Proper Implementation of Enhanced
Mechanical Calibration of
Dissolution Apparatus 1 and 2
White Paper
Authors

Introduction

Kenneth Boda and G. Bryan Crist

Mechanical calibration of Dissolution Apparatus 1 and 2 has become an increasingly popular option for pharmaceutical companies since the FDA’s Guidancefor Industry, The Use of Mechanical Calibration of Dissolution Apparatus 1 and
2 – Current Good Manufacturing Practice cGMP, became official in January 20101.
Mechanical qualification (MQ) has been embraced for many reasons such as thebelief that the qualification supports tighter tuning for the dissolution apparatus,
perceptions of varying results and instrument failures from the USP Performance
Verification test (PVT), and reduced time and cost of analytical instrument qualification. Unfortunately, when the enhanced mechanical qualification procedures
are executed in a laboratory, the focus is often on the physical parameter measurements taken on the dissolution apparatus, and other areas of the guidance areoften not addressed adequately, resulting in an incomplete qualification.

Agilent Technologies, Inc.

Background
Mechanical calibration was developed by the PhRMA Subcommittee
on Dissolution Calibration in order toaddress quality and cost concerns withchemical qualification of dissolution
apparatuses1. The prednisone tablets
were also said by the FDA to show a“…lack of sensitivity to variation anduncertainty” and led them to conclude
that “…sole reliance upon reference
standard tablets to evaluate the performance of USP Dissolution Apparatus 1
and 2 does not provide assurance thatthe apparatus is adequately calibrated
as required by cGMP regulation in
211.160(b)(4). Enhanced MC is advantageous, enabling a dissolution apparatus
operator to minimize the significant
sources of measurement system variation identified in the recently publishedstudies2.”
In response to the trend to identify
sources of variability by the newmechanical qualification (MQ) procedures, the USP released the latest lotof dissolution PVT 10 mg prednisone
tablets with acceptance criteria focusing on accuracy and variability with theholistic PVT. Additionally, the USP published its Toolkit 2.0 which endorses
many of the tighter tolerances discussed in mechanical calibration asrecommendations. However, it should
be noted that the official USP specifications and tolerances for Apparatus 1
and 2 are contained in the current USP<711> chapter.

Key parameters ofmechanical calibration(1) Enhanced mechanicalmeasurements

The mechanical calibration procedure
has fi ve main components that must be
implemented to consider a dissolution
unit qualified. These components are:

The enhanced mechanical measurements are where the greatest amountof focus is placed. The most importantdifference in tolerances between therequirements in USP <711> and themechanical calibration approaches are
the addition of two vessel centering
measurements with tighter tolerance,
shaft wobble, and vessel verticality measurements. The mechanicalcalibration also includes stricter
tolerances for RPM speed and basket
wobble.

(1) Enhanced mechanical measurements of the dissolution systemsuch as RPM speed, centering,
wobble, and so on.
(2) Verification of dissolution components against USP <711> - paddles, baskets, basket shafts, andvessels(3) Preventative maintenance plan inplace according to manufacturer
recommendations(4) Control of vessel variability,
dissolved gasses, and vibration(5) Prerun analyst checks before eachrun for component condition
Many laboratories focus on the firstcomponent, yet omission of any or all of
the other four points can compromise
the calibration and overall performanceof the dissolution apparatus. It is
important to develop a plan to address
all fi ve aspects of the enhanced
mechanical qualification process toensure that the dissolution apparatus isfit for use.

Although MQ has always been a key
component of PVT, a dissolution lab
can choose to adopt the enhanced
mechanical calibration approach outlined by the FDA and ASTM3 standard
procedures or continue performing USP
PVT with the prednisone tablets, bothof which fulfill GMP requirements fordissolution apparatus qualification2.

