Professional Documents
Culture Documents
Commission, and
Qualification of Critical
Utility Systems
Part I: Overview
B Y D AV I D W. V I N C E N T A N D H E R B E RT M AT H E S O N
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INTRODUCTION
ties, this article will only cover general procedures used to
Overview of Critical Utility Systems bring these systems to a validated state and, once they are
The use of critical utility systems in the pharmaceutical validated, to establish a routine environmental program. The
industry is very important to final product quality. That is Routine Environmental Monitoring (REM) program is de-
why the design, construction, commissioning, qualification, signed to ensure that the validation lifecycle is maintained
and routine monitoring of these systems is important in en- for these systems. The REM program also ensures that the
ssuring that the end product will maintain a reproducible systems are capable of maintaining the same quality output
quality. Critical utility systems can be considered the back- throughout the life of the system.
bone of any production facility and should be the first sys- This article will not describe the detailed procedures
tems to be validated. Without properly functioning utilities, needed to validate these systems. It is impractical to discuss
the quality of any product will be open to question. all the existing methods and procedures used to validate
Critical utilities found in pharmaceutical, medical device, utility systems within the scope of this article. However, this
and biotechnology production facilities usually support var- article will discuss an approach to integrate the commis-
ious equipment and processes. These utilities must meet both sioning and qualification phases of the project in order to
quantitative and qualitative specifications in order to be con- streamline the qualification phase while verifying that the
sidered satisfactory. The actual criteria may vary from one critical utilities meet their pre-determined design features.
utility system to another and may even be influenced by the The critical utilities that will be addressed in the article
particular equipment being supported. The design, construc- are as follows:
tion, commissioning, qualification, and monitoring of each 1. Water systems
utility will vary depending on the system. Therefore, it is im- 2. Clean steam system
portant to follow a logical, comprehensive scheme when at- 3. Heating Ventilation and Air Conditioning (HVAC)
tempting to validate or monitor these systems. systems
This article will discuss the various phases of design, 4. Process gases
construction, commissioning, qualification, and the routine This article is the first of three-parts. Part I is an
monitoring of various critical utility systems. While it takes overview of critical utility systems and the planning needed
a great deal of time and effort to qualify most critical utili- before specific utilities may be addressed.
User Requirement Specifications to ensure and record that system design meets user require-
ments.
The development of User Requirement Specifications One of the first steps that should be considered is defin-
(URS) is one of the most critical elements in the compliance ing which areas are to be qualified and what their intended
documentation process. A successful project is dependent uses will be. A facility room classification or design speci-
on clear definition, communication, the understanding of fication should be based on the product being manufactured
project scope and objectives, as well as other stakeholder and the processes being used. It is important that the Archi-
requirements as defined by them and the end user. At the tecture and Engineering (A/E) team who are creating the
outset of the project, after the front end conceptual study has design and layout are aware of those areas.
been completed, the user must specify the requirements for
individual aspects of the utility systems in terms of function, The reasons for this are as follows:1
throughput, operation, and applicable regulatory require- • To define exactly those areas for which qualifica-
ments to the engineering service provider. This enables the tion data must be developed.
development and assessment of specific engineering op- • To prevent any misunderstanding, either by the
tions. These requirements are normally formalized in a de- owner or the Food and Drug Administration
tailed URS document. (FDA), as to what areas will be subject to qualifi-
The URS describes critical installation and operating pa- cation. During a pre-construction review of the
rameters. It includes performance standards that are re- drawings with the FDA, the list of areas that were
quired for the intended use of the equipment and provides specified should be discussed. Then, if there are
the basis for the qualification and maintenance of equip- any differences of opinion between the owner and
ment. The URS should be prepared by the equipment owner the FDA, they can be resolved before construction
in collaboration with representatives from departments that starts. It should also be added that drawings are re-
will participate in qualifying and maintaining the equip- quired of the entire facility noting production fea-
ment, and from departments that will be affected by the op- tures and functions. If the A/E firm knows ahead of
eration of that equipment. time that as-built drawings are required, the field
people who are responsible for monitoring the con-
Design Specifications and the struction activities will make the changes to the
Design Review Phase drawings as the actual changes are being made in
the field. This is the way to be assured that as-built
Design specifications for each system are established drawings will truly be “as builts,” instead of “I
based on engineering and manufacturing provisions, as well think-builts.”
