0
0
Powder and Bulk Engineering, June 1998 43 73
Y
0
S S: cn
0
PhillipA. Cloud Geneva Pharmaceuticals
-0
0
d
Q
%
~~
Comminutingmill validation case study P,
3
How can you be sure your new process equipment Mill basics. The pharmaceutical plant’s new portable Q
comminuting mill reduces granules, as do several other m
will operate as specified?You need to validate it with r_
identical mills in the plant. The mill, like that shown in 7T
a series of qualificationtests. This articledemystifies Figure 1,consists of a feed hopper, feed auger, mill cham- rn
the validation process by explaining how a new
-
3
ber, and control box; the mill has rotating blades, a screen E.
comminuting mill was validated at a pharmaceuti- at the outlet, and a discharge chute. A safety grid over the 6
cal plant. You can adapt the step-by-stepprocess feed inlet and a throat inside the mill prevent workers from
2.
outlined here to validate other size reduction or accidentallycontacting moving parts. 3
ra
process equipmentin your plant.
In operation, the auger carries granules at a controlled rate
from the feed hopper to the mill. In the mill, the rotating
blades impact and reduce the granules. When adequately
I
n processing plants for pharmaceuticals, chemicals,
biotech materials, and other dry bulk materials, new
equipment must be validated -that is, tested -to
ensure it meets several acceptance criteria. These can in-
clude FDA regulations, current good manufacturing prac-
tices (cGMPs) for pharmaceuticals, good laboratory
practices, good clinical practices, and industry standard
I S 0 9000.
In some cases the manufacturer includes a so-called vali-
dation package with the equipment. But if this package in-
cludes only a checklist for verifying that everything is in
place and operational, it’s really a commissioning docu-
ment. While this document can provide some information
for validation, it’s not enough.
Validating requires running enough qualifying tests of the
equipment’s operation to determine whether the machine
operates as designed in consecutive test runs. The opera-
tion -as shown by the test results -must also be repro-
ducible. The test conditions for the runs impose lower and
upper control limits. You then must carefully analyze
these limits to ensure they’re appropriate and that the
equipment won’t fail as long as you operate it within the
limits. Because your new equipment must be installed, op-
erated, and maintained within its design specifications,
these tests are critical for your validation process.
The trouble is that little practical information is available
on exactly how to validate new equipment. The following
information takes you through each step in a plant’s vali-
dation of its new comminutingmi11.l
0
0
73
44 Powder and Bulk Engineering, June 1998
2.
reduced, the granules pass through the outlet screen and
flow through the discharge chute to a collection container
The validation includes three qualificationevaluations:in-
stallation,operation, and performance. The following sec-
-
ra
5
0
below the mill. tions include detailed information about each. cn
0
-0
S
The motor-driven mill is manually controlled by pressing E
-.
on-off pushbuttons on the control box and by adjustingthe Installation qualification cn
speed of the rotating blades and auger. The rotating blades The installation qualification (IQ) evaluation establishes z
3
are set at one of three speeds by repositioning belts on a confidence that the equipment -in this case, the mill - ca
multistep flywheel and motor pulley. The auger speed is is properly installed. The mill’s installation -including
adjusted by turning a dial on the control box. any design changes at installation -must meet the mill
manufacturer’s [Link] electrical utilities for
the mill must meet all electrical codes and the mill’s
Validation basics. The plant’s equipment validation specified voltage and amperage requirements, and the P,
3
method supports cGMPs in a bulk pharmaceutical chemi- safety features must function according to the manufac- Q
cals environment. The method is established by a written turer’s specifications. m
protocol and is based on a qualification testing procedure r_
7i
that determines whether the equipment operates as it’s de- rn
signed and whether that operation is reproducible. The The IQ evaluation requires several elements, most of 3
qualificationtest results are recorded in the validationpro- them from the mill manufacturer, as shown in Figure 2.
cn.
3
(D
tocol. The validation protocol for the comminuting mill They include the mill’s identification information (such
was developed by the plant’s validation specialist. The as model and serial numbers), required documents (such 2.