2

Detailed information on how toachieve the measurements per ASTM
E 2503-07 is available, and the newcentering and vessel verticality
measurements can be achieved with avariety of tools 4.
Vessel centering is shown in literature
to play a key role in vessel variability 5 and as such needs to be tightly
controlled. Vessel centering measurements are taken at two locations within
the vessel – one at the lower and one
at the upper portions of cylinder within
the dissolution vessel. Centering must
be within 1.0 mm from the centerline
in all directions at both locations along
the shaft. Use of vessels designed for
optimal centering, such as the Agilent
TruAlign and TruCenter vessels, haveshown improved variability and performance compared to traditional vessel
types with possible deformities in theglass rim6. Additionally, use of centering rings from the original dissolution
manufacturer for traditional vessels
has attributed to tighter centering
data and lower dissolution variability.
Some manufactured apparatus maketaking accurate measurements withthe mechanical calibration gauges very
difficult. However, surrogate methodsof taking these measurements withthe components removed does notaccurately measure vessel-to-shaft
centering.
Vessel verticality is taken at two points
in the vessel at 90 degrees apart, andmust be within 1 degree of the vertical.
Verticality can either be directly takenwith a level or mathematically derived
from the centering measurements3.
Paddle and basket height is also a
new measurement for most laboratories that traditionally performed the
PVT test. Most laboratories set theirheights through a variety of tools suchas height balls and clip-on gauges, but
few have actually measured that height
to ensure it is correct. Height can be
set incorrectly in a variety of ways suchas using the height setting “hockey
stick” tool at an angle or improperly
using a height ball for basket height
setting which will deform the bottomof the basket. Uses of a height gauge
tool such as the Agilent 5010 Height/
Center Qualification Station can determine the height of the paddle or basket,
and enable height optimization.

Adoption of the tighter mechanicaltolerances provides better control ofthe dissolution apparatus and reduce
variability between vessels. Thesemechanical tolerances are only one
part of a complete mechanical calibration, however and once measured,each component must be operated in
the dedicated position to which it was
qualified.

(2) Verification ofdissolution components
The ASTM standard and FDA SOP
require that the dissolution analyst
must verify or measure the dimensions of the vessels, baskets, andpaddles upon receipt. The FDA statesthat it is the analyst’s responsibility to“check the vessel, basket, and paddle
dimensions on receipt” and the ASTM
states that the analyst must “verify thevessel, basket, and paddle dimensions
through measurement, Certificate
of Analysis (COA), or Certificate ofConformity (COC)2,3. Component
measurement and/or verification of acertificate “ensure the components areappropriate for use 3.”

The COA and COC issued by some manufacturers of dissolution components
have simply not met the requirements
contained in the FDA and ASTM procedures because they do not contain
actual measurements of compendial
specifications and tolerances. The certificates must include measurementsof each component with appropriately
documented measuring devices forthe critical parameters outlined in
USP <711>. The tools used to measure
the components “shall be traceable
to an accepted standard calibration
source from a national or international
calibration laboratory.”3 For vessels, it
is additionally recommended that the
inner surface of the vessel should bechecked to ensure that it is smoothand regular. This can be accomplishedthrough mechanical profiling tools or atactile evaluation of the inner surface 4.
It is felt by the authors that tactile
examination is highly subjective andnot likely to discover imperfections thatwill affect vessel performance.

Vessels

Baskets

Basket shafts

PaddlesInternal dimension

Shaft diameter

Shaft diameter

Shaft diameter

HeightVent hole diameter

Disk width

Blade height

Verify that the vessel is cylindricaland hemisphericThickness of basket/shaft adapter

Vent hole diameter

Blade thickness

Basket heightThree clip design

Blade length

Basket internal dimension

Bottom blade length

Outer screen diameter

Radius on top upper blade portion

Screen height

Radius on outer blade edge

Outer diameter of bottom screen

Distance from shaft to blade tip at midline

Mesh number

Difference of paddle heights at outside top along shaft

Table 1
Critical dissolution component attributes outlined in ASTM3 standard procedures by USP <711>4.

3

Description of part
Serial number of part
Required measurement
parameters andspecifications

As-found values andpass/fail indication

NIST-traceable
measurement
tools used

Technician
performing
measurements

Figure 1
Example of a Certificate of Conformance (COC).

