Frederick National Laboratory for

Cancer Research, Frederick, MD

Standard Operating Procedure

Biopharmaceutical Development Program

Title: Equipment Calibration Program

SOP Number: 21508 Revision Number: 09
Supersedes: Revision 08 Effective Date: AUG 18 2020

Originator/Date:

Approval/Date:

Approval/Date:

Table of Contents

1.0 Purpose
2.0 Scope
3.0 Authority and Responsibility
4.0 Definitions
5.0 Procedure
6.0 Equipment Labeling
7.0 Transportability Testing
8.0 Unscheduled Recalibration
9.0 Standards
10.0 Management of Out-of-Calibration Conditions
11.0 Documentation
12.0 References and Related Documents
13.0 Attachments

1.0 Purpose
This SOP describes the equipment calibration program within the Biopharmaceutical
Development Program (BDP).

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

2.0 Scope
This SOP applies to the calibration of CGMP and non-CGMP control, weighing, measuring,
monitoring, and test equipment within the BDP, unless otherwise exempted by QA Engineering.
This SOP applies to subcontractors and internal personnel who perform calibration services for
the BDP. Instructions for how to calibrate specific devices are found in supporting Standard
Operating Procedures (SOP).
3.0 Authority and Responsibility
3.1 The Director, Biopharmaceutical Quality Assurance (BQA) has the authority to define
this procedure.
3.2 Facilities, Maintenance, and Engineering (FME) is responsible for:
3.2.1 Performing calibration, unless otherwise performed by BDP, or a BDP or FME
subcontractor.
3.2.2 Documenting raw calibration data, any adjustments made to the units under
test, and applicable comments and/or observations in the calibration program
management software.
3.2.3 Notifying at a minimum the Quality Engineering and Validation Manager via
email or via means of the calibration software of any out-of-tolerance events
identified during calibration. Additional staff such as the Equipment Owner and
the Facility Manager would also benefit from the notification. Notification should
occur before close of business on the day detected whenever possible.
3.3 Quality Engineering and Validation, BQA is responsible for (Functions with an asterisk*
may also be performed by validation contractors of the BDP):
3.3.1 Overseeing the execution of this procedure. *Validation contractors may
oversee the performance of calibration by an outside contractor.
3.3.2 Reviewing the Request for Equipment Calibration, Form 21508-01 (Attachment
2). The Quality Engineer is responsible for ensuring that pertinent information
about the equipment is reasonable and customary for its intended use, such as
range, tolerance, interval, et cetera.
3.3.3 *Reviewing equipment calibration records.
3.3.4 Performing investigations and assisting the Manager/Supervisor and Project
Scientist in determining the potential product impact of equipment which is
found to be out-of-calibration.
3.3.5 *Ensuring correct performance and documentation of calibration.
3.3.6 Initiating an Engineering Event (EE) per SOP 21526 - Engineering Event
Management for any out-of-tolerance events requiring an EE.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

3.3.7 Determining acceptability of proposed repair/parts replacement strategies when

required to correct an out-of-calibration or failure condition, in collaboration with
BDP Business Operations, equipment owners, and BDP engineering, as
appropriate. Ensuring the appropriate corrective and preventative actions
(CAPA) have been properly made, documented, and approved.
3.4 Equipment Owners are responsible for:
3.4.1 Ensuring their equipment is entered into the Calibration Program (see Section
5.1 - Entering Equipment into the Calibration Program).
3.4.2 Submitting or preparing equipment/instruments for calibration on schedule.
3.4.3 Units that are beyond their calibration Due Date are considered Out of
Calibration as defined in Section 4.1.1. It is the responsibility of the equipment
owner to placard these units as “out of service” using Form 21508-03
(Attachment 4) or posting the equivalent information. CGMP and GLP
equipment and instruments beyond their calibration expiry may not be used
without an approved deviation, initiated per SOP 21301 - Deviations from
Written Documents and Corrective and Preventative Actions.
3.4.4 Ensuring their equipment IS NOT USED OUTSIDE OF THE CALIBRATED
RANGE AND TOLERANCE.
3.4.5 Determining the root cause and potential impact on production, testing, or R&D
activities for equipment which is found to be out-of-calibration, in consultation
with the Project Scientist and Quality Engineer.
3.4.6 Notifying BQA or designee if they wish to change the calibration status of
equipment, i.e., make the equipment “Inactive,” modify the tolerance, etc.
Consider changing the Calibration Status to “Inactive” if the equipment will not
be used for a long period, as in the case of campaign specific equipment.
Approval must be given by BQA or designee before tolerances may be
modified. This is best done if the unit has not been used since the last
calibration or following a calibration so that there is less risk from as found data
OOT. (The calibration software provides an audit trail of all changes.)
3.5 Quality Assurance is responsible for:
3.5.1 Maintaining the calibration section of the Master Equipment Files (MEF).
3.6 BDP Engineering is responsible for:
3.6.1 Informing equipment owners of equipment past due for calibration and pending
calibrations each month, providing notice in advance of the due date.
3.6.2 Completing and submitting the Request for Vendor Services form indicating
“units to be calibrated according to BDP procedure.” (See Attachment 5).
3.6.3 BDP Engineering or a designee enters external vendor calibration data into the
software and performs the first review.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

