Source: https://ua.b-ok.org/book/5248178/fc5c7c?dsource=recommend
Timestamp: 2020-06-01 22:39:41
Document Index: 2403253

Matched Legal Cases: ['§211', '§211', 'arts 211', 'art 211', '§63', 'art 211', 'art 11', 'art 211', '§63', 'art 211', '§65', 'art 211', '§63', 'art 211', '§67', 'art 11', 'art 11', 'art 11', 'art 11', 'art 11', 'art 11', 'art 11', 'art 11', 'art 11']

Equipment Qualification in the Pharmaceutical Industry | Steven Ostrove | download
Головна Equipment Qualification in the Pharmaceutical Industry
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qualification329
pharmaceutical116
equipment qualification88
validation85
pharmaceutical industry61
performed51
components49
specifications48
component45
appendix b appendix43
vendor40
instruments37
assure35
approved35
reviewed34
calibration34
qualification protocol34
deviations31
critical31
installation qualification31
usp water29
Aspects of Pharmaceutical
STEVEN OSTROVE, PH.D.
negligence or o; therwise, or from any use or operation of any methods, products, instructions, or ideas
ISBN 978-0-12-817568-2
Kiruthika Govindaraju
I would like to dedicate this book to my family, to my wife Karen, who has
stood by me through many years of my being on the road working at many
pharmaceutical, biotech, and device plants and having to take care of everything. To my children Elliot, Philip, and Naomi who have withstood and
understood my absence from home due to my travel, working at home
(where I needed quiet), and much much more. To them, I owe a debt of
gratitude for their caring and support.
In addition, I want to say thank you and acknowledge all the engineers,
scientists, quality assurance personnel, and all those with whom I have met
and worked with throughout my career.
In the preparation of this book, I have had the invaluable assistance from
my good friends and colleagues Mr. Dave Maynard, Mr. Phil DeSantis,
and Dr. Ken Blashka. Each one provided helpful comments on some or
all of the chapters in order to make them better. I appreciate their assistance
and knowledge of equipment qualification.
Introduction to aspects in pharmaceutical
Welcome to a new series of books dealing with various “Aspects in Pharmaceutical Manufacturing.” This series is intended to provide information
to those just coming into the industry, guidance for those already working in
the industry, and/or those who just want to “brush up” on their knowledge
of the various specific aspects of pharmaceutical manufacturing. Each book
in the series will be primarily designed to address the WHY and the HOW of
specific pharmaceutical aspects, for example, equipment qualification,
cleaning, and biotech—upstream and downstream operations.
Examples and references will be provided to help guide and support the
information presented. The authors were all selected because of their expertise and their ability to present this knowledge in a clear and concise manner.
Although many of the topics to be covered in this series may been seen in
other works and covered in general, each book in this series will cover one
specific aspect of the manufacturing process or environment. Reasons
behind and the methods needed to implement a compliant program for that
aspect of pharmaceutical manufacturing will be explained.
Topics in this series can fill in the gaps in the education of pharmaceutical
employees. Knowledge obtained in formal education settings often lacks in
real world conditions such as emergencies that are often encountered in
pharmaceutical or biotech manufacturing. The information provided to
the reader will help stimulate formulating compliant solutions in GMP documentation, resolving problems (getting to the root cause), and more.
Each book could be used in classroom settings (pharmaceutical engineering) or by individuals interested in improving their subject knowledge (for
advancement or other needs), which is important to improving industry
compliance to current government regulations.
It is through continuous improvement from books like this one and
others in the series that the industry and the individual will grow, improve,
and lead to better, more effective, and safer pharmaceuticals.
Steven Ostrove, PhD
There are several aspects to performing a good equipment qualification program. This book presents many of the ideas and possible solutions collected
over many years in the industry.
As we begin the process of understanding how to perform an equipment
qualification, several questions come to mind:
• Why do we need to qualify the equipment?
• Who can or who does the qualification?
• What needs to be qualified?
• What is qualification?
In answer to the first question, qualification is needed for two major purposes.
The first purpose is to demonstrate that the equipment is what was ordered
and that it will function as needed for its intended use. In fact, if you think
about it, everyone performs a qualification every time they purchase a new
item: a new car, a new toaster, or a new house. The same steps are followed
in determining that the unit is the one you want and that it works as you expect
it to work. The big difference is that for the personal items the requirements
and results are not being recorded. The second purpose is it is the law as specified in the Code of Federal Regulations (CFR) Title 21.a
In answer to the second question, qualification usually falls at least in part
on the engineering group but can be done by the validation group or any
other person or group that is qualified and knowledgeable on the use and
operation of the equipment and that has the training and experience to perform the tasks required.b
In answer to the third question, read on. According to interpretation of
the CFR Title 21,c all equipment used in the manufacturing of a pharmaceutical (Aseptic, OTC, Tablet, device, etc.) and all equipment used in the
laboratory for in-process testing or release and/or any unit used for the
Title 21 CFR §211.63, Food & Drug Administration, 2017
Title 21 CFR §211.25
21 CFR Parts 211 and 820.
https://doi.org/10.1016/B978-0-12-817568-2.00001-4
production of a device (classes I–III) needs to be qualified to be sure that they
will work as intended and that the results of the testing are accurate and true
As to the fourth through sixth questions, often asked by management,
this depends on the scope of the project, that is, number of units to be qualified, and the expertise of those doing the qualification (i.e., time it takes to
write and execute the protocols). In short, qualification demonstrates that
the equipment meets the requirements of the users, was received on-site
in working order (or fixable), and will function as the users expect it to work
for their product. Expense is not a valid consideration in determining how
the program will be performed since it is required by the Food and Drug
Administration (FDA) to be able to sell your product in the United States.
In answer to the fifth and sixth questions, it depends. It depends on the
number and complexity of the equipment to be qualified. It depends on the
experience of the qualification team. It depends on previous experience and
availability of protocols for similar units. And it depends on the risk analysis
for each unit as it pertains not only to production but also to patient safety.