3
tests were run and the results recorded by this specialist, as manuals, drawings, and standard operating proce- ra
the mill operator, and maintenance workers. dures), required utilities, major component specifications,
0
0
73
46 Powder and Bulk Engineering, June 1998
2.
component construction material specifications,lubricant
specifications,and safety features. Tests of the utilities and
Required documents. Next, the validation specialist iden-
tified the mill’s required documents and listed them in the
-
ra
5
0
safety features are also required. protocol. The manuals and drawings included: cn
0
-0
S
Zdenti$cation informution. In the pharmaceutical plant, Number M5095, Comminuting Machine Operating E
-.
the validation specialist first checked the mill’s identifica- and Instructions Manual, no release date. cn
tion, most of which appeared on the mill’s nameplate, and s
3
recorded it in the validation protocol:
H Number 3001-7400, Typical SFV ComminutorDraw-
ca
ing, 2128178. 8
H Manufacturer: -.
Number 3001-9153, SFV-SAD60-BSS Drawing, P,
3
IPurchase order number: 009235. 6/23/95. Q
m
r_
H Model number: DAS6O. 7i
W Number 3001-6730, NMEA 4x460 V A C Control rn
Panel Layout Drawing, 5/4/95. 3
W Serial number: 78801.
The standard operating procedures included:
H Equipment number: 6492.
H Number GRAOO5, Mill Auger Feed Setup and Opera-
H Location in plant: Room 270. tion, 2/16/96.
0
0
Powder and Bulk Engineering, June 1998 47 73
2.
ra
Number GRA006, Mill Auger Feed Cleaning Proce- Lubricant specifications. The validation specialist 5
d
dure, 2/23/96. recorded information in the validation protocol about the
mill’s required lubricants, based on information from a 0
comminuting mill preventive maintenance schedule al-
cn
0
Required utilities. The next step was to compare the man- ready on file at the plant: 77
ufacturer’s specified voltage and amperage requirements
for the mill with the as-found conditions of the plant’s
power supply voltage and amperage. A maintenance Mill gearbox: Amolith 2 oil from any oil manufacturer;
worker compared them and recorded this data and the no product contact.
power supply source’s location in the validation protocol,
as detailed in Table1.
Mill pillow block bearings and casters: Lubriplate
630-2 grease from any oil manufacturer; no product
The manufacturer’s voltage specification was 460 volts contact. P,
k10 percent, or k46 (Table I). This gave the mill a voltage 3
Q
specification from 414 to 506. The maintenance worker m
used a multimeter to measure the voltage supply at the re- Safetyfeatures. Next the validation specialist ran tests to r_
ceptacle into which the mill’s power cord was plugged. verify that the mill’s safety features functioned according x
The voltage was measured at three wires in the receptacle, to the manufacturer’s [Link] mill had a safety
and the measured volts were 455,457, and456, which was interlock switch that provided two safety features: When
acceptable. The worker recorded information about the the mill and auger pushbuttons are pressed, the switch pre-
multimeter itself elsewhere in the protocol. vents the mill and auger motors from operating when 1)
the throat is removed or 2) the safety grid is removed. The
tests verified that both features operated as the manufac-
The manufacturer’s specifications were 11 amperes for the turer specified,and the specialistrecorded the results in the
mill motor and 1.17 amperes for the auger motor (Table I). validation protocol (Table I).
This gives a total equipment current draw of 12.17 am-
peres. The worker checked the amperage’s as-found con-
dition by examining the breaker box. The circuit rating Operationqualification
was 20 amperes, which was acceptable because it was The operation qualification (OQ) evaluation establishes
greater than the mill’s maximum current draw. that the mill can operate within specified tolerances and
limits, as shown in Figure 3. The evaluation challenges the
mill’s mechanical ranges as well as its basic operations to
Major component specijkations. Next the validation spe- validate the mill’s mechanical operating ability rather than
cialist verified that the mill’s components had been deliv- how well it reduces granules. The evaluation calls for in-
ered and installed and then recorded the specification (as formation on the mill control instruments’ calibration re-
listed in the manufacturer’s operations manual) and as- quirements, the equipment control functions (including
found condition for each component in the validation pro- switches,pushbuttons, and indicators), and equipment op-
tocol (Table I). eration (including the rotor blades and auger rotation di-
rection and rotor blades and auger motor speeds when the
Component construction material specifications. The mill is empty).’
validation specialist also recorded the construction mate-
rial for each component that would contact the product:
Calibration requirements. Typically, the validation spe-
cialist would log the mill’s critical control instruments into
Mill chamber: Type 3 16 stainless steel. the plant database’s calibration system. This ensures that
any calibrated instruments on the mill are calibrated on a
Rotor blades: Type 3 16 stainless steel. regular schedule along with other instruments in the plant.