3.7 Backup of the database is managed by the IT Operations Group (ITOG) with a routine
backup protocol in place. See SOP 10102 - Computer System Operations Backup
and Recovery for additional details.
4.0 Definitions
4.1 Calibration – The process of comparing measurement and test equipment to
standards of known accuracy to detect and/or rectify deviations.
4.1.1 Out-of-Calibration – The state of measurement or test equipment that is either
Out-Of-Tolerance (OOT) (see below), or that has exceeded its calibration
interval. (Requests for Vendor Service that pull the equipment from
service and are being processed and shipped are not considered to have
exceeded the calibration interval as this process sometimes has duration
of several weeks for turnaround.)
4.1.2 Out-Of-Tolerance (OOT) – The state of measurement or test equipment that
fails to meet its specified level of calibration (calibrated range and/or
calibrated tolerance). Note that this level of calibration may differ from the
manufacturer’s calibration. Failure to meet the manufacturer’s calibration
may therefore not create an OOT. This OOT state must be investigated and
documented within the calibration software or as an Engineering Event (EE) if
there is any potential for system or product impact. EEs are tracked according
to SOP 21526 - Engineering Event Management.
4.2 Range - The smallest and the largest values associated with operation of an
instrument.
4.2.1 Manufacturer’s Range: The range that is specified by the manufacturer of the
unit at the time of sale, over which the Manufacturer’s Tolerance (see below)
applies.
4.2.2 Calibration Range: The range over which the unit is calibrated, which may
differ, by being reduced, from the range over which the unit will operate. The
calibration range is set by the equipment owner and Quality Engineering
keeping in mind the intended process where the device will be used.
4.3 Span – The number of units between the low and high value of the range. For
example, a pressure gauge with a calibration range from 20 to 100 psig has a span of
80 psig.
4.4 Tolerance - The allowable deviation from a known measurement value, based on the
accuracy of the unit under test. A pressure gauge which reads at 100 ± 1 psig has a
tolerance of ± 1 psig, or ± 1% (99 to 101 psig). This is also known as the statement of
accuracy.
4.4.1 Manufacturer’s Tolerance: The statement of accuracy that is guaranteed by
the manufacturer of the unit at the time of sale.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

4.4.2 Calibration Tolerance: The statement of accuracy that is applied to the unit by
the equipment owner and the Quality Engineer. This number reflects the
accuracy established for calibration. The calibration tolerance may be wider
than the manufacturer’s tolerance. The value may never be tighter than the
manufacturer’s tolerance.
4.4.3 Process Tolerance: This number reflects the accuracy required for the process
in which the unit operates. The process tolerance is typically wider than the
manufacturer’s tolerance and is often wider than the calibration tolerance. The
value may never be tighter than the manufacturer’s tolerance. Exceeding the
process tolerance has the potential to impact the process.
4.5 Levels of Calibration
4.5.1 Calibrated (Calibration LEVEL 1): When measurement and test equipment
have been compared to primary or secondary standards to detect and/or adjust
deviations to within the manufacturer's specifications for tolerance over the full
manufacturer’s range.
Units that are CALIBRATED LEVEL 1 meet manufacturer’s range and
manufacturer’s tolerance specifications.
4.5.2 Limited Range Calibration (Calibration LEVEL 2): When measurement and test
equipment have been compared to primary or secondary standards to detect
and/or adjust deviations to within the manufacturer's tolerance specifications
over a limited range, which is less than the range specified by the
manufacturer. Use is only valid within the stated range.
Units that are CALIBRATION LEVEL 2 do not match manufacturer’s range
but do match manufacturer’s tolerance specifications.
4.5.3 Modified Tolerance Calibration (Calibration LEVEL 3): When measurement
and test equipment have been compared to primary or secondary standards to
detect and/or adjust deviations to within stated specifications and tolerances as
established by BDP and not the manufacturer. Use is only valid within the
stated range and tolerance.
Units that are MODIFIED TOLERANCE CALIBRATION LEVEL 3 do not
match manufacturer’s range and/or tolerance specifications.
4.5.4 Single-point Calibration (Calibration LEVEL 4): When measurement and test
equipment have been compared to primary or secondary standards to detect
and/or adjust deviations to within the stated specifications and tolerances at
one specific point. The point at which the device has been calibrated must be
the point at which the device will be used. Measurements taken with the device
are valid only if they are within ± 5% of the calibrated point or within ± the
tolerance BDP specified for the device, whichever is more stringent.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