4A COA/COC or in-house measurements must include measurementsof the critical attributes in Table 1.
The measurements should also be
accompanied with the tools used andtheir calibration due dates to ensure
conformance.
Use of a certificate without the individual measurements of each serialized vessel, paddle, and basket for all
measurements listed in Table 1, does
not meet the requirements of FDA andASTM mechanical qualification guidelines. It is the burden of the dissolution
laboratory and analyst to ensure that
all critical measurements of thesecomponents were taken with traceable, calibrated tools, and that thesemeasurements are properly documented to adhere with the appropriate
guidance. Declarations of manufacturing conformity alone do not meet themechanical qualification criteria andonly indicate that appropriate quality
control and engineering design is inplace, and declares that components
are manufactured to USP specifications. It cannot guarantee conformanceof individual components.
Agilent offers verified components
with individual certificates of eachcomponent that meet the requirements
listed in ASTM and FDA guidance.
These components can be purchasedfrom Agilent with new equipment or as
accessories or replacements toexisting equipment.

(3) Preventive
maintenance plan
Preventive maintenance plans need
to be developed, implemented,
and documented according to themechanical calibration procedures. The
preventative maintenance plan should
follow the recommendations of the
dissolution apparatus manufacturer
and take into account the frequency of
instrument use.

Preventative maintenance is typically done at six-month intervals or
by a number of spindle hours run.
Preventative maintenance should
encompass all aspects of the dissolution apparatus, not only to lubricate
and maintain, but also to inspect for
any current problems with the unit
including areas of excessive wear that
could cause a future performanceissue.
Procedures should include periodic
checks inside the drive unit to ensure
there is no excessive belt wear, fraying, and so on, and that the tension isappropriate. The spindles themselves
should also be manually rotated toensure that they move smoothly. Any
points that require lubrication should
also be checked and the appropriate
lubricant applied. Use of a non-recommended lubricant can cause a buildup
of dust or other issues resulting in
potential excessive vibration. Sealed
bearings may be irreversibly damaged
when light machine oils are applied
to sealed bearing assemblies, which
unintentionally dissolve the greaseand eventually render the apparatus
inoperable.
Temperature probes should be checked
to ensure they are within proper tolerances against NIST-traceable devices,typically within 0.2 °C.
Electric boards, wires, and so on,
should also be checked to ensure thatthey are clean, free of corrosion, andconnections are intact.
In addition to the checks of the system
above, the water bath should also
be cleaned, and refilled to the proper
operating level with the addition of analgaecide approved for heater/circulator systems. Most algaecides will
prevent buildup for three to four weeks
before another cleaning is necessary.

5(4) Control of vessel
variability, vibration, anddissolved gasses
One of the major concerns about themechanical calibration procedure isthat it is unable to determine unacceptable levels of vessel variability,
vibration, or dissolved gasses. The
prednisone PVT tablet has demonstrated sensitivity to these parameters,
so many laboratories are hesitant totransfer to the mechanical calibration
alone until there are specifications,tolerances and procedures to measure and quantify them. Each of theseparameters can be controlled to adegree and will help properly qualify
the dissolution apparatus. FDA states
manufacturers “should take appropriate measures to control the following recognized sources of significant
variability in dissolution testing2.” Thismeans that the laboratory must havewritten and validated procedures inplance to measure and control thesesources of significant variability.

Vessels
Vessel variability is one on the mostimportant aspects of the dissolution test to control, and is cited as
the greatest cause of variability inthe dissolution environment7. Vessel
variability can lead to very high %CVvalues with the USP PVT as shown
when vessels from various manufacturers are used on the same apparatus6.
To reduce vessel variability, the same
supplier should be used for all of thevessels on the dissolution unit. In addition, the COCs for the vessels should
be reviewed not only to meet the USP
criteria, but also to assess the variability of that set of vessels. Vessels
should also be examined prior to eachrun for their condition and cleanliness;this is discussed in more detail in the
pre-run analyst checks section.