To further our understanding of the qualification process, three basic
terms need to be defined and understood prior to taking on a Food and Drug
Administration (FDA) qualification project. These are the following:
According to the web dictionaryd:
• “…the action or fact of complying with a wish or command”
• “… the state or fact of according with or meeting rules or standards”
According to the web dictionarye:
• “a condition or standard that must be complied with”f
According to the web dictionaryg,h:
• to make legally
• to support or corroborate on a sound or authoritative basis
• to give legal force to; legalize
• to give official sanction, confirmation, or approval to, as elected officials,
election procedures, documents, etc.
The obvious first reason heard for qualifying process equipment is because
the Food and Drug Administration (FDA) of the United States requires all
pharmaceutical companies who manufacture, hold, or distribute a drug
product or substance (virtual or other) to be compliant with the rules set
out in the Federal Food, Drug, and Cosmetic (FD&C) Act as promulgated
in the Code of Federal Regulations (CFR). But, qualification is employed
for another very important (business) reason: “Did you receive what you
ordered, and does it work as you need it to work?” As in the opening paragraph, qualification is performed every time a new purchase is made:
For example, you purchase a new toaster. First the box is inspected,
intact, and not damaged. Then the unit is removed from the box and
placed on the counter. Question, is it what you expected the unit to
be? Does it have two slots or four? The unit is then plugged in, and a
piece of bread is inserted into one of the slots. The toast level is set,
and the bread plunger is depressed. When it pops out, you check it
for the level of darkness you like. Repeat as necessary (commissioning)
until it is correct.
This example just followed all of the qualification steps that will be followed
in manufacturing except it was not written down.
To accomplish the state of compliance (meeting rules or standards, in this
case the FDA’s), companies need to have a program of qualification and one
of validation. In the pharmaceutical industry, all qualification work needs to
be completed following a written program. Industry standard currently uses
the term qualification for all process equipment or utilities used in or
supporting the manufacturing operation to say or demonstrate that they
meet the conditions required to perform their job in the pharmaceutical process. The term validation or compliance applies to the demonstration of the
successful testing of the entire process (i.e., the entire manufacturing
process). Thus a company cannot achieve the “compliant” state without
completing equipment qualification first and then process validation.i
Both equipment qualification and process validation follow similar
procedures. As stated in Title 21 of the CFR Part 211 §63:
Equipment used in the manufacturing, processing, packing, or holding of a drug
product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
Note here that the FDA is not specific about what needs to be done. The
equipment needs to be appropriately designed and of a size that accommodates the process, as well as cleanable and maintained. It is up to each company to decide how to “qualify” the equipment. That is, proving that the
equipment meets its intended use, its design will make the product effectively without adding to or taking anything out of the product, and it can
be cleaned (all components or ingredients or materials used in the
manufacturing process can be removed to a provable safe level), and it
can be effectively maintained.
The CFR does not specify or even hint at what to do. Qualification
(meeting the standard established by the industry and the FDA) of the equipment is one part of reaching a compliant state. It is up to the individual company to determine how to qualify each piece of equipment or utility used to
This book will provide information on interpreting the requirements set
forth in the CFR and explain how to meet current industry standards and
expectations. This is Current Good Manufacturing Practice (CGMP).
Please note the word current as it underscores current industry standards
and practices in the manufacturing operation. It implies that current good
engineering practices (GEP) and techniques and current industry standards
are used in the equipment design and that current scientific thought is used
to test and approve the function of each piece of equipment. In addition, the
FDA has promulgated a guidance document that discusses not only the use
of the equipment but also the risk associated with a failure.j
• Computer control of equipment and where to include in the equipment
• Cleaning considerations
S. Ostrove, “How to Validate a Pharmaceutical Process”, Elsevier, 2016.
International Commission on Harmonization (ICH) Q9 and FDA Guideline for Risk Management
• Preparing the qualification protocol(s)
Chapter 9 will provide a matrix for some of the major types of equipment
used in pharmaceutical manufacturing. The chapter is not meant to be an
absolute requirement for the equipment listed, but a guide for consideration.
Remember that the use, cleaning, risk, and maintenance must be carefully
considered and evaluated prior to starting the qualification procedure.
There are four recognized types of qualification today. The FDA prefers the “prospective” approach since the acceptance criteria are preplanned
removing the possibility of “testing into compliance.”
The four types are the following:
• Prospective—preplanned tests with preplanned results.
• Concurrent—same as prospective except, the unit can be used as it is
• Retrospective—basing qualification on past history of the unit.
• Requalification—to be performed only when there is a change to the
equipment (e.g., moving or other changes) or process or, as required
to demonstrate continued compliance due to its function, for example,
drying oven or autoclave.
As above the expected approach is the prospective one. It gives the highest
assurance that the unit will function as intended and will reliably fulfill its
intended function. To perform a prospective qualification program, one
needs to first know what the user wants the equipment to do. From this
a plan can be made to test the ability of the unit to perform those functions
with known expected results.
The order of the qualification process
As can be seen in this introduction, the qualification of process equipment and even some of the utilities supporting the equipment can be quite
complex. However, there is a basic order to completing the process successfully as shown in the succeeding text (Table 1).
Table 1 Order of the Qualification Program
Need established
Equipment type determined to meet needs
Process engineers design process and specify needs
Submit bids to vendors for each specific piece of equipment
 Fix up (as necessary)
 Installation qualification
 Operational qualification
 Performance qualification (as needed)
Equipment removed from production line
One extra note of caution: writing, reviewing, and executing the qualification documents take time (see Chapter 6). Allow sufficient time for
proper conduction of this part of the entire qualification program. It takes
more time than originally planned—remember Murphy’s rule. If it can
go wrong, it will and at the worst time.