4.5.4.1 This level of calibration is intended for measuring devices that are an
integral part of a larger system and cannot, with ease, be used in
some other application. It will be employed when other levels of
calibration are not feasible because of concerns for safety of product,
equipment, or personnel. The technician must cause a small
fluctuation in the reading to ensure that the device under calibration is
not stuck in position.
4.5.5 Verified (Calibration LEVEL 5): When a non-calibratable signal is tested for its
on/off (binary) characteristic, it is labeled as verification for calibration records.
4.5.6 For Reference Only (Calibration Not Required): This status is applied to
instruments that are qualitative indicators only. It also applies to instruments
whose output results in no action except directing the user to another
CALIBRATED instrument for additional information. Typically, the BDP applies
a “For Reference Only” (or FRO) status to instruments with qualitative readouts
such as color zone (red/yellow/green) indicators on pneumatic filters or where
redundant instruments that are not used for control or process decisions are
found. These FRO instruments may also be found on “Indirect Impact” or “No
Impact” Systems as defined by ISPE’s Pharmaceutical Engineering Guides for
New and Renovated Facilities, as well as those utility systems and equipment
designated as lowest risk level according to the FMEA-based risk assessment
as described in the BDP’s Facility Validation Master Plan.
4.6 Interval: The period between calibrations of measurement and test equipment.
4.7 Measurement and Test Equipment: Instruments or devices used to measure,
gauge, test, inspect, or otherwise examine.
4.8 Primary Measurement Standard: An instrument or device of known accuracy which
is used in a calibration system as a standard of reference and is directly traceable to
the National Institute of Standards and Technology (NIST) or equivalent institution.
4.9 Secondary Measurement Standard: An instrument or device of known accuracy
which is used in a calibration system as a standard of reference and is traceable
through other standards to the NIST or equivalent institution.
4.10 Intrinsic Standard: A standard of reference by whose construction causes it to follow
natural and physical laws of nature. The accuracy of the standard is controlled by the
natural and physical laws of nature. Examples include the freezing and boiling points
of purified water at standard sea level pressure.
4.11 Test Accuracy Ratio (TAR): The ratio of the tolerance of the unit under test (UUT) to
the tolerance of the standard being used for calibration. BDP requires that the TAR be
greater than or equal to 4:1. See Section 9.4.
4.12 Accuracy of Scales and Balances: Calculate the overall accuracy for a scale or
balance, unless specified by the manufacturer, using the NIST Handbook 44, 2000,
Section 2.20, Scales, T.N.3. Tolerance Values, Table 6, Maintenance Tolerances,
Table 3.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

4.13 As Found: The condition of an instrument/equipment prior to having an adjustment

made to it. This also pertains to the data taken from this instrument/equipment.
4.14 As Left: The final condition or condition of an instrument/equipment after having an
adjustment made to it. This also pertains to the data taken from this instrument/
equipment.
4.15 Multichannel Instrument: A unit that has either separate physical or logical
pathways for measurement; for example, multichannel pipettes (separate physical
pathways), or airborne particle counters that give results by particle size (separate
logical pathways).
5.0 Procedure
5.1 Ente ring Equipment into the Calibration Program
5.1.1 Purchase Requests (PRs) will be routed through Quality Engineering (QE)
and/or FME before new equipment is ordered. QE and/or FME indicates in
writing on the PR or via e-mail whether calibration, validation, and other
considerations for this equipment are required upon arrival.
5.1.2 BOP Purchasing provides a copy of this PR to the equipment requester.
5.1.3 When the equipment arrives on-site, if QE has indicated that calibration is
required for that piece of equipment, the Equipment Owner completes Form
21508-01, Request for Equipment Calibration (Attachment 2).
5.1.4 The Equipment Owner routes the form to BQA Engineering for review and
approval.
5.1.5 BOP Engineering or authorized designees enter the information into the
calibration software system.
5.1.6 If equipment comes with a Calibration Certificate, the Equipment Owner
forwards the certificate to BQA Engineering for review.
5.1.6.1 If BQAE approves the certificate, the calibration due date for the
equipment is entered as the date of calibration on the approved
certificate plus the calibration frequency (to the end of the month).
If BQAE does not approve the certificate or if equipment does not
come with a Calibration Certificate, the initial calibration due date for
the equipment will be the day the equipment is entered into the
calibration management program.
5.1.7 The approved Request for Calibration is filed in the MEF folder for that piece of
equipment.
NOTE: Some equipment may not be acquired via PR and some equipment
may have calibration requirements entered directly in the calibration
management software without Form 21508-01. Direct entry occurred
for many components during relocation to the - Direct entry is
not intended to replace the need for an owner or user to provide and
receive consultation on calibration requirements.
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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

