CLE ANING C OMPLIANCE FO RUM
Spray Coverage Testing
Jennifer Carlson
“Cleaning Compliance Forum” discusses scientific principles, strategies, and
approaches associated with cleaning that are useful to practitioners in compli-
ance and validation. We intend this column to be a valuable resource for daily
work applications. The key objective for this column: Useful information.
Reader comments, questions, and suggestions are needed to help us fulfill
IMAGE COURTESY OF ROCHE
our objective for this column. Please send your comments and suggestions to
column coordinator Jenna Carlson at carlson.jenna@gene.com or to managing
editor Susan Haigney at shaigney@advanstar.com.
KEY POINTS
The following key points are discussed:
• Coverage testing should be performed as part of equipment qualifica-
tion for all process-contacting equipment utilizing spray devices for
cleaning
• Coverage testing is used to verify that all process-contacting surfaces
are wetted by cleaning liquids and to identify any potential blind
spots or hard-to-clean locations on the equipment
• Locations on equipment that are not adequately cleaned are identi-
fied through riboflavin fluorescence testing
• Procedures should be in place to prevent or look for clogging of spray
coverage devices over time that would potentially affect the spray
pattern
• Coverage testing is a regulatory expectation.
INTRODUCTION
In order for process equipment surfaces to be cleaned, they must be able
to be contacted with cleaning liquid. Spray devices are an efficient means
of delivering cleaning solution to a surface. It is much more efficient to
clean a large vessel using spray devices than to fill it completely with liq-
uid and clean by a soak method. Also, by spraying liquid up along the top
head of a vessel, the sidewalls and other internal components are cleaned
by the resulting turbulent falling film of solution. This turbulent falling
film provides a more thorough cleaning of surfaces than the relatively
quiescent flow of solution in a fully flooded and mixed tank. In these
44 Journal of GXP Compliance
Jennifer Carlson
ways, utilizing spray devices is a more effective and cleaning, health agencies expect to see documenta-
efficient means of cleaning. tion of spray coverage testing.
Spray coverage testing is performed on equipment The US Food and Drug Administration is known
that is cleaned using a spray device or devices (e.g., to give FDA-483 observations for not having
balls, nozzles, etc.). Spray coverage testing provides completed spray coverage testing. An example and
assurance that spray devices used during cleaning for observation of not having spray coverage testing
a particular piece of equipment are able to reach and from a FDA-483 is as follows:
rinse all interior process contacting surfaces. Spray “Documentation of sprayball coverage for
coverage testing identifies any potential hard-to-clean processing tanks is not found in cleaning
or inadequately cleaned locations (blind spots) on the validation studies or I/OQ studies for these
equipment. Riboflavin fluorescence is used to identify processing tanks” (5).
blind spots on tanks. If blind spots are identified dur- A 2004 FDA warning letter (6) included two sepa-
ing spray coverage testing, a corrective action should rate mentions of inadequate spray ball coverage:
be performed to ensure that the blind spot is cleaned. “Your firm failed to establish and follow
In addition, spray coverage testing results help provide written procedures to assure the cleaning
scientific evidence to support grouping of equipment and maintenance of equipment used in the
for cleaning validation activities. manufacture, processing, packing, or hold-
ing of a drug product [21 CFR 211.67(b) and
REGULATORY REQUIREMENTS 600.11(b)]. For example, cleaning validation
There are no specific regulatory requirements that for the clean-in-place (CIP) process vessel
require spray coverage testing. US Code of Federal [redacted] which is utilized in the aseptic
Regulations (1) and Eudralex Volume 4 Part II (2) formulation of trivalent bulk influenza vaccine,
both specify equipment should be of appropriate did not include an assessment of the spray ball
design to facilitate cleaning. One part of demonstrat- coverage for the vessel. The spray ball is used
ing this is through spray coverage testing. for cleaning product contact equipment.”