Getting ready: Documentation
Preparing for the process equipment qualification program is probably
the most important step in the qualification program. It takes time, but it is
well spent if done correctly. Management often feels that this part is easy and
that the operators, qualification specialists, engineers, and others have
knowledge of the equipment without further reading, understanding,
and/or researching to be able to write and execute the qualification protocols without any further research. Here is an example of what I mean:
A question was asked how I knew how to qualify all of the process equipment in
their facility. While they had several items that were similar (e.g., tanks and
blenders), each has a unique purpose in their operation. The answer I gave is really
quite simple: “Before investigating I don’t know the specific function of each one.
But I do understand their implied function (blending components, holding liquids,
etc.) the documentation supplied by the vendor, or operations staff, will tell me
But before any qualification activity takes place, a series of events need to
occur, for example, designing the equipment to the specific function, ordering the equipment, and reviewing the bids form the vendors.
Please note that even with research, there needs to be a basic knowledge
of the use of the equipment before preparing any qualification protocol
(Chapter 8) or performing any commissioning (Chapter 7). As in my answer
earlier, most people have this basic idea of the use of the equipment: blenders
blend, granulators granulate, tanks hold liquid, etc. But we also need specific
knowledge of the function of the unit that can be obtained from the process
engineers and/or the operation group. The purchasing department then has
to be informed (e.g., by process engineers, operations, and development) of
the needs and requirements of the equipment to be ordered. The manufacturers purchasing group in turn needs to communicate their needs clearly to
the vendors so that the vendor can produce a bid that meets the specific
https://doi.org/10.1016/B978-0-12-817568-2.00002-6
requirements. For example, when ordering an autoclave for sterilization as
part of the process, one would need to be sure that there is a “validation
port” and that it can have a pressure hold test. On the other hand, if the autoclave is just for “kill” purposes, then the validation port may not be needed.
The following is a short list (also see Fig. 1) of things that should be done
in obtaining a new process unit:
• Operations discuss needs with process engineers.
• Process engineers’ design determine the type, size, and other specific
• Process engineers confirm all specifications with operations.
• If, and when, all are in agreement, the purchasing department requests
bids from vendors.
• Vendor bids are reviewed (VERY IMPORTANT) by validation/engineering/operations for consistency with needs.
• Vendor is selected, and the order is placed (be sure to order sufficient number of manuals, for example, operation, cleaning, and maintenance at this
Bid package for
Vendor bid package
Fig. 1 Basic swim diagram for equipment orders.
Once the order is submitted to the vendor and the unit is ready to be sent to
the site, some pretesting to assure that the unit works as the company needs is
often performed (for large or expensive units). This is called the factory
acceptance test (FAT). The manufacturer of the unit usually prepares the test
protocol for this test, but it is very important that the operation company
both witness and add some specific tests of their own to assure it will meet
the requirements of the purchase order. Assuming all goes well with the
FAT, the unit is ready to be shipped to the operation company. Upon
receipt at the operations site, the site acceptance test (SAT) should then
be performed followed by commissioning (see Chapter 7).
Thus it is important to make sure that the qualification team has all of
the necessary documentation for each unit and that the person assigned to
prepare the commissioning protocol (Chapter 7) and the qualification protocol (Chapter 8) speaks to the users to understand the unit’s specific function in the process.
As stated in the beginning of this chapter, obtaining and reviewing
the documentation supplied by the operations group, the process engineers,
and the vendor take time. This time is well spent and is needed to collect the
relevant documents, to review the documents, and to be sure that they are
fully understood. It should not be considered “wasted” time nor be thought
of as unnecessary training. Regardless of the experience of the qualification
person, time up front collecting and reviewing documents as well as talking
with those who are involved in the process design or use will certainly pay
off with a professional, well-prepared, and unquestioned protocol and thus
a faster release of the unit to production and process validation.
The following is a general list of sources for the information required
While the documentation obtained from the sources earlier is critical to a
successful qualification, so is talking to the operators and the process development staff. Here are some examples of questions to ask (Table 3).
In preparing for a qualification program that includes commissioning and
qualification and process validation, there are two main components.
Each of these requires their own unique set of documents or protocols.
The commissioning protocol, as discussed further in Chapter 7, is needed to
guide the commissioning process and prepare the equipment for qualification and thus use. The qualification protocols are prepared specifically for
Table 1 Usual documents needed for protocol preparation.
Specific doc.
Only for WFI
Welder qualification, weld reports
User (URS)
Functional (FRS)
For example, welders
each unit system. This means that each is set into a protocol representing the
process equipment as a stand-alone unit (e.g., a cold room or an autoclave).
Thus the unit can be used independently to achieve a given process function. For example, as in the preceding text, a refrigerator is a stand-alone
Table 2 Where some of the documents are to be used.
IQ/OOQ/PQ
P&ID (as built)
LOGS (cleaning/use/maintenance)
Calibration (last/next)
Reports (e.g., weld)
Include in OQ
Table 3 Some basic questions to be asked.
How critical is the equipment to the process?
Product contact: direct, indirect, none?
Is the unit part of or involved in a critical process parameter (CPP)?
Are the P&IDs available?
Is there anything specific or unique about the process or operation of the
7. What speeds, temperatures, pressures, etc. are to be used?
8. Are there any safety issues for the equipment (e.g., solvents and acids/bases)?
a. Safety concerns for the operators?
b. Other safety concerns?
unit. It contains many key components that allow it to function as a unit. A
pump, while able to operate on its own, does not constitute a stand-alone
unit since a pump isolated from a tank or other vessels does nothing for
the process. This is where the engineering drawing(s) come into play in preparing the documents. System boundaries need to be established before any
writing can begin. This is why the piping and instrument drawing (P&ID),
the process flow drawing (PFD), and the vendor drawings are so important.
The collection of the correct documentation is critical to completing a successful qualification program (Table 4).
Table 4 Usual SOPs for the preparation of qualification documents.
• Writing a protocol
 IQ
 OQ
 PQ
Reviewing a protocol
Execution a protocol
The validation master plan (VMP)a is a key document to guide the entire
compliance program. The VMP presents the approach to the qualification
and validation of the project. It provides guidance as to which process units
require full qualification and which units require commissioning only (see
Chapter 7 for commissioning). It provides basic information about the testing that is expected and the documents that support those tests.