5.2 Maintaining a Calibrated Status

5.2.1 BDP Engineering accesses the computer database at least monthly to identify
equipment coming due for calibration, as well as overdue calibration dates.
This report, which includes Contact Name and Due Date, is distributed to
equipment owners monthly. This ensures that equipment owners have
advanced notice that their equipment is due for calibration.
5.2.2 The Instrument Shop technician contacts the equipment owner or designee to
coordinate a schedule for calibration.
5.2.3 In the event that the calibration is performed by an outside vendor, BDP
Engineering completes a “Request for Vendor Services Form,” or RVS, and
submits it to the FNLCR Purchasing Department. FNLCR Purchasing attaches
a cover letter indicating that the calibration must be completed to meet BDP
specifications. A sample cover letter to accompany an RVS Form is given in
Attachment 5.
5.2.4 In the event that an instrument has exceeded its calibration interval, the
instrument is now “Out of Calibration,” as defined in Section 4.1.1. Once
notified of or detecting the condition, equipment owners are responsible for
placarding the instrument as “Out-of-Service” and handling these units
according to Section 3.4. QA will verify that required placarding is in place.
NOTE: The user or equipment owner is also responsible for informing QE or
BDP Engineering in writing (e-mail is acceptable) if an instrument is
suspected to be out of calibration for any reason. Upon notification,
QE, its designee, or the owner will remove the instrument from service
using Form 21508-03 (Attachment 4), until the problem is resolved.
5.3 Changing the Calibration Status
5.3.1 The Calibration Status, including the level of calibration, may be changed for
equipment based on usage and criticality/process tolerance.
5.3.2 Change in the level of calibration which includes changing the calibrated range
or tolerance will be considered based on system use and criticality/process
tolerance.
5.3.3 Changing the status to “Inactive” should be considered if the equipment will not
be used for a long period as in the case of campaign specific equipment. This
will reserve program resources although the possibility of failure on as-found
data since the last usage and calibration must be considered. The unit must be
tagged as “out of service” using Form 21508-03 (Attachment 4) or otherwise
posted with the equivalent information. Removing calibration stickers from
inactive equipment is recommended but not required. The Area Clearance
process per SOP 21104 - Pre-Production Clearance will review calibration
status prior to any GMP use of equipment.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

5.3.4 The status will be changed to “Retired” for equipment no longer in service. This
would typically occur for components that are damaged beyond repair, totally
removed from service, or for equipment that has been retired from use in the
MEF program. Placarding of this status is not required as the component or
equipment affected is no longer present in the facility or has been changed to a
“For Reference Only” status.
5.4 Performing Calibration (In House)
5.4.1 The Instrument Shop technician calibrates the instrument using the BDP
instrument-specific SOP for calibration. Follow guidance in SOP 22012 –
Significant Figures and Rounding of Numbers with calibration data.
5.4.2 When performing a calibration, the instrument should be adjusted whenever
the as-found value excessively approaches the calibration tolerance. Failure to
readjust the instrument will reduce the safety margin against drift during the
next calibration interval. As a guide, the as-left value is recommended to
provide for a safety margin ≥30% of the calibration tolerance. For example, if
the tolerance is ±10 units, the as left should not exceed ±7 units when possible
via adjustment. (If consistent tolerance cannot be achieved over the range of
the equipment, target the operating range for the lowest deviation.) In the case
that the instrument is not adjustable, it is recommended to indicate this fact in
the master record of the calibration software. This can also be noted in an
equipment history as a comment.
5.4.3 The technician records all data including the application of an electronic
signature in the calibration data management software per SOP 21555 - Use
and Management of Blue Mountain Regulatory Asset Manager
5.4.4 The technician must enter the necessary information into the equipment logs
according to SOP 21531 - Equipment Logs. For Calibration entries this would
include at a minimum; date, time, generic description of calibration activity, and
the technician’s initials. If the work takes more than one day to complete, at
least two entries should be made. The first entry will indicate the start of the
task and the second would indicate when the task is completed. If the activities
are part of a work order, the WO # should be recorded. Failures or
replacements should provide sufficient detail to identify the component(s)
involved and the action taken.
5.4.5 Details of how to review and approve calibration data are found in SOP 21523 -
Calibration Data Review.
5.5 Performing Calibration (External Vendor)
5.5.1 The request for calibration is initiated with a Request for Vendor Service or
RVS.
5.5.2 Either the unit is shipped to the vendor site or the vendor comes on-site
depending on the agreement to complete the calibration.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