However, the only control instrument on the mill -an
Feed hopper: Stainless steel.
Auger: Stainless steel.
Screen: Type 3 16 stainless steel.
0
0
73
50 Powder and Bulk Engineering, June 1998
2.
ra
5
d
0
cn
0
52 Powder and Bulk Engineering, June 1998
analog ammeter - was noncalibrated. The specialist 2. Jogging the mill motor and verifying that the auger is
recorded the required information about the noncalibrated rotating in the same direction as the mill’s direction
instrument, as detailed in Table II. arrow.
Equipment control functions. Next the validation spe- The validation specialist recorded the results of both steps
cialist tested the mill’s control switches, pushbuttons, and in the protocol (Table II).
indicators to verify that they operated according to the
manufacturer’s [Link] specialist recorded the
results in the protocol (Table 11). Rotor blades and auger speed tests. Again with the mill
empty, the validation specialist tested the speed of the
rotor blades and auger. Both tests required a calibrated
Rotor blades and auger rotation direction test. Next the tachometer.
specialist tested the rotor blades and auger to ensure they
rotated in the correct direction when the mill was empty.
The procedure included two steps: The procedure for the rotor blades speed test required run-
ning the rotor blades at three fixed speeds by repositioning
the belts on the motor’s multistep flywheel and pulley. The
1. Jogging the mill motor and verifying that the rotor specialist measured the rotor blades’ speed with the
blades rotate in the same direction as both the incoming tachometer to verify that the measured speed was within
feed from the auger and the mill’s direction arrow. +lo percent of the three specified speed settings.
54 Powder and Bulk Engineering, June 1998
The specialist then compared the measured speeds with The procedure for the auger feed speed test required set-
the speed settings. The minimum speed setting was 1,000 ting the auger’s speed control dial at the minimum and
rpm 210 percent -that is, from 900 to 1,100 rpm; the maximum settings to control the auger [Link] valida-
measured speed was 1,028 rpm, which was acceptable. tion specialist measured the minimum and maximum
The medium speed setting was 2,450 rpm f 10percent or speeds with the calibrated tachometer and then verified
from 2,205 to 2,695 rpm; the measured speed of 2,580 that they were acceptable by comparing them with the
was acceptable. The maximum speed setting was 4,600 specified minimum and maximum speeds.
rpm +lo percent or from 4,140 to 5,060 rpm; the mea-
sured speed of 4,747 rpm was well within this range. In
the validation protocol, the specialist recorded the mea- The minimum specified auger feed speed was 21 rpm 210
sured speeds (Table n) as well as the identification num- percent at the speed setting 0 -that is, from 18.9 to 23.1;
ber and calibration due date for the tachometer used in the the measured speed was 21 rpm, which was acceptable.
tests. The maximum specified speed was 208 k10 percent or
Powder and Bulk Engineering, June 1998 55
auger rototion direction test results
Yes
Auger speed test results
Yes
Yes
from 187.2 to 228.8 rpm; the measured speed at 211 rpm granules. The test procedure, which required a placebo
fell in this range. The specialist recorded the information sample (lactose hydrous granules), sieve, pan, and scale,
in the validation protocol (Table II). was to weigh the granules remaining in the sieve before
and after milling to verify the size reduction.
Performance qualification First, the mill operator poured 1 kilogram of granules
After the mill has been properly installed and is operating through an 80-mesh sieve; the mesh size was sufficient to
as specified, the performance qualification (PQ) evalua- retain some granules. Undersize granules fell through the
tion establishes that the mill performs reliably under rou- sieve into the pan. The operator recorded the tared weight
tine, minimum, and maximum operating conditions. of the granules remaining in the sieve and in the pan in the
Elements required for the PQ evaluation, as shown in Fig- validation protocol, as shown in Table III. Then the opera-
ure 4, are information on the mill’s ability to reduce gran- tor poured the granules from the sieve and the pan into a
ules and the rotor blades and auger speeds. container and recorded the granules’ tared weight to ver-
ify any loss from the original sample (Table In).