In addition, the VMP will provide a list of expected standard operation
procedures (SOPs) for each unit in the process and information on how the
ancillary GMP programs will be incorporated and more.
The engineers who designed the process will provide the drawings necessary
to prepare the protocols. The drawings that are needed are the process flow
drawing (PFD) and the piping and instrument drawing (P&ID). Other
drawings from the engineering staff may also be required when the utilities
are qualified. Drawings from the vendors will also be needed as verification
as to what is actually built. Vendor drawings are needed when collecting
documents so as to understand what components are contained, in what
International Society for Pharmaceutical Engineering (ISPE) Baseline “Commissioning and Qualification” Vol. 5. Chapter 6, March 2001.
order, and each unit they is used and connected. Note that all of the drawings used will be verified during the protocol execution (also known as
“walking the drawing or protocol”).
The P&ID is needed so that the qualification personnel can set the “system boundaries” for each unit. This means that the P&ID is reviewed and
marked (using colored markers) so as to indicate that all components (pipes,
valves, pumps, etc.) are included, in a protocol, as needed so as to make the
unit “stand-alone.” In the P&ID, all components of the equipment are numbered for easy identification. The piping is also numbered as are the valves
and all other major operational components (e.g., tanks, heat exchangers,
controllers). These numbers are often used in the preparation of the
One of the items that needs to be requested at the time of ordering a piece of
process equipment is the associated manuals for that unit. At a minimum the
operation, cleaning, and preventive maintenance manuals should be
requested. In fact a copy should be requested for each of the following
groups (NOTE: depending on the operation size, some groups may not
need the equipment documentation):
• Qualification/validation
Requesting additional copies at a later date can prove to be very costly in
both lost time and money spent.
The first SOP that should be reviewed is “How to prepare a qualification
protocol.” There may be others specifically for preparing the installation
qualification (IQ), the operational qualification (OQ), or the performance
qualification (PQ). Other SOPs (e.g., how to execute a qualification protocol, good documentation practices, reviewing the executed protocol, and
writing the final report) will probably be required to be reviewed so that
the document preparation and protocol execution will meet corporate standards and FDA documentation requirements also (Table 4).
Thus the Code of Federal Regulations Title 21 (21 CFR) Part 211b and
any other relevant FDA, International Council on Harmonization (ICH), or
other guidelines should also be reviewed and consulted.c
The following rule of thumb should be considered when developing the
SOPs. First the IQ protocol does not need any SOPs for its preparation or
execution. The list of SOPs to be needed is to be found in the VMP or as a
list in the IQ. For the OQ the SOPs should be available in draft form for
execution so as to be used during the execution as needed, and changes
can be made without going through the change control process. However,
for the PQ, the SOPs need to be signed and effective.
Operations/vendors/others
Before beginning the planning of a qualification and validation program, all
those assigned to preparing or executing the qualification protocols need to
have a basic understanding of the process. As discussed the PFD is thus
important as is a talking point between the process engineers, operators/
users, vendors, etc. Look for previous protocols or documents for the equipment to be qualified. Look at the FDA warning letter sited for information
about related FDA warning (forewarned is forearmed as the saying goes).
Collecting all the expected information takes time. It is worth the
effort. Having the information available when the protocol is prepared saves
time in errors, in writing the protocol, and in being sure all components are
included. The P&IDs are needed to correctly determine system boundaries.
Keep in mind that a single P&ID may contain one or more systems to be
qualified. The PFD is useful in guiding the reader through the protocol,
while not all the documentation listed in Table 1 is necessary to complete
the protocol (most of it will be needed at some point).
21CFR211.63, and 21CFR211.65.
International Commission on Harmonization, e.g., “ICH Q10, Pharmaceutical Quality System” May
The last chapter discussed the basics of the documentation generally needed
for the preparation of a qualification protocol. This chapter goes further in its
discussion of other aspects of the qualification program that need to be considered (usually before the qualification begins). There are other activities
and documents that need to be considered, completed, and/or developed
for the qualification program to be complete. These documents and programs are known as the companies’ quality system programs and are an integral part of all qualifications. Some of these will have, or should have, been in
place all along before the qualification; others such as the preventive maintenance program may still be a “work in progress” depending on the company’s status (start-up or developed operation). The quality systems used in
equipment qualification (a more complete list of quality systems is seen in
Table 1) include but are not limited to the following:
• Qualification investigations (different than production investigations)
• Corrective action (CAPA)
• Calibration/metrology
These systems are key to a successful qualification program. Others, as seen in
Table 1, may also be important for your project. The quality system approach
includes more than just ICH Q10a; it includes Q8b and Q9c and others.
ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL QUALITY SYSTEM
ICH HARMONISED TRIPARTITE GUIDELINE Pharmaceutical Development Q8.
ICH QUALITY RISK MANAGEMENT Q9.
https://doi.org/10.1016/B978-0-12-817568-2.00003-8
Table 1 Other quality systems.
Qualification—equipment
Validation—process
a. Quality agreements
d. Document reviews (e.g., SOPs)
Packaging (primary through shipping)
Labeling (control)
a. Lab OOS
c. Production (OOS and others)
Today, all qualification and validation processes should be based on
good science and a risk-based approachd,e according to the FDA.f The risk
management program itself should be based on a good scientific background. There are two aspects of risk analysis that can or should be
FDA GMPs for the 21st Century.
PHARMACEUTICAL CGMPS FOR THE 21st CENTURY—A RISK-BASED APPROACH—
considered. The first is risk to the patient, and the second is risk to production. The FDA’s key interest is making sure there is no or at least very limited
risk to the patient due to production issues (dose, packaging, distribution,
etc.) or to the manufacturing process itself. This would include the loss of
product due to equipment failure, thus leading to a possible shortage of
the medication or device. The FDA statesg that patient safety should always
be the primary concern of all manufacturing.
Thus, this is every manufacturer’s goal. An analysis needs to be made of
each process step and therefore each process piece of equipment, with a
determination of its criticality and its impact on the process.