5.5.3 The vendor’s Calibration Certificate is scanned and attached to the file in the
calibration software and any pertinent information entered. The electronic
history is then electronically signed for authorship per SOP 21555 - Use and
Management of Blue Mountain Regulatory Asset Manager.
5.5.4 Details of how to review and approve calibration data are found in SOP 21523 -
Calibration Data Review.
5.5.5 The hard copy of the certificate, with the MEF ID indicated by writing or
highlighting it, is sent to BQA for filing in the MEF.
5.5.6 The hard copy need only be filed in the MEF. There is no need to enter the
documentation into the MEF TOC as the details, including a link to the scanned
document, are sufficiently captured in the Blue Mountain Software.
5.6 Calibration Specifications
5.6.1 Calibrations require as-found and as-left data to be recorded. The only
exception to this is in the case of new equipment or disposable equipment such
as timers. If new equipment comes with a Calibration Certificate that has been
approved by Quality Engineering that data may suffice as “as-found.”
Otherwise, if no as-found data is available, the unit is considered Out-of-
Tolerance (OOT) as defined in Section 4.0. Timers and flowmeters for the glass
vessel Celligen are received and placed into service using the Calibration
Certificates. These devices may not receive further calibration when their
interval is reached and may simply be retired from service. If any other
equipment is desired to be handled this way, written justification and approval
of Quality Engineering is required.
5.6.2 There must be at least three measurements taken (preferably five), covering at
least 70% of the BDP established calibration range of the device or as
otherwise specified.
5.6.3 The preferred calibration points are 10% and 90% of the BDP established
calibration range and normal setpoint (mid span if no normal or operational
setpoint).
5.6.3.1 For loops containing multiple components, the smallest read-out
range will be the basis for the manufacturers’ specifications and
tolerances.
5.6.3.2 For multichannel devices with separate physical channels (i.e.,
multichannel pipettes), at least three measurements must be taken
per channel.
5.6.3.3 For multichannel devices with separate logical channels (i.e., particle
counters), at least one measurement must be taken per channel.
5.6.4 The standard used to calibrate has an accuracy of at least four times better
than the accepted accuracy of the unit to be calibrated (see Section 9.4 for
additional detail).
5.6.5 Standards are NIST traceable whenever available.
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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

5.6.6 Calibrations will take the system's approach. Whenever possible, the
transducer, transmitter, and read-out device will be calibrated together as a
loop.
6.0 Equipment Labeling
6.1 Internal Calibration
6.1.1 After calibration, a calibration label is created by running the Cal Label Report
in BMRAM. Generating labels this way removes the chance of typographical
errors on the label as it is automatically generated from the calibration record
which is seen by the calibration technician and reviewed by QA.
Examples are included in Attachment 1.

Information Found on Calibration Stickers

Sticker Type (A) B C D E F G
Calibrated X X X X X X
Lim ited Range
X X X X X X
Calibrated
Modified Tolerance
X X X X X X
Calibrated
Single Point Calibrated X X X X X X
Verified X X X X
For Reference Only

A) The level or type of calibration

B) The identification number (ID number) of the instrument;
C) Date the instrument is next due;
D) Calibrated Range for instrument;
E) Calibrated Tolerance of the instrument
F) Name of person who calibrated the instrument;
G) Date the instrument was calibrated (MM/DD/YY);

6.1.2 The calibration due date for the equipment is the last day of the month of the
established interval. For example, if the calibration date was 6/23/20, and the
interval for that instrument is 1 year (12 months), then the calibration due date
will be listed as 6/30/20.
6.1.3 The calibration attaches the generated calibration stickers. Stickers must be
placed in clear view on the instrument. When calibration is performed, the old
sticker must be removed and discarded before attaching the new sticker.
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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

6.1.4 If review of the calibration record finds an error that impacts the calibration
sticker, a new sticker will need to be generated once the record is corrected. If
the range or tolerance was modified the sticker will need to be generated
manually as those values cannot be changed on an open work record.
6.1.5 For on demand calibrations, the due date is not displayed on the sticker. A
supplemental sticker to display the due date shall be placed adjacent to the
calibration sticker or the date added with permanent ink and initial and dated.
6.2 External Vendor Calibration
6.2.1 Due to vendor variability, stickers from external vendors will vary with the
format and type of information included.
6.2.2 Stickers must contain at a minimum the following: ID of the equipment and the
calibration date. If the calibration interval is anything other than 1 year (due at
end of month calibrated) the date calibration is due must also be included.
6.2.3 If the vendor sticker lacks required information a supplemental calibration
sticker may be applied.
6.2.4 Alternatively, a BDP sticker may be applied to equipment calibrated by external
vendors. This sticker should indicate “Additional calibration information found in
calibration database” or similar wording with the same meaning. This is a result
of the variability and reduced information as compared with the internal sticker.
7.0 Transportability Testing
7.1 Equipment in the Calibration Program is either portable or non-portable. The non-
portable equipment must be recalibrated each time that it is moved over 10 feet.
7.2 Portable equipment is equipment that is deemed portable by the manufacturer. In most
cases, it has wheels or has a carrying case or some indication that the manufacturer
meant for it to be moved frequently. Along with this assumption is the understanding
that the unit has been tested to ensure that it will maintain its calibration throughout its
moves. Transportability testing using Form 21508-02 (Attachment 3) addresses
equipment that is generally possible to move but may not have appropriate testing by
the manufacturer to ensure that it will maintain its calibration after a move.
7.3 Procedure
7.3.1 Calibrate the unit. Record the required data along with the location of the unit
under test (UUT).
7.3.1.1 Move the UUT to a new site that would approximate the conditions
and move distance that the unit is expected to encounter in a “worst-
case” operation. Calibrate the unit. Record the required data along
with the location of the unit under test (UUT).
7.3.1.2 Move the UUT a second time. It may go back to the original or to a
new site.
7.3.1.3 Calibrate the unit. Record the required data along with the location of
the unit under test (UUT).
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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

