STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

1.

2.

Page 1 of 12

1.1

To comply with the requirement of policy XYZ on revalidation/requalification.

1.2

To outline the procedure by which the Validation Services Department periodically evaluates
the performance of previously validated facilities, equipment, systems, and processes. This
evaluation includes a periodic review of performed critical changes/repairs. Reviews will be
performed to determine the impact to the validated state of the facilities, equipment, systems,
and processes. The objective of the program is to verify that systems continue to operate
within the criteria established in the original validation and according to current Company
guidelines.

SCOPE
This procedure applies to previously validated facilities, equipment, systems, and processes
that are used to manufacture or to support the manufacture of pharmaceutical products
intended for clinical or commercial distribution at XXXXX facilities.
2.1.1

2.2

Planned and emergency changes to validated facilities, equipment, systems, and

processes are documented and evaluated via the Change Control system (SOPXXXX).

Critical changes/repairs to facilities, equipment, systems, and processes are documented in

the Critical Changes/Repairs database (e.g., Maximo, EQMS). Review of the database
involves identifying the Critical Change/Repair performed by equipment name, service
manager, system association, technician, ID number, work order number, or author. The
database includes Changes/Repairs from Buildings 001, 002, 003, and 004.
2.2.1

The Critical Change Review (CCR) will include applicable Change Control,
Preventive Maintenance Interval Evaluation, Maintenance Work Orders, and
Quarterly EM Trend Report Review (where applicable).

REFERENCES
3.1

4.

XX

OBJECTIVE

2.1

3.

Revision:

SDSOP-XXXX

RESPONSIBILITY
4.1

The Validation group is responsible for verifying that facilities, equipment, systems, and
processes used in the manufacture of product for clinical or commercial distribution remains
in a validated state.

4.2

The Validation group maintains a system that is capable of providing notification when critical
validated facilities, equipment, systems, and processes requires requalification.

4.3

The Validation group is responsible for generation of a protocol and final report per SOPXXXX to obtain approval and documented evidence of the requalification activities. SOPXXXX provides guidance on the responsibility of the Validation Department and approval of
the protocol and final report.

4.4

Validation, Quality Assurance (QA), and identified impacted departments are responsible for
reviewing the summary reports and taking the appropriate actions as requested.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

5.

6.

Revision:

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Page 2 of 12

DEFINITIONS
5.1

Key Performance Test A functional challenge that is indicative of the operation or

performance of the particular system typically a part of the qualification. Performing a key
performance test during the system requalification enables a more direct comparison of the
current system operation relative to the validated state. These are identified in the applicable
requalification procedures and protocols.

5.2

Last Significant Data Point Either the date of last data generated or the date of the
reviewed lab test results.

5.3

Routine Periodic Recertification

5.3.1

HEPA filters inside controlled areas are recertified following established schedules
per SOP-XXXX.

5.3.2

Classified rooms/areas are recertified following established schedules per

SOP-XXXX.

5.4

Revalidation/requalification are validations/qualifications performed as part of continued

process verification to assure that the facilities, utilities, equipment and process remains in a
state of control after changes or accumulated changes have been made or observed, or after
certain period of time. At a minimum, the revalidation/requalification plan is to include a
review of change control since the last validation, and functional challenge of the appropriate
critical process variables or a review of routine monitoring as applicable.

5.5

User The functional area that principally utilizes, or is responsible (Owner) for, the
equipment or facility.

PROCEDURE
6.1

General
6.1.1

Once facilities and/or equipment have been validated, they are considered to be in
a state of control. If validated conditions and control parameters remain
unchanged, the system continues to operate in a validated state.

6.1.2

It is important for any significant change to be recognized and assessed before or

at the time it occurs (refer to SOP-XXXX) so that appropriate action(s) can be taken
to maintain a validated state.
6.1.2.1

Depending upon the assessment no additional validation or revalidation

may be judged as necessary to demonstrate the suitable ongoing state
of control for a given system.