In addition, both the Pharmaceutical Inspection
Convention and Pharmaceutical Inspection Co- The lack of spray coverage testing is mentioned
operation Scheme (PIC/S) (3) and Health Canada (4) again later in the warning letter as follows:
specify “critical areas (i.e., those hardest to clean) “In addition, the cleaning validation did not
should be identified, particularly in large systems include an assessment of the spray ball cover-
that employ semi-automatic or fully-automatic age for the tanks” (6).
clean-in-place (CIP) systems.” Spray coverage testing
enables identification of blind spots for the equip- IMPLICATIONS FOR COMPLIANCE
ment spray devices to clean by an automated clean- For equipment that is cleaned-in-place (CIP) by
ing cycle. automated cleaning systems, documentation of
An important aspect of grouping of equipment spray coverage should be performed as part of
is demonstrating that the “equipment is similar in equipment qualification for all process-contacting
design and function” (3, 4). One part of demonstrat- equipment. In addition, procedures should be in
ing that equipment is of similar design to support place to prevent or look for clogging of spray cover-
grouping for cleaning validation is through spray age devices. Obstruction of spray openings over an
coverage testing. extended time period could potentially affect the
spray pattern. Clogging of a spray ball could also
REGULATORY EXPECTATIONS affect the ability of the cleaning cycle to deliver ef-
When spray balls or nozzles are used to deliver fective cleaning.
cleaning agent to equipment for the purposes of
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CLE ANING COMPLIANCE FORUM
SPRAY COVERAGE TESTING qualified. Oils from hands may cause riboflavin to
Qualification of equipment containing a spray de- abnormally adhere to surfaces and may result in a
vice must include identification and documentation false positive.
of the spray device including its proper orientation, Shake the riboflavin solution prior to use. Settling
alignment, and coverage results. Spray coverage test may occur while solution is idle.
should assure complete coverage of internal surfaces of Apply a fine mist of riboflavin solution on re-
equipment. If spray coverage testing demonstrates that quired equipment surfaces to create uniform surface
equipment has blind spots that would not be contacted coverage. Avoid over-application or a solid stream.
by cleaning liquid introduced by any other means (i.e., With a solid stream setting, the riboflavin will tend
direct flow of cleaning solution into a vessel via a port to form larger droplets and will be less likely to
on that vessel), the company should document reme- adhere to the surface in a uniform manner. A fine
diation activities to correct the blind spot and assure mist of riboflavin liquid is preferred when spray-
that cleaning of the blind spot will be successful. ing equipment surfaces. Likewise, if riboflavin is
Testing should be performed for each tank and spray over-applied, droplets will tend to pool together and
ball configuration. If a change has occurred to the tank drip down, preventing the riboflavin solution from
configuration or the spray ball, the test should be per- uniformly covering equipment surfaces.
formed again as part of change control or revalidation. Verify required surface(s) has complete and uni-
form riboflavin coverage by using a UV light source.
EXAMPLE PROCEDURE Ensure hard-to-reach areas have been uniformly cov-
FOR SPRAY COVERAGE TESTING ered with riboflavin. Document inspection results.
Equipment being tested must be cleaned and verified Ensure that the spray ball has been verified to be
to be visually free of any residue that may fluoresce free of any foreign objects prior to use in testing.
and give a false positive when inspected by a UV light
source. Ensure that hard-to-see areas (e.g., bottom of Equipment Coverage Testing
impellers, dip tubes, and ports) are verified. Record The following steps should be taken when spray-
any initial inspection observations. coverage cleaning equipment.
Ensure that equipment is properly set up for clean-
Application of Riboflavin to Tanks ing per applicable procedure.
The following steps should be taken in the application Record rinse flow rate and pressure, or pump
of riboflavin to tanks for cleaning. speed, and rinse time (or flow total) set points. Com-
Apply a 0.2g/L solution of riboflavin to the interior pare to actual cleaning parameters and document.
surfaces of each tank. Verify that complete coverage Perform coverage testing utilizing a water rinse
is attained using a UV light source. Dextrose (20g/L) that is equivalent to the shortest phase of the clean-
solution may be used to help the riboflavin bind to the ing cycle. Verify the equipment is drained after test-
tank surface, if needed. Riboflavin solution is typically ing is complete.
used for coverage testing. Other chemicals may also be Change and inspect gloves and gowning prior
used as long as they allow determination of coverage. to inspection to prevent any contamination from
Other chemicals used include uranin and flourescein. garments. Wipe down all equipment that may enter
Confirm that the riboflavin fluoresces by using a the equipment being tested prior to inspection in
UV lamp source. This is accomplished by applying order to prevent false positives. If possible, dim the
a small amount of riboflavin solution to a stainless room lighting.
steel surface (i.e., stainless steel coupon) and fluores- Once equipment is accessible for inspection,
cence is verified. search for areas of pooling or drips that may con-
Wearing gloves is required during application tain riboflavin by using available UV light. If there
of riboflavin on equipment surfaces that are being is riboflavin residue in equipment, it will fluoresce.