7.3.1.4 Move the UUT a third time.

7.3.1.5 Calibrate the unit. Record the required data along with the location of
the unit under test (UUT).
7.3.1.6 The three moves must be completed in less than the calibration
interval.
7.3.2 For the initial calibration the unit should be adjusted to the centerline of the
tolerance.
7.3.2.1 For subsequent calibrations, “as-found” data must be within tolerance.
7.3.2.2 No adjustment is allowed after the initial calibration.
7.3.2.3 If the unit fails the “as-found,” then perform an investigation to
determine the cause. If it is determined that it was not the fault of the
move, then the testing can be repeated in its entirety.
7.3.2.4 To be deemed portable for calibration purposes, the UUT must pass
calibration each time after a move for three consecutive times.
7.3.3 The testing must be documented.
7.3.3.1 A final report must be written by BDP staff reviewing the data and
stating the outcome of the testing.
7.3.3.2 The final report is approved by the Quality Engineer and stored in the
calibration file of the Master Equipment Files.
8.0 Unscheduled Recalibration
8.1 Calibrated equipment will be assessed for recalibration after repair, damage, or
physical, electronic, or other changes that could impact operation, range, accuracy, or
tolerance.
8.2 Any repair that causes the instrument case to be opened may be reason for
recalibration of the equipment.
8.3 Any repair that deals with that section of the instrument that affects the parameters
being calibrated will be reason for recalibration.
8.4 The equipment owner and BQA Engineering will decide if the date of recalibration may
become the calibration date and the start of the new calibration cycle. By system
default, the due date will not change with an on-demand calibration event.
8.5 The BDP Engineer, the Equipment Owner, or the BQA Engineer can require
recalibration.
8.6 The calibration program will indicate that the reason for calibration was unscheduled
and why. The comments shall state whether the unit was repaired or changed.
9.0 Standards
9.1 Standards must always be maintained in a calibrated state or labeled as “Out of
Calibration - Do Not Use.”
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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

9.2 Standards must be kept in a clean, secured, low-traffic area when not in use.
9.3 The calibrating agency will have records directly traceable to the NIST.
9.4 Standards must be, at a minimum, four times more accurate than the instrument or
device with which they are being compared (4:1), whenever possible. If the standard
used for calibration is not at least four times more accurate than the instrument or
device, this must be noted on the history for internal calibrations and on the certificate
for external calibrations. State the test accuracy ratio (TAR) of the standard to the
instrument or device. The 4:1 TAR shall be maintained for internal calibrations unless
the BDP does not have an available standard to achieve the required TAR.
9.5 If a standard is found to be out-of-calibration, the investigation shall include a review of
all instrumentation calibrated in the past interval using this standard, to determine
possible impact.
9.6 Intrinsic standards do not require calibration. However, as all standards must be
approved in order to be used per BRRAM, they shall be treated like other standards
with respect to history records and review.
10.0 Management of Out-of-Calibration Conditions
10.1 An Out-of-Calibration condition (OOC) occurs when quantitative equipment fails to
meet its specified level of calibration (has been found out-of-tolerance or OOT) or has
exceeded its calibration interval.
10.1.1 When an OOC is the result of an out-of-tolerance (OOT) condition,
encountered during the “as-found” testing, it is recorded, and every effort is
made to rectify the situation. How the situation was rectified is recorded by the
calibration technician if the method goes beyond calibration adjustment
considered standard for the device. If the OOT condition cannot be rectified,
the calibration technician removes the equipment from service and attaches an
“out-of-service” tag or Form 21508-03 (Attachment 4) to it and the calibration
“Fails.” The calibration technician then notifies, at a minimum the Quality
Engineering and Validation Manager, of any out-of-tolerance events identified
during calibration. Additional staff such as the Equipment Owner and the
Facility Manager would also benefit from the notification. (This function may be
handled via e-mail or automated notification.) Notification should occur before
close of business on the day detected whenever possible.
10.1.2 OOT Investigation
10.1.2.1 Each OOT must be investigated. The investigation intent is to
determine the impact of the event to the operation of the equipment
and any direct or indirect impact to product. In addition, the
investigation looks at cause if known, history of the component
during previous calibration cycles, and determines if the calibration
interval should be reduced or the calibration tolerance widened if
allowable based on the process.