Vibration
The only requirement for vibration in
the USP, FDA, and ASTM procedures isthat “no significant vibration” should
be present. The original PhRMA
collaborative study suggested themaintenance of a calibrating tablet
until a definitive vibration specification is developed. Although an FDA-led
collaborative effort is underway todetermine a vibration specificationand tolerance, no such specification isavailable for vibration at the time of thispublication.
Vibration is a very significant force
in dissolution and can cause variable
results and, depending on the sourceof vibration, it may affect paddle andbasket analysis differently. It is difficult
to set a vibration limit for a varietyof reasons. Vibration is virtually thequantification of chaos with respect tocancelling and additive effects of sine
waves, and vectors associated withthe direction of wave forms. Frequency
and amplitude variations also must be
considered. Vibration can be sustained
or intermittent, so it is not clear what
cumulative vibration is acceptable,
nor what limit there is for an intermittent effect. As a result, vibration must
be controlled as much as possible
in order to preserve the dissolution
environment.
Sustained vibration is typically causedby issues within the dissolution apparatus, a defective water bath circulator,
or nearby equipment. The dissolution
apparatus and circulator vibration canbe controlled through proper preventative maintenance, particularly looking
at the belts and spindles for wear, andperforming proper lubrication of thesystem. The dissolution apparatus
must not be closely associated withequipment known to vibrate such as
fume hoods, vacuum pumps, shakers,
ultrasonic cleaners, and even a radio
playing music. Intermittent vibration
should also be controlled as much as
possible. The dissolution apparatus

should be in a location of the laboratory
where it is not susceptible to vibrationfrom heavy foot traffic, slamming doors
or near walls where heavy machinery
is running in an adjacent room. Even
highways, railroads, and construction
have drastically affected dissolution
apparatus performance. Vibration canalso be controlled to a degree using
shock absorbing pads under the feetof the dissolution apparatus which will
help limit vibration from the environment from impacting the performanceof the dissolution test. Please remember vibration may be transmitted long
distances through the bench top itself.

Dissolved gasses
Dissolved gasses are identified asanother important aspect to be properly
controlled during the dissolution test.
Dissolved gasses can lead to considerable variability, and can alter hydrodynamics, distribution of particles in
the media, and several other effects.
A proper degassing scheme such as
vacuum degassing at 41 °C througha 0.45 µm filter in USP <711> shouldbe implemented in order to reduce
dissolved gasses below 6 ppm O2.9
Alternative approaches for degassing
media include helium sparging, sonication under vacuum, and media preparation devices. When using a non-USP
degassing method, the media should bechecked using a total dissolved gasses
meter to ensure the proper level ofdeaeration has occurred.
Once the media is prepared, heated,and degassed, it should be poured into
the dissolution vessels immediately.
As media is left to sit, it will begin toabsorb gasses from the environment.
Pouring of the media into the vessels
should be done as gently as possible
to prevent re-aeration of media, andweighing of the media may further
help prevent reaeration since you candirectly pour media from the source tothe vessel.

6

The main point is that deaeration mustbe performed sufficiently so when
it is measured and poured into thevessel, the level of dissolved gasses
still remains well below the level ofsaturation, which will prohibit bubbles
from forming on the vessel and paddle
surface and within the mesh of thebasket. Deaeration is often overlooked
as a critical component of dissolution
integrity. Particles rotating around asurface coated with bubbles will experience increased agitation resulting
in higher dissolution results. Bubbles
forming within the basket mesh willoften suppress dissolution results. In
either case, dissolved gasses must be
removed from media when it is shownto interfere with the test 8.

(5) Prerun analyst checks
The final part of the mechanical calibration procedure is to perform on-goingchecks of the dissolution unit eachtime before testing. These checks
should ensure the paddles, baskets,basket shafts, and vessels are all clean
and in good condition. The analyst will
also need to make sure that the vesseltemperature is measured each time,
and that vibration is not present.
Unfortunately, this may be one of themost subjective portions of the proper
execution of MQ. If analysts are notproperly trained to recognize equipment problems such as peeling paddle
shafts, dented or misshapen baskets
or scratched vessels, variability will
persist and the MQ may not succeed
in detecting sources of variability.
These important observations must be
properly performed and documented
to provide the greatest assurance
that the apparatus integrity is maintained. Prior to each run, analysts
need to perform appropriate examination and documentation to meet thisrequirement.

Paddles examination

Vessel examination

Paddles should be examined to ensurethat they are in appropriate condition
for use. Stainless steel paddles tend tobe very durable, however, one should
check to ensure that there are no
defects and that there is no discoloration of the paddle due to corrosion fromhydrochloric acid and other dissolution media. PTFE-coated paddles andsimilarly composed paddles need to be
more closely examined for flaking andpeeling of the surface which can alter
the surface area of the paddle and also
provide a site for cross contamination
between runs.