One of the most common approaches to determining the risk of a unit is
the use of the failure mode effect analysis or FMEA. An example of an
FMEA can be found in Tables 2 and 3. There are several good references
on how to set up and perform a FMEA.h,i
Table 2 Example of an FMEA.
Detectability Occurrence Severity Cause RPN
Intermittent fast and slow
Product level low
Product level high
High trace metals
Combined different
Particle distribution low
Particle distribution high
Not approved completely 4
Detectability: 1 ¼ easily detectible; 5 ¼ not easily detectable.
Occurrence: 1 ¼ not often; 5 ¼ often.
Severity: 1 ¼ not severe; 5 ¼ very severe.
FMEA—you-tube.
FMEA for beginners—www.ASQ.org.
Table 3 FMEA sorted by RPN.
Compounding Combined different
Compounding Smell
Intermittent fast and
Compounding High trace metals
Compounding Color incorrect
Compounding Combined lots
Compounding Clumped
Compounding Particle distribution low
Compounding Particle distribution
Detectability Occurrence Severity RPN
Change controlj
Once the CGMP process has started, a change control program needs
to be in place. But what is change control? This is a system that records and
approves all changes regardless of how small or seemingly inconsequential
they may be. This is one reason that current pharmaceutical practice is to
perform commissioning activities prior to starting the formal GMP activities.
Thus changes made during commissioning do not generally fall under the
change control umbrella. As will be discussed in Chapter 7, commissioning
tests are sometimes included in the installation qualification (IQ) and/or the
operational qualification (OQ). If this is done with the approval for the quality unit (QU) and the commissioning document is officially signed, then
these test results would be allowed (officially accepted) and there is no need
S. Dara, “A Practical Guide to Change Control Systems Management”, Journal of cGMP Compliance,
Oct. 1999, V.4 #1 pp. 62–102; “Validation of Pharmaceutical Processes,” 3rd Edition, Ed. By James P.
Agalloco, Frederick J. Carleton, Chapter 9.
to retest these items as part of the IQ or OQ protocol. That is, commissioning documentation is not generally a CGMP function.
Change control affects all changes, not only a change made during an
emergency but also a change made to improve the functioning of the unit.
If you plan to utilize the “like for like” component of change control, then
the two (or more) units need to be qualified and demonstrate that they can
function as identically. Thus, if you are qualifying a pump and a tank as a
stand-alone functioning unit and you want to be able to use two or more
different pumps (just in case), then all of the pumps need to be qualified with
the tank to demonstrate equal functionality. The IQ and OQ of each pump
can be individual, but the performance qualification (PQ) needs to show
similar results. So even if you have two pumps of equal output (not of
the identical manufacturer), they cannot be used interchangeably on a given
process system without a “joint” process qualification (except in emergency
situations and under QU review). This leads to the need for “like for like”
equipment. In that case, the process line is composed of identically functional units that can be “swapped out” as needed. However, a great deal
of caution needs to be taken when claiming computer equipment is identical
Investigationsk
Another key quality system that needs to be in place prior to performing an equipment qualification is that of investigations. The investigation program needs to include investigations for the following:
• Any missed dates in a schedule
• Any deviation from the written procedure
• Any out of specification (OOS)—laboratory-derived or other
• Any deviation from the expected results of the testing
Generally speaking the ROOT CAUSE does not need to be reached for an
investigation performed for a deviation uncovered in the IQ, OQ, or PQ,
because it is very often very obvious. As an example a blue pump rather than
a red pump is received. However, during manufacturing the ROOT
CAUSE (or at least most probable cause) needs to be determined. This is
one very important difference between a qualification investigation and a
manufacturing investigation.
B. Andersen & T. Fagerhaug, ‘Root Cause Analysis—Simplified Tools and Techniques’, 2nd Ed.,
American Society for Quality, 2006.
Deviations encountered during or part of the qualification program are
often handled in a little different manner than deviations that occur during
production. For example, deviations during production need to be logged
and recorded as individual events and correlated to other similar events. A
tracking program is used to track these events (not necessarily the one used
for manufacturing investigations). In the case of deviations that occur during
qualification testing, there is often just a log on the protocol in question, and
the investigation is centered on resolving the deviation. This often results
with interaction with the engineering department and/or operations to correct the problem. In either case a log of the event is needed, and a resolution
to the protocol deviation needs to be completed before it can be signed off as
Corrective action—Preventive actionl
The CAPA program is important as it insures that the results of an
investigation are correctly implemented. Thus, there are two phases to a
CAPA program:
Corrective action is the immediate “fix” to the problem. For example, it
may require revising an SOP. This is a long-term fix. The short-term fix
in this case could be a “planned deviation” allowing the company to operate
with the recommended change, for example, increased flow rate, prior to
the SOP being revised and approved. If a planned deviation is used, it needs
to be a short duration and very specific. Planned deviations are not a panacea
for all problems. The preventive action is the “long-term fix” to the problem. Here again is maybe the revision of the SOP.
Once the preventive action is deemed to be “in place,” it means that the
corrective action (the immediate fix resulting from the investigation) has
been implemented or at least started, whereas the term “in use” means that
the preventive action (or the continuation of the corrective action) is being
used correctly over time. This part is evaluated after a period of time such as
https://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm170612.htm.
Calibration/metrologym
The “calibration program” is another quality system program that
should be in place prior to starting the equipment qualification program.
There are two calibrations that need to be considered. The first is the calibration of the instruments on the process equipment itself, and the second
is the calibration of the test instruments to be used in the actual testing.
All instruments located on the process equipment itself need to be
precalibrated prior to starting the OQ since some or all may be used in
the actual test procedures. Calibration of process instrumentation is usually
performed during the commissioning of the unit so that you know that the
unit is performing correctly when placed in operation. For example, it is not
necessary to install a pressure gauge in a line if one exists on the equipment
already and it is calibrated.
