uncovered hopper containing product to be
filled, a leaking gasket in the product transfer line
during filling, and two leaks in the Purified Water
system. While your response appears adequate, we are
concerned about the condition of your manufacturing
facility in that during the inspection our investigators
observed multiple conditions of disrepair.
Preventative Maintenance (PM)
n Scheduled for defined intervals
n Inspection of equipment for wear
n Replaces items such as gaskets, diaphragms, valves,
etc as necessary
n Ensures that the equipment is mechanically sound
prior to use
n Inspection of spray devices
Failure Example
n Utensils and equipment that directly contact sterile API
during transfer are inadequate to ensure that these
APIs are maintained sterile and pyrogen-free. For
example:
�Several pits/holes were observed in the weld at the end and there was a
crack observed between the handle and the end. These holes and crack
create a challenge for sterilization.
What is Monitoring?
n Monitoring refers to the routine measurements taken
on the cleaning process that serve as indicators of
whether the process is in a state of control ( or
considered from the opposite point of view, serve as
indicators that the process either is not or may not be
in a state of control).
Cleaning Validation, U.G. Barad, 2005
Why Monitor the Cleaning Process?
n Control over a cleaning process can be demonstrated by a review
of all relevant data at specified time increments.
�Relevant data includes sample results and trending of those results.
n Monitoring the cleaning processes ensures the process is
performed correctly and also provides an early warning if it is not
performing as validated.
n Provides additional reassurance to the visual assessment and
conductivity verification that is performed with each cleaning.
n Consistent with the lifecycle approach to validation (Design,
Formal Validation Studies, and Ongoing Controls) as well as
continuous improvement for manufacturing quality and efficiency.
Monitoring Cleaning Cycles
n Temperature, flow, pressure, fluid level, drainage,
cleaning agent concentration, conductivity, and pH
may play a role in monitoring the cleaning program.
n The nature of the cleaning method will determine the
critical parameters to be monitored during cleaning.
n Instrumentation for monitoring critical parameters
should be accurate and subject to a routine calibration
program.
Data Analysis
0
2
4
6
8
10
12
14
16
1 3 5 7 9
1
1
1
3
1
5
1
7
1
9
2
1
2
3
2
5
2
7
2
9
UCL
Average Line
LCL
Performance Data
Hanford PI Forum
Identifying Trends
n One point outside the control limits
n Two out of Three points two standard deviations
above/below average
n Four out of Five points one standard deviation
above/below average
n Seven points in a row all above/below average
n Ten out of Eleven points in a row all above/below
average
n Seven points in a row all increasing/decreasing.
Hanford Forum
Trending
n In all cases, trends should be investigated to
determine the special cause(s)
n A circle or a shift in the baseline is a trend
n Generally, short term shifts are left circled, long term
shifts have a new baseline
n Remember – the goal is Prediction of Future
Performance
Hanford Forum
Trend Identification
Initial Indication of Trend
0
5
10
15
20
O
c
t
-
9
8
D
e
c
-
9
8
F
e
b
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9
9
A
p
r
-
9
9
J
u
n
-
9
9
A
u
g
-
9
9
O
c
t
-
9
9
D
e
c
-
9
9
F
e
b
-
0
0
A
p
r
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0
0
J
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0
0
A
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0
0
O
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g
-
0
1
Average = 9.5
(Oct 98 - Oct 00)
2 of 3 at
2 standard
deviations
above average,
circled
Hanford PI Forum
Identifying a Trend
n Report the trend
n Search for Special Causes
n Compare detailed data during the trend to previous
stable time interval
n Consider Corrective Action Management necessary
steps
Monitoring Cleaning Cycles
n Options for monitoring
�Periodic Sampling (TOC, Bioburden, Endotoxin, Conductivity)
�Monitor Critical Operating Parameters (temperature, flow, pressure)
�Monitoring can occur using equipment that is in-line or off-line but ensure
that it is accurate and in a routine calibration program.
�Cleaning procedures should be monitored at appropriate intervals after
validation to ensure that these procedures are effective when used during
routine production.
�Equipment cleanliness can be monitored by analytical testing and visual
examination, where feasible.
Automated vs. Manual Cleaning
n Automated Cleaning
�May not require on-going verification
if the system is designed, installed,
and validated appropriately
n Semi-automated Cleaning
�Dependent on the reproducibility of
the system
n Manual Cleaning
�Periodic Verification Required
�Verifies how appropriate the training
is and how well the operator can
perform the cleaning
�Collected sample data should be
analyzed
Verification vs. Revalidation
n Verification
�Performed as part of cleaning
monitoring
�Sampling can be less aggressive
- Fewer areas
- Indirect vs direct sampling
n Revalidation
�Could require portions of the initial
cleaning validation to be repeated
�Samples that are required can be
more aggressive than verification
(Rinse vs Swab)
�Can include aspects of both
verification and validation
�May be triggered by a change to
equipment or cleaning procedures
Change Control
n May Impact all of the cleaning process
�Standard Operating Procedures (SOP)
�Assay methods
�Equipment
�Detergents
�Times
n Any changes to items determined during PQ as
impacting to the cleaning process must be evaluated
and ultimately approved.
Failure Example
n SOP XXXX, was revised May 17, 2004 to remove the
requirement for [redacted] after use/prior to cleaning if
inactivation time and temperature requirements were
met during the inactivation process. These new
cleaning procedures were not validated to establish
the impact of the changes on the cleaning process.
Change Control
n Changes must be pre-approved
n If the maintenance required is deemed a change
�The change control team determines the level of testing that is required
�This could include
- New cleaning samples (TOC, Conductivity, Bioburden, Endotoxin, etc)
- Verification of flow rates
- Confirmation of pathways
- Verification of spray coverage
n A validated process can be easy to maintain if an
efficient and effective change control program is in
place.
Revalidation Assessment
n Paper Exercise
n SOP Governed
n Frequency Based on Rationale
�Criticality of the equipment could determine if its assessed annually or
every three years, for example.
n Assessments Can Include
�Review of open and closed work orders
�Review of related change controls
�P&ID walk down of equipment
�Review of related SOPs for updates that could affect the validated state
n Assessments provide reassurance that the equipment
has remained in a validated state.
Summary
Validation
Cleaning Program Lifecycle
Design
Development
Commissioning
Operations
MaintenanceValidation
Cleaning Program Lifecycle
Design
Development
Commissioning
Operations
Maintenance
Summary
n Compliance with Standard Operating Procedures
(SOP)
�Visual inspection of internal equipment surfaces prior to use
�Conductivity verification
n Maintenance Program for Equipment
�Preventative Maintenance Program (PM)
�General upkeep of equipment
n A Cleaning Monitoring Program
�Sampling
�Critical parameters
n A Revalidation Program
�Some or all elements of the original validation
n A Revalidation Assessment Program
�Assessment of equipment to verify it is still in a validated state
Thank you!!
Questions????