as input from various organizations and departments. Design
specifications are the foundation for the development of the Good Manufacturing Practices (GMPs) call for the fol-
qualification document acceptance criteria. It is necessary to lowing pertaining to layouts:
track compliance with specifications throughout the valida- • Smooth flow of personnel and product
tion project. In the end, validation activities will demonstrate • Adequate space to perform each operation
that the design intent has been achieved through the proper • Spatial separation, where appropriate, to prevent
tracking and control of design specifications. product mix-ups, component mix-ups, etc.
A formal design review process at the beginning of the • Adequate lighting
project will decrease the number of deviations associated • Environmental controls
with improper control of design specifications during the
execution of Installation and Operational Qualification The design and construction of any facility requires a
(I/OQ) protocols. A design review process compares the de- team effort. The Design Qualification (DQ) phase of the
sign of equipment and systems with the applicable user and project requires the assistance of various departments and
process requirements as defined in the current URS, pro- professionals such as Quality Control (QC) and Quality As-
cessing requirements, product specifications, license com- surance (QA), Regulatory Affairs (RA), Facilities/Engineer-
mitments, manufacturing records, and applicable Standard ing, Validation, Manufacturing, as well as the general con-
Operating Procedures (SOP). The design review is intended tractor and sub-contractors.
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David W. Vincent and Herbert Matheson
Figure 1
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Impact Assessment Questions
Challenge Yes No
1. Does the system have direct contact with the product (e.g. air quality) or
direct contact with a product contact surface [e.g.: Clean in Place (CIP)
solution]?
2. Does the system provide an excipient, or produce an ingredient or solvent
[e.g.: Water For Injection (WFI)]?
3. Is the system used in cleaning, sanitizing, or sterilizing (e.g.: clean steam)?
4. Does the system preserve product status (e.g.: nitrogen purge for oxygen
sensitive products)?
5. Does the system produce data that is used to accept or reject product (e.g.:
electronic batch record system, critical process parameter chart recorder, or
release laboratory instrument)?
6. Is the system a process control system (e.g., PLC, DCS) or does it contain a
process control system that may affect the product quality and there is no
system for independent verification of control system performance in place?
7. Is the system expected to not have a direct impact on product quality, but
supports a direct impact system?
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David W. Vincent and Herbert Matheson
Figure 2
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Component Criticality Assessment Questions
Challenge Yes No
A/E team determines that a component is acceptable even • Attach supporting vendor technical literature to the
though it does not exactly match all of the project specifica- submittal review form.
tions; they indicate approval with a stamp on the submittal. • Appropriate representatives of the building owner
should check the submittal review package. These
In the real world, gaps in the submittal process are com- representatives typically should include the system
mon, such as in the following situations: owner along with Facilities, Engineering, and Qual-
• Contractors often submit generic product data ity Assurance personnel. The acceptability of a com-
sheets that do not adequately specify the compo- ponent is determined based on its intended use and
nent that will be installed. In example, a generic its compliance with project specifications. The dis-
valve data sheet may identify the options available position of a component is identified typically as
for materials and finishes, but may not identify ACCEPTED, ACCEPTED WITH COMMENTS, or
which of these options the contractor will select. REJECTED. The reviewers then approve the form.
• The submittal process is often slow and may not be
completed for all components before the compo- This process ensures that there is an approved submittal
nents are installed in the facility. package for each of the critical components identified dur-
• Submittals are often stamped as approved by the ing the component criticality review.
A/E but not by a designated representative of the
client for whom the facility is being constructed. Note: The IQ protocols can be simplified, be-
cause the IQ need only verify that the in-
Submittal Review stalled critical components match the ap-
proved submittals by manufacturer and
A review and approval of the submittals by the building model numbers. This is allowed because the
owner is a useful process to resolve these discrepancies and critical attributes of the components have al-
to improve the efficiency of the IQ process. A submittal re- ready been approved through the submittal
view should be completed for each of the critical compo- review process.
nents identified by the component criticality assessment.