Test instruments need to be calibrated prior to the test performed and
again after the test. This is to demonstrate that the test instrument has
remained in calibration during the testing. For example, a tachometer used
to measure the speed of an agitator should be calibrated prior to the test and
after the test. This applies to test instruments like thermocouples, while the
unit the thermocouples are attached to (the recorder) can usually be calibrated only once a year depending on the manufacturer specifications.
Calibration of critical instruments (those absolutely needed for the process to function correctly) is often completed at least every 6 months,
whereas all other instruments can be calibrated as needed (as determined
by regular testing).
Scheduled calibrations according to a written program and performed
according to a written SOP cannot be missed and still have the unit considered
operational. If a scheduled calibration is missed, an investigation needs to be
performed to determine the reason for the missed calibration. The unit cannot
be used until calibrated according to the SOP, and the investigation is closed.
Preventive maintenancen
While the preventative maintenance program need not be in use for
commissioning on the particular unit being qualified, it certainly needs to be
https://www.pharmamanufacturing.com/assets/wp_downloads/pdf/Vaisala_quality.pdf.
Hao Yinghua, Liang Yi,“Targeted Preventive Maintenance of Pharmaceutical Equipment” Journal of
Drug Design and Medicinal Chemistry, 2018; 4(2): 10–15 http://www.sciencepublishinggroup.com/
j/jddmc.
in place upon completion of the qualification. This is assuming that the unit
is new and is not being repurposed.
The preventive maintenance program is first based on the manufacturer
recommendations for the specific unit. Each unit should have a defined
maintenance schedule, just as your car does. Some items such as lubrication
may be required weekly, annually, or something in between. The vendor
will or should supply the frequency for this. After the unit has been in
use for a period of time, adjustments may be made to the preventive maintenance schedule. In no case should a scheduled maintenance be skipped.
This would lead to a deficiency and thus an investigation.
Cleaningo
Keeping the equipment clean is an important part of the qualification
process. While cleaning is not needed for the IQ portion of the program, it
may be needed for the OQ and certainly the PQ portions of the program.
The reason for keeping the equipment clean is another way to assure that the
correct test results are achieved. There may be tests that require the use of the
product that may influence further testing.
While cleaning verification and certainly cleaning validation are not
required at the IQ, clean equipment is a critical aspect of completing the
qualification program. Depending on the testing to be performed during
the OQ, a cleaning verification may be necessary. This entails swabbing
or rinsing the unit to remove any nonproduct material that may impact
the testing. However, when performing the PQ tests (when necessary),
cleaning verification, to show that the equipment is cleanable, is important
to do. This is because cleaning validation becomes a big part of the process
validation program.p
A robust document control system is another quality system that
should be in place prior to starting a qualification program. It is critical to
know the status of all documents being prepared and the status of all documents being executed.
Guide to Inspections of Cleaning Validation, FDA, July 1993.
S. Ostrove—“How to Validate a Pharmaceutical Process”, Academic Press, 2016.
The person(s) tasked with the execution of the protocol should be sure to
obtain a complete set of the protocols or those sections assigned, prior to
starting the execution. All pages need to be accounted for, and copies of
the original should be used for all executions. The document control
group/department needs to maintain a careful and complete record of all
documents in and out and all copies (e.g., sign out/in unless it is fully electronic and under 21 CFR Part 11). Remember whenever copies are used,
they need to be marked as “copy” before use in the field.
As stated in Chapter 1, requalification is not needed except in
certain situations (includes but not limited to):
• There is a significant change to the equipment.
 A change is needed that takes the unit outside of the proven acceptable
range (PAR).
• The equipment has been moved (even a little).
 NOTE: A full qualification is usually not required; however, a check
on calibrations, utility connections, and components are just some of
the checks necessary.
• Temperature mapping needs to be confirmed (e.g., autoclaves and
 Checking to determine if the hot and cold areas already mapped during
the qualification remain the same.
• There is a change is the process (requiring the equipment to be run at a
previously nonqualified condition)
In order to have an easy qualification, the equipment needs to be designed
properly. The first step in designing process equipment is to consult with the
users (operations). They need to tell the process engineers the specific use of
the equipment. For example, a tank is needed to hold 500 gal of liquid with a
pH below 5.0. The user is expected to be able to give specifics as to volume,
flow rate needed, etc. They know what the process is and will be based on
the development reports from the R&D group. (NOTE: Keep in mind that
according to the 2011 FDA Process Validation Guideline,a all development,
including equipment design, is now included in the full process validation
program.b) For examples of user specifications, see Table 1.
Not only is equipment design important for the proper operation of the
process itself, but it also directly impacts its qualification. The qualification
group should be included as part of the design process so as to assure that all
aspects of the unit will be tested appropriately and that requalification, if necessary, can be achieved with minimal effort. For example, if an autoclave is
to be ordered or a tank to be built, the qualification team should have input
as to some specific requirements, for example, a validation port on the autoclave or the welds used for sample ports on the tank. In the design process,
not only the actual function of the equipment but also its cleaning, its maintenance, and its calibration need to be considered. These factors are also part
of the unit’s complete qualification.
In the design of a piece of process equipment, not only the reaction
chemistry but also the physical and thermodynamic properties of the reaction have to be considered. Is the unit to be under pressure or vacuum? If so,
does it have the required ASTM rating? Some other considerations overlap
into cleaning validation, computer system validation, and process validation.
Regardless of the similarities in the equipment (i.e., tanks are tanks), each
type of equipment has its own unique design requirements. As can be
Guidance for Industry—Process Validation: General Principles and Practice, FDA, Jan. 2011.