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SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

10.1.2.2 Investigations are documented in one of two ways; directly within

fields in the calibration management software when there is no risk
of product impact as supported by the nature of the OOT or facts of
the investigation, or via an Engineering Event per SOP 21526 -
Engineering Event Management, when there is a possibility of
product impact, and should consider other factors such as criticality
and the need for additional input from other BDP staff. Examples
are provided later in this section; when unclear which method to
use, document the investigation using an EE.
10.1.2.3 In the case of an OOT standard, the first step is to perform a
reverse traceability report to determine where the standard was
used. This report should be included in the investigation whenever
results are returned. If the standard was not used during the interval
in question, simply state that fact.
10.1.2.4 Example 1. Temperature standard X is found OOT at two points
(300°C and 500°C) across the range of 0-500°C. A reverse
traceability shows that all components calibrated had a max
temperature in their range of 200°C. The calibration points of 0°,
100°, and 200°C met calibration tolerance. It is clear that the failures
above 200°C do not impact the calibrations performed. This
investigation may be documented without an EE.
NOTE: If the range required is not clearly bracketed i.e., the
calibration point of 100°C and the next of 300°C which
failed was used you cannot ascertain that things were OK
at 200°C. The degree of failure must now be considered in
the investigation.
10.1.2.5 Example 2. Pressure standard X has a calibration tolerance of
±0.002 psi and has an OOT with a result of 0.005 psi. As standards
should maintain a 4:1 ration unless otherwise stated the OOT
difference of 0.003 x 4 = 0.012 psi. If the calibration tolerance of the
Unit Under Test (UUT) is not less than 0.012 the calibration is still
valid. If the ratio is followed there is no impact, if the ratio is not met
there may be impact and an EE should be initiated.
10.1.2.6 Example 3. An analog pressure gauge on an autoclave has failed
and as found data cannot be obtained. This calibration would be
both OOT and FAIL. The investigation shows that the gauge
measures chamber pressure. This failure is not critical in this case if
the chamber pressure transducer calibration has met specification.
The gauge is non-controlling. The transducer is the instrument that
is more accurate and controlling for steps in the autoclave cycle. An
EE would not be required.

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FNLCR, BDP Page 16 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

NOTE: An OOT discovered and reported by calibration services

vendor may not be OOT according to BDP specifications.
Calibration vendors are required to calibrate BDP
instruments according to manufacturers’ specifications. If
BDP uses a modified tolerance or range (i.e., “process”
tolerance or range), and the instrument’s calibration data
meet those specifications captured for the equipment in
the calibration software application, this situation is not
considered an OOT. The BDP Quality Engineer who
reviews the data from the vendor is responsible for
determining whether an OOT per BDP specifications has
occurred.
10.2 Equipment that has been removed from its place of operation to be calibrated must not
return to that place in an OOC condition. If the article cannot be repaired, it must be
given to QA Engineering or BDP Engineering for disposition.
11.0 Documentation
11.1 Calibration is captured in an electronic system via SOP 21555 - Use and
Management of Blue Mountain Regulatory Asset Manager.
11.2 Calibration activities must be recorded in the equipment log, when applicable. Refer to
Section 5.4.4.
11.3 The calibration section of the MEF contains hard copies of calibration records
performed by outside vendors and is maintained by BQA Documentation and kept in
accordance with SOP 21520 – Equipment Management and Control.
12.0 References and Related Documents
12.1 SOP 10102 Computer System Operations Backup and Recovery
12.2 SOP 21104 Pre-Production Clearance
12.3 SOP 21301 Deviations from Written Documents and Corrective and
Preventative Actions
12.4 SOP 21520 Equipment Management and Control
12.5 SOP 21523 Calibration Data Review
12.6 SOP 21526 Engineering Event Management
12.7 SOP 21531 Equipment Logs
12.8 SOP 21555 Use and Management of Blue Mountain Regulatory Asset
Manager
12.9 SOP 22012 Significant Figures and Rounding of Numbers

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FNLCR, BDP Page 17 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