The submittal review process proceeds as follows: Systematic Risk Assessment for System
• Identify the critical component by description and Qualifications
tag number as appropriate.
• Identify the system that contains the component. The Risk Assessment section discusses the potential im-
• Identify the specification number that applies to the pact on current Good Manufacturing Practice (cGMP) op-
critical component. erations associated with the use of the equipment, and the
• Identify the submittal number that applies to the steps that will be taken to reduce those risks. Identify con-
critical component. ditions that could lead to failure of the equipment and the ef-
• In a “Specified Attribute” column, list the critical fects of failure on cGMP operations. Evaluate the degree of
attributes of the component as indicated in the ap- risk to product quality, company operations, and the safety
plicable specification, such as manufacturer, model of personnel and equipment.
number, materials of construction, capacity, etc. During the risk assessment, it is important to perform an
• In an “Actual Attribute” column, enter the existent impact assessment on the system. An impact assessment is
component information for each of the critical at- the process by which the effects of the system - and the crit-
tributes as determined by the component vendor. ical components within those systems - on product quality
are evaluated. System risk assessment is measured in a min-
Note: It is especially important to identify imum of three categories: direct product impact, indirect
where the component varies from the speci- product impact, and no direct product impact. By perform-
fied attribute in order for reviewers to make ing design impact assessments, companies can reduce the
an informed decision as to the acceptability scope of the systems and the components subject to qualifi-
of the component. cation, and allow appropriate focus to be placed on the com-
ponents that may present a potential risk to the product.
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David W. Vincent and Herbert Matheson
The elements in Figures 3 and 4 indicate one example of how applying risk assessment to a validatable
system can be beneficial in developing a scientific rationale and justification for the selection of the differ-
ent types of qualification needed to support a system.
Figure 3
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Impact Analysis
• Summarize risks and associated controls in an impact and complexity analysis. Rate the impact of the
equipment on product quality, safety, and purity, and on the safety of personnel and equipment. Evaluate
the systems in place to control those risks.
Figure 4
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Complexity Analysis
• Describe the technological risks and controls associated with the equipment. The complexity analysis
evaluates the risk of failure due to technical sophistication of the equipment, and the relative difficulty of
maintaining the equipment in a state of control.
Risk Score
• The calculation used to evaluate the overall risk (as seen in Figure 4) of the equipment combines the individ-
ual impact and complexity scores in the following formula:
(A + B) x (C + D)
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David W. Vincent and Herbert Matheson
Validation Requirements
Identify the qualification requirement for the equipment based on the impact and complexity analysis as
shown in Figure 5. For smaller, less complex system qualification, protocols can be combined into I/OQ or
IQ/OQ and Procedure Qualification (PQ) protocols. Any additional information to support and justify the valida-
tion requirements should be included.
Figure 5
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Qualification and Validation Justification
M a y 2 0 0 5 • Vo l u m e 11 , N u m b e r 3 245
David W. Vincent and Herbert Matheson
➣ Material certifications • Audit the construction site for cleanliness and com-
➣ Calibration data pliance with specified construction sequences, prac-
➣ State and local code compliance tices, and craftsmanship standards. Enter observa-
➣ ASME, ANSI, and other certifications tions into a Construction Site Audit Log.
➣ Pipe specifications • Document and report any problems that may affect
➣ Cleaning and passivation reports the construction schedule or have a negative impact
➣ Stainless steel weld documentation on the qualification phase of the project.
➣ Instrumentation specifications
➣ Drawings Specific Documentation Packages Format
➣ Material and finish verification
➣ MSDS Items listed in the previous sections are included in the
➣ Any other useful documentation CQ packages according to the following guidelines:
Figure 6
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Tests Required for Two Common Critical Utility Systems
➣ Additional Sections
Any additional sections will be included in the CQ
between the Test Reports and the Drawings sections.