46 Journal of GXP Compliance
Jennifer Carlson
Inspect all surfaces under qualification with UV 2. EC, Rules Governing Medicinal Products in the European Com-
light. It is important to inspect the hard-to-reach ar- munity. Volume IV, Good Manufacturing Practices for Medicinal
eas. Use mirrors to assist in inspection, if necessary. Products, October 2005.
In some cases, equipment surfaces that are under 3. PIC/S, Recommendations on Cleaning Validation, Document PI
qualification may become dry prior to inspection. If 006-1. Pharmaceutical Inspection Cooperation Scheme,
surface is dry during inspection, a spray bottle con- Geneva, Switzerland, August 3, 2001.
taining water should be used to check for illumina- 4. Health Canada, Cleaning Validation Guidelines (GUIDE-0028),
tion—riboflavin does not illuminate when dry. Health Canada, January 1, 2008.
Lightly spray water mist on the dry surface and 5. FDA, FDA-483 issued to Evans Vaccines, a Division of Chiron,
check for riboflavin illumination by using available Liverpool UK, October 10-15, 2004, http://www.fda.gov/
UV light. Avoid excessive application of water to AboutFDA/CentersOffices/ORA/ORAElectronicReading-
reduce the chances of dripping or dilution. Room/ucm166572.htm
The interior surface of the vessel must show no 6. FDA, FDA Warning Letter issued to Chiron Corporation,
evidence of residual riboflavin after the partial December 9, 2004, http://www.fda.gov/ICECI/Enforcemen-
(worst-case) cleaning cycle. Document inspection tActions/WarningLetters/2004/ucm146700.htm
results. If riboflavin is apparent on equipment
surface(s) during testing, initiate an investigation GENERAL REFERENCES
and deviation. LeBlanc, Destin A., Validated Cleaning Technologies for Pharmaceu-
tical Manufacturing, Interpharm/ CRC Press, 2000.
GROUPING FOR COVERAGE TESTING Verghese, George and Paul Lopolito, “Cleaning Engineering and
One important consideration for grouping of equip- Equipment Design,” Cleaning and Cleaning Validation for the
ment for cleaning validation is the cleanability of Pharmaceutical and Medical Device Industry, Volume 1. Paul L.
process-contacting surfaces (hard-to-clean areas). Pluta, ed., PDA and Davis Healthcare International Publish-
Spray coverage testing is one way to determine if ing, 2009. GXP
equipment has hard-to-clean areas or if similar
equipment has the same hard-to-clean areas. It is dif-
ficult to justify grouping for spray coverage testing.
If spray devices are shown to be of consistent design
with the same spray pattern, then it should be pos-
sible to justify grouping of spray devices for use in ARTICLE ACRONYM LISTING
cleaning equipment of the same design. CIP Clean-in-Place
FDA US Food and Drug Administration
CONCLUSIONS PIC/S Pharmaceutical Inspection Convention and
Spray coverage testing assures that spray devices Pharmaceutical Inspection Co-Operation
used for cleaning of a particular piece of equipment Scheme
are able to reach and rinse all interior (process- UV Ultraviolet
contacting) surfaces. While spray coverage testing
is not specifically identified as a requirement by the ABOUT THE AUTHOR
regulations, it is a regulatory expectation. Jenna Carlson is a senior technical manager in Genentech’s Cor-
porate Quality System and Support, Validation department. She
is responsible for developing and overseeing governance activities
REFERENCES
for cleaning validation, including the corporate requirements and
1. FDA, 21 CFR 210, Current Good Manufacturing Practice In procedures. She has more than 11 years experience focusing on
Manufacturing, Processing, Packing, Or Holding Of Drugs: validation and quality assurance. She may be reached by e-mail at
General, April 1, 2008 (revised). carlson.jenna@gene.com.
Spring 2011 Volume 15 Number 2 47