S. Ostrove, “How to Validate a Pharmaceutical Process”, Academic Press, 2016.
https://doi.org/10.1016/B978-0-12-817568-2.00004-X
Table 1 Examples of user specifications
• Mix times
• Volumes to be used
• Flow rates (e.g., chromatography systems)
• Chemicals to be used
• Length of contact time
• Gassing rate (bioreactors)
• Heating rates needed—time
• Cooling rate needed—time
ascertained in 21CRF 211.63,c the equipment “…shall be of appropriate
design, adequate size, and suitably located…” “for its intended use.” This
is taken to mean that the equipment needs to be designed for its specific purpose. This does not preclude using a piece of equipment for multiple processes or using a stock unit made for multiple purposes. However, the
amount of material in the reaction and the ability to maintain temperature
and flows need to be established and shown to be appropriate for its intended
use. 21 CFR 211.65(a)d takes this further by stating that the materials of construction “…shall not be reactive, additive, or absorptive….” This means
that the materials of construction (MOC) should not in any way change
or alter the process reaction or the product.
Table 2 lists some basic questions that should be included as part of the process/equipment design. These questions can come from either the users or the
process engineers. Other questions may arise during design that may be answered
by either the user’s needs or the R&D group. For examples, see Table 2.
After consulting with the users of the equipment, the process engineers
need to consider needed design characteristics. The first rule of thumb is that
if you don’t want to overdesign (or underdesign), don’t use equipment that
is too large or too small for your process. Make sure that the operation group
is also included in the design phase of the equipment so that all user
Code of Federal Regulations (CFR) Subpart D specifically 21 Part 211 §63.
Code of Federal Regulations (CFR) Subpart D 21 Part 211 §65.
Table 2 Some basic design question
• What are the user’s requirements?
• Can the unit serve its expected purpose?
• Can it be cleaned effectively/safely?
 Can it be disassembled/assembled easily?
Are there special instruments needed to test its function?
Can it be placed in an area that is environmentally correct for its operation?
Are there special requirements for mounting or positioning the unit?
Do the users or validation specialists know the key or major components for its
 Capacity/volume
 Support structures (concrete, wall mounts, etc.)
 Space requirements
Temperature/flow maintenance
 Manual
 Microchip
 Programmed logic controller (PLC)
 Supervisory control and data acquisition (SCADA)
 Clean hold time
 Dirty hold time
 Ease of disassembly
 Clean in place (CIP) versus clean out of place (COP)
 Storage—clean
 Storage—dirty
 Where used
 Preventive maintenance program
 Emergency
Portable versus nonportable
Attachments to other units in the process (e.g., welds and flanges)
requirements (URS) can be met. For example, a tank that needs to hold
100 gal of reaction mixture should be sized to hold 150–175 gal (+50%–
75%) of liquid. Make sure that the impeller (agitator) will reach a point near
the bottom of the tank for proper agitation and that the fill and exit ports are
large enough to fill and empty the unit efficiently (Table 3). Other things
that may need to be considered are the following:
• Design the speed controls so that the range to be used is included in the
liner portion of the control curve.
Table 3 Process engineer design considerations
• Size/location
• Are the heating units
 too large or small?
 able to be controlled to the correct temperature to make an effective
seal on the blister?
• Are they correctly placed?
• Are the caps torqued to the correct degree?
• Can all areas of the tank be reached for proper cleaning (baffles, tops,
• Avoid dead legs (Fig. 1).e
After completing the design requirements of the equipment, the unit specifications are usually sent to a vendor for a bid on its construction (note:
depending on the equipment, construction may be in-house). These bids
should be reviewed for CGMP and other regulatory needs before they
are submitted to the vendor by the qualification/validation group.
Depending on the process, the cleaning, or the thermodynamics to be
A dead leg is per WHO.org http://apps.who.int/medicinedocs/en/d/Js14060e/16.html.
2(+) X Diam
Fig. 1 Example of a dead leg.
encountered by the unit, the vendor will need to be appraised of this prior to
bidding on the unit so that the proper material of construction can be used.
When the bids from the vendors are received back, they should be again
reviewed not only for price but also for conformance with user specifications
requested and CGMP compliance. Where this bid review is not done, or is
incomplete, problems may be found during commissioning or even during
the qualification process, which can greatly slow or even stop a construction
program and delay product reaching the market. After an appropriate bid
review, the selected vendor will fabricate the unit.
As discussed earlier the specific use of the unit is a must consideration
when designing a piece of process equipment. The material of construction
as noted in 21CFR211.65f is critical to all operations. In most cases the
industry choice of material is stainless steel (SS). Keep in mind the various
qualities of SS. For example, there are 304, 316, and 316L; the class depends
on the amount of chromium, nickel, carbon, and other metals in the
stainless-steel formulation. Depending on the product and the position of
the unit in the process, any may be acceptable. However, for most pharmaceutical operations, 316L is the one most often used for piping, tanks, and
other process equipment. Other popular choices for production equipment
are glass-lined vessels, polytetrafluoroethylene (PTFE),g or Hastelloyh (resistant to most organics, acids, bases, etc.).
http://www.crp.co.uk/technical.aspx.
https://www.titanmf.com/alloys/applications-of-hastelloy/.
Cleaning agents to be used in the cleaning process may also affect the
composition of the unit construction. As noted in the succeeding text,
halides will erode stainless steel, and some acids will dissolve glass (HF).
Other product contact materials that need to be considered are the materials used in the primary packaging and consequent product safety. For
example, blister packages need heat to seal the blister to the base. How thick
is the blister material? Will it let too much air into the package or too little?
Will the heat damage the product?
Location from both an environmental perspective and equipment
repair or maintenance perspective is part of the equipment qualification process and is included as part of the installation qualification (IQ) protocol.
Items such as air flow for cooling, ability to open ports or lids, or even
the ability to disassemble and assemble the unit for cleaning are just some
examples that need to be considered in designing the equipment. Is the location environmentally sound for the operation over a long period of time
(temperature and humidity)?
Another consideration is cleaning or replacing piping connected to a
larger piece of equipment. Fig. 2 shows sanitary links that connect piping
to tanks and other units in the process.
Consideration also needs to be given to the manner of mounting the unit.
Wall mounts will require shims to allow proper operation; floor mounts may
require specific thickness of concrete pads or vibration-absorbing materials.
Are the unit’s legs to be bolted down, or are they to be pointed so as to present
as little contact area for cleaning, as in a clean room?