6.1.2.2

Prospective testing is performed when something about the process,

materials, equipment, operating parameters, or procedures, originally
validated, has significantly changed in such a way as to put the validity
of the validation work in question relative to the new status.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

6.2

Revision:

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Page 3 of 12

CCR
6.2.1

The Validation group performs CCR for major equipment, processes, and/or
systems and summarizes the results in a CCR report. In instances where several
changes were made in which each was identified separately to have "no impact" to
the validation, the collective changes will be reviewed to reassure that a validated
state has been maintained. These reviews may also initiate additional testing or
data gathering activities (e.g., another change control) up to and including, when
appropriate, a comprehensive revalidation.
6.2.1.1

As part of routine scheduled requalification, it is preferable that the CCR

is performed prior to testing activity execution.

6.2.2

Access the Critical Changes/Repairs database and select the method for identifying
the critical changes/repairs for the equipment, process and/or system that requires
a review to be performed.

6.2.3

Review the critical changes/repairs that were performed during the period of the
review that are not PM based (i.e., corrective work orders). Review the database
list for the specified equipment, process, and/or system selected and obtain a copy
of each Critical Change/Repair and associated Maintenance Work Order (MWO)
performed.
6.2.3.1

Include in the review how many MWOs were generated and what they
were for. Compare the number of MWOs and critical changes/repairs to
determine the collective impact (if any) to the equipment, process,
and/or system. Include this data in the summary report.

6.2.3.2

Determine if there were any related validation protocols, protocol

addenda, and/or studies performed during the period of the review and
assess relationship (if any) to any review trends.

6.2.3.3

Determine if there are any trends to the type and number of MWOs and
critical changes/repairs that have occurred. If a trend is identified,
discuss the findings with the impacted departments and QA to
determine the appropriate action(s) to be taken. This data will be
included in the summary report.
6.2.3.3.1

In the case of Preventative Maintenance (PM) work

orders, determine if the applicable PM task(s) intervals
are sufficient and make recommendations as needed
based on work order history review.

6.2.4

Review pertinent quarterly EM trend reports, where applicable, to determine

potential impact due to events against the equipment or system under review.

6.2.5

Review and evaluate the critical changes/repairs performed and determine the
collective impact to the equipment, process and/or system (per SOP-XXXX).

6.2.6

Generate a summary report that will consist of, but not be limited to, a summary of
change control and/or MWO files reviewed, and evaluation of quarterly EM trend
reports (if applicable).

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

6.3

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6.2.7

The summary report to be generated may be a stand-alone document, with its own
distinct protocol number, or part of a revalidation package.

6.2.8

If the summary report identifies any adverse impact to the validated state of a
process, environment, equipment, or utility, contact the impacted department(s) and
QA to determine the appropriate action(s) to be taken.

6.2.9

When applicable, responsible individuals from impacted departments review the

summary report to assess collective impact to their respective programs.
6.2.9.1

For example, Maintenance reviews the summary report to assess any

impact to the Maintenance programs (e.g., change in PM interval).

6.2.9.2

For example, Engineering reviews the summary report to assess any

impact to the Engineering programs (e.g., Engineering design or
drawings).

Revalidation
6.3.1

At the discretion of the Validation Services management, systems may be

subjected to revalidation testing to address instances where the original (or
previous) validation does not comply with current company and regulatory
guidelines.

6.3.2

The need for revalidation may also be triggered by any of the following:

6.3.3
6.4

Revision:

6.3.2.1

The Change Control Program has determined that revalidation is

necessary as a result of a change to a facility, equipment, system, or
process.

6.3.2.2

An audit of the facility, equipment, system, or process indicates that

revalidation is necessary.

6.3.2.3

An equipment-related Event investigation indicates that the operational

state of the system may not be consistent with the original validation.

6.3.2.4

An assessment is performed every three years covering a six-year

review period for all revalidation using the three-year revalidation
module, with the exception of chambers where the review period
currently covers only two years. The purpose is to determine if the
totality of these minor changes impact the validate state of critical
utilities, equipment, and systems.

The format, issuance, tracking and approval of validation protocols are described in
SOP-XXXX.

Periodic Requalification
6.4.1

Requalification of critical facilities, equipment and processes described in this

procedure (i.e., with the greatest potential for product impact) is performed
periodically beyond any revalidation resulting from change control.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

6.5

Revision:

XX

Page 5 of 12

6.4.2

Requalification of equipment that is on a rotational basis (e.g., Building 001

Manufacturing autoclaves) is performed whereby system performance testing is
scheduled for one unit which then triggers critical change review for the duplicate
item to be performed at the same time.