The vessel should be inspected
when dry to ensure that it is “free ofscratches, cracks, pits, and residue1”.
Vessel scratches, cracks, and pits tend
to occur in the hemispheric portion of
the vessel due to dropped shafts, roughheight setting procedures, and so on`.
The rim of the vessel should also beinspected closely, as defects in thisarea can result in compromised vessel
centering and verticality. If residue ispresent, use of alcohols for scummy
residue or diluted nitric acid for scalingor other buildup can be used to restore
the vessel. The upper portion of thevessel should be “examined to ensurethat any material from the waterline
mark of the media used in previous
tests has been removed 4.”

Basket examination
The basket should be examined in several ways to ensure proper shape andcleanliness. Since baskets are quitefragile, it is recommended that they bechecked prior to each use for excessive wobble, dents, and so on. Wobble
can be checked each run visually byrotating the baskets at a low RPM
prior to lowering them into the media.
If wobble appears to be high, then theanalyst can measure with an appropriate run-out gauge. The basket should
be checked for dents as well, both on
the sides of the basket and the bottom
mesh.
Basket cleanliness should be checked
as well, especially at the seams
between the upper and lower metalrims and the mesh. The baskets
should be free of frayed wires and notexhibit any rust spots. Baskets canbe effectively and gently cleaned byplacing them in a beaker of alcohol andsonicating for fi ve minutes and thenallowing them to air dry before placing
them in a protected container.

Conclusion
The mechanical calibration procedurecan be a viable alternative to the USP
PVT. However, a laboratory mustensure that they are not merely taking
measurements of the various physicalparameters, but also putting the otherprocedures and controls in place as
required by cGMP. A dissolution apparatus that has been checked through aseries of measurements, along with aset of verified components and otherlaboratory controls, will help maintainlow variability and ensure data integrity
has been preserved.

Care should be taken at the beginning of the run to ensure that air is
not trapped beneath the basket which
restricts flow through the basket andlowers performance.

7

References
1. PhRMA Subcommittee on
Dissolution Calibration: Oates M, Brune
S, Gray V, Hippeli K, Kentrup A et al.,July-Aug 2000, Dissolution Calibration:
Recommendations for Reduced
Chemical Testing and Enhanced
Mechanical Calibration, Pharmacopieal
Forum; 26(4): 1149-1151.
2. The Use of Mechanical Calibrationof Dissolution Apparatus 1 and 2 –Current Good Manufacturing Practice(cGMP); Guidance for Industry;
U.S. Department of Health andHuman Services, Food and Drug
Administration, Center for Drug
Evaluation and Research (CDER),
U.S. Government Printing Office:Washington D.C, January 2010.

6. Boda, K; USP Performance
Verification Testing Recommendations
and Troubleshooting for Lot P1I300;
Agilent Technologies, August 2011,
literature part number 5990-8530EN.
7. Salt, A and Glennon J, Enhance
Mechanical Calibration of Dissolution
Test Equipment, Dissolution
Technologies, May 2011.
8. USP 35 - NF 30, Physical Test
<711> Dissolution, p. 299. USP 2012,
Rockville, MD, USA
9. USP Dissolution Toolkit Proceduresfor Mechanical Calibration and
Performance Verification Test
Apparatus 1 and Apparatus 2 Version
2.0; March 22, 2010.

3. E 2503-07 Standard Practice for
Qualification of Basket and Paddle
Dissolution Apparatus; ASTM
International; April 2007.
4. Moore TW, Long Abbott MA,
Kentrup WA, Oates MD, Kelley
C, Sojkowski SP, Implementation
Guidance for American Society for
Testing and Materials (ASTM) E 250307 “Standard Practice for Qualificationof Basket and Paddle Dissolution
Apparatus”, The Open Drug Delivery
Journal, 2010, 4, 14-20.
5. Gao Z, Moore TW, Smith AP,
Doub W, Westenberger B, andBuhse L, 2007, Gauge Repeatability
and Reproducibility for Accessing
Variability During Drug Testing: A
Technical Note, AAPS PharmSciTech;
8(4): E1-E5.

www.agilent.com/
lifesciences/dissolution© Agilent Technologies, Inc., 2012
Published in USA, May 1, 2012
Publication Number 5990-9866EN