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David W. Vincent and Herbert Matheson
and team can plan for completion when project engineers • Pre-Delivery Activities
and construction staff are actively involved in the daily rig-
ors of construction. Selection of the commissioning manager Provide detail and instructions for each pre-delivery ac-
is extremely important; the individual must have operations tivity.
experience as well as good planning and interpersonal skills.
The commissioning manager must then select an appropriate Examples of pre-delivery activities include:
complement of field technicians, calibration and metrology ➣ Control of specifications
staff, document specialists, and technical writers. Some of ➣ Review of vendor submittals
these individuals may be sometimes "loaned" by mainte- ➣ Vendor audits
nance and operation groups and then returned to those ➣ Third party inspections of off-site fabrication
groups after project completion. In fact, the loaning of team ➣ Module and equipment vendor quality control and
members is often the best solution because it enables start- inspections
up knowledge to transfer from project team to operations. ➣ Factory Acceptance Testing (FAT)
➣ Factory inspection plan
Commission Plan
• Equipment and Material Receipt Control
The commission plan is, properly, one of the most im-
portant criteria documents that will be used on the project. Describe the procedures, documentation, and methods of
The commissioning plan should indicate the various com- control to be utilized for equipment and material receipt.
mission activities for both GMP and non-GMP systems. The system should include the following:
The plan should identify the overall commissioning strategy ➣ Approving and rejecting components and equip-
for the project and complement the Validation Master Plan ment
(VMP) to identify the integration of commissioning and ➣ Defining storage locations and conditions for criti-
validation activities. It also should define the roles and re- cal components (direct contact copper tubing verses
sponsibilities of each functional department and their ven- non-critical copper) to minimize mix-up
dors as they relate to the commissioning and integration of ➣ Separation of non-GMP materials from GMP mate-
the qualification activates. rials
The following items describe the key elements of suc- • Construction Quality Assurance Activities
cessful commissioning plan:
• A description of the equipment and systems to be com- It is critical to define the role and responsibility of the
missioned including their means of automation quality unit during the commissioning phase. While it is
• A description of the methods and tools to be used in clearly understood that commissioning is usually an engi-
commissioning execution neering function, sometimes it is not clear what the Quality
• A detailed description of the commissioning strategy in- Unit role is during the commissioning phase of the project.
cluding integration of commissioning and validation ac- During the engineering phase of the project, QA may audit
tivities the approved equipment and utility system vendors to ver-
• Overall sequence of commissioning activities ify that they have the necessary quality systems in place to
• A detailed description of project deliverables including ensure the quality of their product or service. Part of the in-
identification of the parties responsible for providing the tegration concept also involves auditing design and con-
deliverables struction activities for compliance with cGMPs, verifying
• Roles and responsibilities of personnel involved in the documentation, and keeping a close eye on the installation
commissioning effort throughout construction and com- progress throughout the project’s construction phase.
missioning The Quality Unit must be aware that GMP requires qual-
The commissioning plan should include a strategy for ification activities. Whether some of the qualification is per-
integrating the qualification phase into the commissioning formed during the commission phase or not, the regulations
activities. require these activities be reviewed and signed-off by the
Quality Unit. Therefore, if any aspects of the qualification
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David W. Vincent and Herbert Matheson
activities are being captured during the commissioning ➣ Startup and Formal Commissioning
phase, the Quality Unit must at least agree and sign-off on
the commissioning plan or strategy. (Because some qualifi- This section of the commission plan should de-
cation activities are integrated into the commissioning phase scribe, in detail, the components of startup and
does not mean that they are no longer GMP activities.) commissioning execution.
Components may include:
➣ Describe the roles and responsibilities for all proj- • Special pre-startup checks
ect quality control and quality assurance activities. • Notification to stake holders that startup activi-
➣ Define the scope of the quality control program, ties will commence that may affect certain
authorized documentation, and responsibilities for process equipment or systems, i.e.: backup gen-
the implementation and maintenance of the pro- erator, etc.
gram. • Startup procedures
➣ Detail the requirements for in-process inspections • Setting to work and initial shakedown
and the methods to be used to document the in- • Software structural testing
spections. • Inspections
➣ Describe the requirements for the creation, mainte- • Functional testing
nance, and verification of red-line, as-built drawings • Cycle development
➣ Specify the requirements, methods, and procedures • Special testing
to be utilized for foreign material exclusion for di-
rect impact components and materials. ➣ Commissioning Documentation and Turnover Pack-
ages
• Commissioning Execution
This section of the commission plan should de-
➣ Pre-Commissioning scribe, in detail, the commissioning documents and
requirements for turnover packages.