6.4.3

Requalification activities may include prospective and/or concurrent testing, and/or

a retrospective review of system performance data. The retrospective review
should indicate that previous validation efforts meet current company standards,
effective quality systems are in place, and effective change control is in place (e.g.,
via SOP-XXXX). Prospective or concurrent testing is performed to demonstrate
that the system operation continues to be in a validated state of control.

6.4.4

If any test, acceptance criteria, or protocol requirement is not met, the activities are
halted (as applicable) and deviation is generated in accordance with SOP-XXXX.

Requalification Schedule
6.5.1

The management of Validation Services establishes the schedule to re-qualify a

facility and equipment. Requalification is performed individually on a facility and
equipment basis. When there are multiple pieces of equipment with identical
functionality, testing is required for each piece of equipment unless there is an
approved justification to utilize a bracketing or rotational approach. The CCR
aspect, at minimum, should couple the piece of equipment being function tested.

6.5.2

The schedule for requalification is established based upon the critical nature of the
facility and equipment in question and regulatory requirements. Without the
documented approval of at least the system owner, Validation, and QA, the time
period between requalification of the systems described in this procedure does not
exceed the time specified in this procedure.

6.5.3

6.5.2.1

The requalification date is derived from the last significant data point in
the current Validation review.

6.5.2.2

In the case of a CCR, the requalification date is derived from the QA

approval date of the review.

6.5.2.3

The requalification schedule should allow for a 45 day review window,

which includes the requalification testing, Validation review, and final
report approval.

6.5.2.4

The appropriate Requalification review schedules (i.e., one-year or

three-year Requalification) are added in database XYZ according to the
frequency identified for facilities and equipment.

The testing specified for requalification may be conducted in conjunction with, or as

part of, a separate CRRA or validation protocol. The evaluation of a change control
may be on a different schedule from the documentation review but cannot exceed
the frequency specified in this procedure to satisfy the requalification requirements.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

6.6

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Requalification Execution
6.6.1

The Validation Services Department prepares requalification forms (per appropriate

SOP) or protocol (as needed) for the facility or equipment system in question prior
to test execution.
6.6.1.1

6.7

Revision:

Steam sterilization, depyrogenation and chamber requalification are

executed per approved SOPs.

6.6.2

The minimum protocol requirements for critical systems are defined in the protocol
and are approved per SOP-XXXX (which includes Quality Assurance).

6.6.3

Any revisions to the approved protocol are subject to review by original signatories.

6.6.4

Requalification activities are executed under the direction of the Validation

Department.

6.6.5

The requalification data are assembled and summarized in a final report by

Validation Services. The report, executed protocol (as appropriate), and test data
are submitted to the management of Validation Services or designee for review and
approval.

6.6.6

Deviations and exceptions from the protocol procedure or acceptance criteria are
documented in the final report.

6.6.7

The completed requalification final report is submitted for review and final approval.
The approved final report is filed with the original validation package.

6.6.8

An assessment of the control system [i.e., PLC (programmable logic controller),

data logger, MMI (man-machine interface)] for the system in question is performed
according to SOP-XXXX and included in the requalification plan.

6.6.9

Critical Alarm(s) simulation will be performed (where applicable) as part of the

requalification to verify functionality. Execution will follow pertinent forms per the
individual procedures.

Requalification of Individual Systems

6.7.1

Sterilization Systems Autoclaves and Dry Heat Ovens

6.7.1.1

In addition to the annual autoclave Requalification all current autoclave

commercial load configurations are individually requalified biennially
(every two years). Each load is challenged using biological indicators
(BIs) that are placed inside the load adjacent to the thermal sensor, e.g.,
thermocouples.

6.7.1.2

The requalification plan includes a review of related events, work orders,

and change control documents generated for the equipment since the
last validation/requalification.

6.7.1.3

Autoclave requalification function tests are performed in accordance

with SOP-XXXX. The plan for autoclaves includes an empty chamber
thermal distribution study to verify chamber temperature uniformity, and

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

Revision:

XX

Page 7 of 12

an extended vacuum leak challenge to verify chamber seal integrity.