Size reduction test. The size reduction test objectives were
to document that the mill performed as specified when Next the operator set up the mill with a screen that had the
loaded with granules and to verify that the mill reduced the same size perforations as the sieve. Running the mill at
0
0
73
56 Powder and Bulk Engineering, June 1998
2.
ra
minimum speed and then at maximum speed, the operator The validation specialist measured the rotor blades’ speed 5
d
poured the granules into the mill and recorded the mea- at minimum, medium, and maximum speed and compared
0
sured speeds in the protocol (Table III). The milled gran- these speeds with the specified feed ranges. As in the OQ cn
ules were caught in a container. evaluation, the specified speeds including A 0 percent ac- 0
ceptable variation were from 900 to 1,100rpm (minimum -0
S
speed), 2,205 to 2,695 rpm (medium speed), and 4,140 to E
-.
The operator then poured the milled granules through the 5,060 rpm (maximum speed). The measured speeds - cn
sieve, caught the undersize granules in the pan, and 1,010 rpm (minimum), 2,461 rpm (medium), and 4,652 s
3
recorded the tared weight of all the granules in the proto- rpm (maximum) -were all within the specified ranges. ca
col (Table III). Finally, the operator verified that the mill’s The specialist recorded this information in the protocol -0
0
operation acceptably reduced the granules’ overall parti- (Table III). d
cle size distribution by decreasing the granules (by Q
weight) retained on the sieve. %
P,
For the auger speed test, the procedure was to verify that 3
Q
the auger speed was within k10 percent of the mill’s fixed
Rotor blades and augerfeed speed tests. Both speed tests auger speeds at the minimum and maximum settings. m
r_
required a calibrated tachometer, as in the OQ evaluation. 7i
For the rotor blades speed test, the test procedure was to
verify that the rotor blades’ measured speed (at the shaft) The validation specialistused the tachometer to measure
was within the specified fixed speed range by measuring the auger speed and compared it with the auger’s fixed
the speed with the tachometer. speeds at the minimum and maximum speed settings of 0
and 6. As in the OQ evaluation, the minimum specified
fixed speed range was from 18.9 to 23.1 and the maxi-
mum speed range was from 187.2to 228.8. The measured
speeds - 20 (minimum) and 209 (maximum) - fell
within the specified ranges. The specialist recorded the
data in the protocol (Table III).
Results summary
The pharmaceutical plant successfully validated the com-
minuting mill and proved that the equipment will operate
properly within the tested limit^.^
ZQ. The mill was properly installed. The utilities met the
mill’s specified voltage and amperage requirements, and
the safety features functioned as intended.
[Link] the mill was empty, the mill’s control switches
operatedproperly and the rotor blades and auger rotated in
the right direction and at the specified speeds.
[Link] operating while loaded with granules, the mill
reduced their size under minimum and maximum condi-
tions. The rotor blades’ and auger’s speeds were within the
specified ranges. PBE
Editor’s notes
1. This article concentrates on validating the operation of new
equipment rather than quality control testing of the equipment over
its service life to meet product requirements.
2. Unlike the comminuting mill, some process equipment can’t be
operated without a material load and so can’t be completely
validated.
Powder and Bulk Engineering, June 1998 57
3. Once validation is complete, you’ll need to validate your equipment reduction,” pages 106-107,in Powder and Bulk Engineer-
again if any equipment components are changed and then revalidate ing’s comprehensive“Index to articles,”December 1997.
the equipment typically once every 1 or 2 years.
For further information Phillip A. Cloud is a validation specialist at Geneva Phar-
More details on the comminuting mill’s validation and maceuticals, 2655 West Midway Boulevard, Broomfield,
on equipment validation in general are available from the CO 80038-0446; 303/438-4542 (fax 303/438-4590; e-
author. mail: pacloud@[Link]).He has developed validation
protocols and performed qualijkation testing on hundreds
ofpieces of equipment and is the author ofpharmaceutical
For more information on size reduction equipment, see the Equipment Validation: The Ultimate Qualification Guide-
“Product summary” and “Resource catalogs” departments book (InterpharmPress, 1998) and The Engineering Pro-
elsewhere in this issue. Also see articles listed under “Size cedures (SOP) Handbook (NoyesPublications, 1998).