A pre-commissioning phase includes the comple-
tion of tasks necessary to verify that the system is Components may include:
mechanically complete and ready for the initiation • Commissioning Documentation that specifies the
of subsequent commissioning activities. requirements for commissioning including: re-
quired documentation, references, documenta-
These activities include: tion practices, and final reports.
• Mechanical completion
• Safety reviews • Turnover Packages, which provide an outline of
• Code inspections the procedures and requirements for the assem-
• Site Acceptance Testing bly and turnover of system manuals and other
• Tagging and labeling verification turnover packages.
• Valve or damper lineups
• Installation of temporary strainers and filters ➣ Commissioning Completion and Turnover to Owner
• Walk down of the system
This section of the commission plan should de-
scribe, in detail, the commissioning completion
and turnover to owner. Project closeout procedures,
deliverables, and responsibilities must be clearly
defined well before construction commences. The
method of project turnover, whether phased or in
single project completion turnover package, should
be clearly defined in this section.
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David W. Vincent and Herbert Matheson
Figure 8
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Typical Validation Flowcart
Engineering Validation
• Adherence to compliance requirements pletion of the facility, thus tying IQ/OQ closely to the con-
• Overall project quality improvement struction contractor’s scope of work that includes commis-
sioning. To avoid the effort and inconvenience of discover-
During streamlining, the commissioning and validation ing and rectifying basic problems, it is recommended that
activities should adhere to the following basic principles: all systems go through an informal shakedown phase before
• Start the project by evaluating the impact of a system IQ/OQ commences. This will help ensure a smooth transi-
on product quality tion between IQ and OQ, and will minimize the number of
• Focus resources on the qualification of systems with deviations that may occur during the IQ and OQ phases.
"direct impact" on product quality according to Scheduling of PQ is particularly critical because PQ
GMP testing is often the most time consuming part of the qualifi-
• Focus on critical components that will have a direct cation. Scheduling should take into account any prerequi-
impact on the project quality sites that should be achieved prior to PQ execution (such as
• Establish system boundaries in the early phase of the commissioning of all support systems, availability of SOPs,
project system interdependencies). The PQ protocol often receives
• Evaluate system design from both a quality perspec- the greatest amount of scrutiny from the approval team.
tive and a risk-based approach Again, it is important that IQs and OQs are completed and
• Provide contractors, vendors, and engineers with the that there are no major deviations that may have negative
project validation requirements up-front to enable impact on the PQ phase.
them to plan installations to meet these requirements
• Design and commission those systems that have no Integrate Commissioning with Validation Activities
"direct impact" on product quality according to GEP There are considerable advantages of time, cost, and
• Enhance the commissioning, qualification, and vali- quality in integrating the many functions carried out by
dation documentation generation, review, and ap- skilled resources, such as engineering, contractor, and vali-
proval processes dation teams. The responsibility for timely and appropriate
• Integrate the commissioning and qualification activ- execution should be a combination of both the validation and
ities to avoid duplication of work engineering teams, this will reduce the time spent on vali-
• Conduct training of employees, contractors, con- dating the facility and scaling up to production. The use of a
sultants, and other personnel early in the project competent, expert, multi-disciplinary team will ensure that
lifecycle best practice is deployed and that duplication of activities is
avoided.