The results of the requalification study are assessed with the data from
the previous requalification, original, or most current validation for
consistency.
6.7.1.3.1

6.7.1.4

6.7.2

Depyrogenation ovens/tunnel requalification function tests are

performed in accordance with SOP-XXXX. The requalification plan for
depyrogenation ovens/tunnel includes a single loaded chamber heat
distribution/penetration test run performed consistent with the original
validation or most current requalification. The run includes endotoxin
challenges that are placed inside the chamber adjacent to the thermal
sensors. The results of the requalification study are assessed with the
data from the previous requalification, original, or most current validation
for consistency.
6.7.1.4.1

The requalification of depyrogenation ovens/tunnel

includes the acceptable integrity test results of the HEPA
filters, if applicable.

6.7.1.4.2

In addition vial washing requalification is performed as

part of the system since vial washing is always done
concurrent with vial depyrogenation.

Steam-In-Place (SIP) Process

6.7.2.1

Each SIP process is evaluated annually (i.e., for tanks and lyophilizers).
The thermal mapping/BI challenge must be repeated such that the
locations are consistent with the most recent PQ.
6.7.2.1.1

6.7.3

In conjunction with the autoclave revalidation, an air

removal test is performed at the beginning and end of the
study and reviewed.

Each equipment item is challenged annually e.g. each

tank, each lyophilizer.

6.7.2.2

The requalification plan includes a review of related events, work orders,

PM, and change control documents generated for the equipment since
the last validation/ requalification.

6.7.2.3

The plan includes a single test run performed consistent with the original
validation. The run includes biological indicators (BI) that are placed
inside the system adjacent to the thermal sensors, e.g., thermocouples.
At the end of the BI challenge, the BI Test must be performed within
4 hours. The results of the requalification study are assessed with the
data from the previous requalification, original, or most current validation
for consistency.

Controlled Temperature Storage Chambers/Warehouses

6.7.3.1

Controlled storage chambers used to house in-process samples,

finished product, stability samples, and/or approved components are
evaluated every year for walk-in refrigerator and every two years for the

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

Revision:

XX

Page 8 of 12

remainder (freezers and incubators). The evaluation includes a CCR

and requalification. Chambers are qualified or requalified per
SOP-XXXX, where temperature mapping (and humidity mapping as
required) is performed along with review of related events, work orders,
and change control documents generated for the equipment since the
last validation/ requalification. Upon completion of any of the above
procedure, summarize the data for the chamber (including hot and cold
spot assessment) in a Final Report.

6.7.4

6.7.3.2

Controlled Storage Warehouses used to house in-process samples,

finished product, stability samples, and/or approved components are
evaluated every two years. The evaluation includes a CCR and
requalification. Warehouses are qualified or requalified per SOP-XXXX,
where temperature mapping (and humidity mapping as required) is
performed along with review of related events, work orders, and change
control documents generated for the equipment since the last validation/
requalification. Upon completion of any of the above procedure,
summarize the data for the warehouse (including hot and cold spot
assessment) in a Final Report.

6.7.3.3

If the requalification mapping results are acceptable and the CCR

indicates no trends impacting the chamber/warehouse performance
then the requalification is summarized and routed for approval. If the
requalification mapping results are not acceptable or the CCR indicates
a trend with potential impact to the chamber performance then an
evaluation is performed. If the identified root cause requires a repair or
adjustment impacting the chamber performance (temperature/humidity
control or distribution) it must be documented by a work order and/or
change control, and the requalification mapping must be repeated. The
activities and results are summarized in the final report.

Controlled Manufacturing Areas (HVAC)

6.7.4.1

HVAC systems are evaluated every three years, with a review period
that covers six years. The cumulative review period is integrated into
the CCR review period wherein a six-year time frame is evaluated.

6.7.4.2

The requalification plan includes a review of related events, work orders,

and change control documents generated for the equipment since the
last validation/ requalification.

6.7.4.3

A review of environmental monitoring data are included as part of Room

Qualifications.

6.7.4.4

A comparison of the baseline and current HVAC Variable Frequency

Drive (VFD) set point parameters is performed during requalification
activities. An assessment of the state of control for the associated VFD
set point parameters is performed.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

6.7.5

6.7.6

6.7.7

6.7.8

Revision:

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Critical Utility Systems WFI, RO Water, Pure Steam, CDA, Nitrogen

6.7.5.1

Critical utility systems are evaluated every three years, with a review
period that covers six years. The cumulative review period is integrated
into the CCR review period wherein a six-year time frame is evaluated.