12.10 Regulatory References

12.10.1 21 CFR 211 Subpart D – Equipment
Section 211.68 Automatic, mechanical, and electronic equipment.
a) “Automatic, mechanical, or electronic equipment or other types of
equipment, including computers, or related systems that will perform a
function satisfactorily, may be used in the manufacture, processing,
packing, and holding of a drug product. If such equipment is so used, it
shall be routinely calibrated, inspected, or checked according to a written
program designed to assure proper performance. Written records of those
calibration checks and inspections shall be maintained.”
12.10.2 21 CFR 211 Subpart I – Laboratory Controls
Section 211.160 General requirements.
b) (b) (4) “Laboratory controls shall include….The calibration of instruments,
apparatus, gauges, and recording devises at suitable intervals in
accordance with an established written program containing specific
directions, schedules, limits for accuracy and precision, and provisions for
remedial action in the event accuracy and/or precision limits are not met.
Instruments, apparatus, gauges, and recording devices not meeting the
established specifications shall not be used.”
12.10.3 21 CFR 58 Subpart D – Equipment
Section 58.63 Maintenance and calibration of equipment.
c) (a) “Equipment shall be adequately inspected, cleaned, and maintained.
Equipment used for the generation, measurement, or assessment of data
shall be adequately tested, calibrated, and/or standardized.”
d) (b) “The written standard operating procedures required under 58.81 (b)
(11) shall set forth in sufficient detail the methods, materials, and schedules
to be used in the routine inspection, cleaning, maintenance, testing,
calibration, and/or standardization of equipment, and shall specify, when
appropriate, remedial action to be taken in the event of failure or
malfunction of equipment. The written standard operating procedures shall
designate the person responsible for the performance of each operation.”
e) (c) “Written records shall be maintained of all inspection, maintenance,
testing, calibrating, and/or standardizing operations. These records,
containing the date of the operation, shall describe whether the
maintenance operations were routine and followed the written standard
operating procedures. Written records shall be kept of non-routine repairs
performed on equipment because of failure and malfunction. Such records
shall document the nature of the defect, how and when the defect was
discovered, and any remedial action taken in response to the defect.”

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FNLCR, BDP Page 18 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

12.10.4 Guidance for Industry: CGMP for Phase 1 Investigational Drugs, July 2008
f) Section (V) (C.), Facility and Equipment, states that “Each facility shall
provide the following described work area and equipment: Appropriate
equipment that will not contaminate the phase 1 investigational drug or
otherwise react with, add to, or be absorbed by the phase 1 investigational
drug; and that is properly maintained, calibrated, cleaned, and sanitized at
appropriate intervals following written procedures.”
12.11 Technical References
12.11.1 BDP Facility Validation Master Plan, VMP-003.
13.0 Attachments
13.1 Attachment 1 Calibration Stickers
13.2 Attachment 2 Form 21508-01- Request for Equipment Calibration
13.3 Attachment 3 Form 21508-02 - Transportability
13.4 Attachment 4 Form 21508-03 - Out of Service
13.5 Attachment 5 Requirements for Requesting Vendor Calibration

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FNLCR, BDP Page 19 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

Attachment 1
Calibration Stickers

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FNLCR, BDP Page 20 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

Attachment 2
Form 21508-01 - Request for Equipment Calibration

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FNLCR, BDP Page 21 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

Attachment 3
Form 21508-02 – Transportability Testing

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FNLCR, BDP Page 22 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

Attachment 4
Form 21508-03 - Out of Service

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FNLCR, BDP Page 23 of 23
SOP Number: 21508 Revision Number: 09 Effective Date: AUG 18 2020
Title: Equipment Calibration Program

Attachment 5
Request for Vendor Services Sample Cover Letter
To Whom It May Concern:

The equipment that you are about to calibrate is for the BIOPHARMACEUTICAL
DEVELOPMENT PROGRAM (BDP) – Leidos Biomedical Research, Inc. All calibrations must be
in accordance with ANSI/NCSL Z540.3 - 2006 or equivalent. These calibrations must have, as a
minimum, three (3) data points that cover at least 70% of the range of the unit under test (UUT).
The preferred calibration points are 10% and 90%, and normal setpoint (mid span if no normal
setpoint). Multi-channel devices with separate physical channels (i.e., multi-channel pipettes)
must have at least 3 measurements taken per channel. Multi-channel devices with separate
logical channels (i.e., particle counters) must have at least one measurement taken per channel.

Both the “as received/as found” and “as returned/as left” data must be recorded on the Calibration
Certificate by the person(s) performing the calibration procedure(s). Repairs must be authorized
before being performed and shall use like-for-like components whenever possible. The
description of the repair shall be included on the Calibration Certificate. The Calibration
Certificate must be signed by a responsible person within the organization. If the received unit is
inoperable, a written statement to that effect must accompany the Calibration Certificate. The “as
returned/as left” data can be the same as the “as received/as found” data if no adjustments were
made to the UUT.

Standards must be, at a minimum, four times more accurate than the instrument or device with
which they are being compared, whenever possible. If the standard used for calibration is not at
least four times more accurate than the instrument or device, the test accuracy ratio (TAR) of the
standard to the instrument or device must be noted on the calibration datasheet/certificate.
Standards shall be NIST-traceable, whenever possible.

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