Strategies Integrating activities such as Design Qualification, Con-
struction Qualification, Factory Acceptance Testing, Site Ac-
The following section includes some detailed strategies ceptance Testing and commissioning into qualification and
that could be followed to reduce project resource require- validation activities can control validation costs and mini-
ments and improve the efficiencies of the commissioning mize project delays. Instruments, components, and equip-
and validation programs. ment can be verified at the vendor site during the FAT and
CQ phases of the project. This reduces delays caused by
Integrate Validation Schedules into the Overall Project identifying potential problems before equipment is delivered
Schedule to the job site. If these items are not altered or dismantled in
The project manager, with support of team members, any way for transport, these checks, if properly documented,
should ensure the development of a commissioning and val- could be used in support of SAT or qualification activities.
idation plan as an integral part of the project plan and sched- For OQ, the duration of the testing can be shortened by
ule. Integrating validation into the overall project schedule identifying the critical operational criteria that require test-
can save both time and money. Integrated schedules should ing prior to the facility, utility, or equipment being used in
be developed with input from the construction and valida- production and planning the schedule accordingly. This
tion project teams and be maintained and updated at regular can be performed by determining which functional con-
intervals. trols are critical and non critical in the early stages of the
IQ/OQ may be conducted as part of the physical com- DQ phase of the project. Testing the non-critical functions
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David W. Vincent and Herbert Matheson
during the FAT or SAT will reduce the amount of testing direct impact systems are appropriately planned,
required during OQ phase. created, organized, and authorized so that they may
If FAT is executed for equipment, i.e., alarms and inter- become an integral part of the qualification support
locks testing, some or all of these tests can be performed at documentation.
the vendor site, or these tests can be performed as part of • Combining engineering and validation information
commissioning, and can be used in support of the OQ. Per- to minimize duplication.
formance testing carried out as part of commissioning can
contribute to PQ when performed consistently with qualifi- Once qualification protocols are written, they should be
cation practices. Thus, if the integrated approach is used and approved, and this may be a time consuming process. Sev-
proper inspections, field verification, documentation, and eral ways to streamline this process include:
certain required field execution work is accomplished by the • Minimizing the number of approvals required by
construction vendors and contractors, then the qualification developing approval matrixes.
scope can be reduced to that of review, verification, cross • Clarifying the review process with all parties early
linkage to FAT and SAT documents, monitoring, and com- in the project.
piling. The integration of commissioning and qualification • Instituting a formalized protocol tracking process.
merges activities, minimizes resource requirements, and • Minimizing the number of review cycles allowed
streamlines the validation effort by reducing the number of by the team.
protocols and reports. • Implementing a simple review and approval proce-
Approaches to streamline the amount of paperwork re- dure with time limit for the review cycle.
quired to give sufficient documented evidence of validation • Instituting protocol review meetings for all parties
may include: involved.
• Using standardized protocol and report templates • Ensuring the protocol review and approval process
wherever possible, so that reviewers become accus- is included in the overall project schedule.
tomed to protocol formats and contents.
• Using procedures and forms that can minimize re- Define which activities the vendors are responsible for
dundancy normally found in qualification proto- executing when utilizing an integrated approach to com-
cols. missioning and validation activities. Figure 9 is an example
• Structuring executed protocols as reports to obviate of the integration of commissioning, qualification testing,
the need for writing a separate report. and verification activities related to WFI skid and distribu-
• Combining IQ and OQ documents (to I/OQ) will tion system (See Figure 9):
result in fewer documents to develop, track, review,
and approve. However, the IQ section must be Note: Vendors performs 100% loop check
completed before OQ commences. during commissioning phase. Validation
• Including only critical tests in the protocol, and not engineer performs 10% during Qualifica-
repeating non-critical ones already conducted in tion Phase. If failure is detected during
FAT or SAT phases, simply verifying that these test the 10% verification, then 100% inspec-
have been performed in the qualification protocols. tion is performed by validation engineer
• Understanding upfront the critical and test items to or validation engineer witnesses 100%
be included in the qualification can reduce both performed by vendor. ❏
cost and unnecessary deviations.
• Establishing realistic protocol acceptance criteria
based upon the process demands for reproducibil-
ity and product quality.
• Recording deviations in the qualification protocol
attachments and then having them immediately re-
viewed and approved by the Quality Unit rather
then waiting until the entire protocol is executed.
• Ensuring that commissioning documentation for
Figure 9
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Commissioning and Qualification Integration Approach
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David W. Vincent and Herbert Matheson
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