6.7.5.2

The requalification plan includes a review of related events, work orders,

PM, and change control documents generated for the equipment since
the last validation/ requalification.

6.7.5.3

Review the results of recent environmental monitoring for evidence of

trends or routine excursions that may indicate a loss of system control.
This review may be performed by Quality Control Microbiology as part of
the review of environmental monitoring.

6.7.5.4

Clean steam attributes are confirmed annually.

Packaging Line
6.7.6.1

Packaging lines are reviewed and evaluated annually for their impact on
the validated processes.

6.7.6.2

The requalification plan includes a review of work orders, and change

control documents generated for the equipment since the last validation/
requalification. A review of the packaging process as compared to the
original process validation is also included as appropriate.

6.7.6.3

The equipment train includes all the major equipment on the packaging
line.

Continued Verification of Process Validation

6.7.7.1

To maintain the state of control, continued verification of validated

processes is performed annually. The continued verification of a
process is performed for processes with an approved Standard Process
Parameters (SPP) document.

6.7.7.2

The collective impact from change control, work orders, and events
since the last validation or verification are reviewed in terms of their
collective impact on the process performance. Revalidation can be
performed as needed.

6.7.7.3

As part of continued verification, review the in-process data against the

SPPs to evaluate process stability and capability.

6.7.7.4

As part of the process validation review, the process equipment train

includes a review of the major equipment not already covered in this
procedure.

6.7.7.5

Review of the process validation is segmented based on the processes

listed in approved SPP documents.

Media Fill

STANDARD OPERATING PROCEDURE

Document No.:

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Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

Page 10 of 12

Media fills are reviewed annually to assess the current line

configurations for the aseptic process.

6.7.8.2

The aseptic process is reviewed.

6.7.8.3

Commercial lots should be trended as part of the continued verification

process, at minimum, to include the following items to ensure that the
media fill program and commercial process are aligned:
6.7.8.3.1

Sterile Hold Times

6.7.8.3.2

Fill Duration

6.7.8.3.3

Corrective Interventions

6.7.8.3.4

Batch Size

The trending data is captured from documents such as the MPRs and
filling event log.

Room Qualification
6.7.9.1

Classified rooms are periodically recertified and summarized.

6.7.9.2

Recertification/Requalification of existing/modified classified rooms

includes, if applicable:

6.7.9.3

6.7.10

XX

6.7.8.1

6.7.8.4
6.7.9

Revision:

6.7.9.2.1

A measurement of room air volumetric flow (air changes

per hour)

6.7.9.2.2

Air velocity (unidirectional flow areas only)

6.7.9.2.3

HEPA filter leakage as appropriate

6.7.9.2.4

Date of HEPA replacement and next due date for

controlled areas

6.7.9.2.5

Temperature, relative humidity, and room to room

differential pressure

A separate CCR is not required for classified rooms as environmental

monitoring results to determine if an environment has drifted outside its
normal operating range are trended and summarized.

Cleaning Validation
6.7.10.1

Routine cleaning monitoring is performed and the frequency is governed

per SOP-XXXX.

6.7.10.2

A review of the CIP process as compared to the original validation is

also included as appropriate.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

7.

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ATTACHMENTS
7.1

8.

Revision:

Requalification Schedule

REVISION HISTORY
Rev.
XX

Summary of Changes
Update continue verification of process validation section to align with standard process
parameters document. Delete process that has no SPP document on Attachment 7.1.

STANDARD OPERATING PROCEDURE

Document No.:

SOP-XXXX

Title:

REVALIDATION OF SYSTEMS, EQUIPMENT, AND PROCESSES

Revision:

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Page 12 of 12

Attachment 7.1
The systems listed in the table below is intended to be a representation of types of equipments or
systems incorporated into the requalification schedule at the site.
BUILDING
001
002

002

001
002

TYPE
Steam
Sterilization
Dry Heat
Depyrogenatio
n

HVAC &
Critical Utilities

CURRENT SYSTEMS

REQUALIFICATION
SCHEDULE

Autoclaves

Lyophilizer

Tank SIP

Dry Heat Oven

Depyrogenation
Tunnel

HVAC

RO

3 years

WFI

PS

Nitrogen

(Note: this CCR

covers a 6 year
review period)

CDA

Annually

Annually

REFERENCE
DOCUMENTS