Cleaning and maintenancej
While equipment qualification does not actually include cleaning verification or validation, it is certainly an important consideration when planning and designing a piece of process equipment. The unit must be cleaned
between uses and verified to have removed to an acceptable level both the
API and the excipients. Connections to large units (tanks, e.g., before tanks)
need to have piping that is short enough to be easily cleaned (Fig. 2) but not
Code of Federal Regulations (CFR) Subpart D, 21 Part 211 §63.
Code of Federal Regulations (CFR) Subpart D, 21 Part 211 §67.
Fig. 2 Sanitary fitting connecting a tank.
too short to add possibilities of contamination upon disassembly. Note in this
figure that the length of piping is short allowing for complete cleaning not
only of the pipe but also of the valve attached to the tank.
A major consideration when selecting the material to be used is the
cleaning or removal of all components (active pharmaceutical ingredients
and excipients). SS is susceptible to degradation (pitting) from halidesk
(F, Br, Cl, I, and At) when they are combined with other metals (NA, K,
etc.). Other materials, as mentioned earlier, can be used such as glass, PTFE,
or Hastelloy depending on temperatures or chemicals to be used in that process step, the cleaning agents (halides, detergents, solvents, etc.).
Cleaning of tanks or other large items may require cleaning-in-place
(CIP) procedures or sanitize-in-place (SIP) systems. Testing to assure that
all areas are completely covered and clean is often done through the use
of riboflavin at 100 ppm.l It is also necessary to assure that all welds or other
Pitting corrosion of martensitic stainless steel in halide bearing solutions, S.Pahlavan, S.MoazenI, TajiK.
Saffar, M.Hamrah, M.H.Moayed, S.Mollazadeh Beidokhti; Corrosion Science, Vol. 112, Nov. 2016,
www.abprocess.com.
connections of piping, etc. are smooth internally and externally so as to minimize surface area for chemical or bioburden buildup. This applies to the all
product contact surfaces regardless of material of construction. This is why
passivation is usually required.
Maintenance of the equipment is also a critical aspect to the design process. As discussed earlier, in location, the ability to get to all sides or areas
of the unit for maintenance is just as important as the actual design. This
is also the precursor for the preventive maintenance (PM) program that is
one of the quality systems that will be part of an FDA audit.
There are some other considerations when designing or specifying a
piece of process equipment, for example, location of the instruments associated with the unit, calibration based on criticality of these instruments, and
the preventive maintenance program needed to maintain the unit in full
Where product is or may be exposed to the environment, the units need
to be covered for their operation so that the product is protected (i.e., objects
falling into tanks or onto process lines (Fig. 3) or into bottles during filling
Fig. 3 Covered operation.
from above). In other cases, the product needs to be protected from the
operators, or the operators need to be protected from the product. The
design of these protective coverings will vary from very simple as in
Fig. 3 to more elaborate using plexiglass or other materials based on the
product (cosmetic, OTC, or parenteral) on the use but need to be included
in the design of the equipment since workers may still need access to the unit
for adjustments, cleaning, or maintenance (Fig. 3).
Still, other items that need consideration in process equipment design are
• Internal wall smoothness (cleaning, flow, etc.)
• Possibility of dead legse
• Turbulent versus linear flow of materials
• Weld type (smoothness and material used for the weld)
• Drainability
Obviously, the list can contain numerous items depending on the product,
the materials used in its production, cleaning requirements of the product
and excipients, etc. Again, as always, think about the design as a vital aspect
of production not just a vessel or unit to perform a function such as holding
Computer or automated control systems for pharmaceutical process equipment are almost ubiquitous in the industry.a It seems that every piece of
equipment has or is associated with some sort of automated or computer
control. This chapter is presented to give the reader a basic understanding
of what and how and where to include (or certainly consider) computer system validation (CSV) as part of the equipment qualification program. It is
not intended to be a full CSV guide. While computer systems are often
referred to as a validation program for the most part, it really is a qualification—since computers or computer systems can be treated as equipment not
processes. There are many good references for CSV (e.g., GAMP5b or the
PDA TR18c). This chapter will provide information as to what to include or
at least be aware of the need when qualifying your process equipment.
In considering the qualification level (Per GAMP-5) or the extent of
structural versus functional (see later) qualification, there is always a question
as to whether, how, or where to qualify a computer-controlled unit or automated system—should it be qualified as a separate independent unit or as a
functional piece of the equipment? Should the equipment be qualified as a
separate unit or its qualification be included into the process equipment
itself? The answer here is not always easy and will take some thought and
understanding of the computer or controllers’ actual function. In any case,
the controller or computer system must be qualified. One aspect of the analysis on the approach to take is to ask, “How integrated into the operation of
the unit is the control system, and can it be removed from the unit and have
the equipment have some functional value?” Thus—for example, the
programmed logic controller (PLC) that controls an autoclave—while relatively easily removed from the autoclave, the autoclave will not function at
“Validation of Pharmaceutical Processes,” 3rd Ed, edited by James P. Agalloco, Frederick J. Carleton.
GAMP 5 A Risk-Based Approach to Compliant GxP Computerized Systems ISPE, 2008.
Parenteral Drug Association, Technical Report 18, “Validation of Computer-Related Systems”,
Vol. 49, 1995.
https://doi.org/10.1016/B978-0-12-817568-2.00005-1
all without the PLC, and the PLC will not function for its, or other purposes,
since it is programmed for the specific autoclave. Thus, the autoclave PLC is
usually qualified as a major component of the autoclave. On the other hand,
a PLC that functions for a laboratory information management system
(LIMS) is used to collect data from a variety of laboratory units. This system
is mostly qualified or validated alone since each unit connected to the LIMS
can function independently and data can be obtained with or without the
LIMS. The distinction is the function of the computer system control.
As stated, there is some sort of computer control for almost every piece of
process equipment. Controls range from microchips all the way through full
computer controls (e.g., supervisory control and data acquisition—
SCADA). It is important to include some type of qualification of any type
of “computer or automation” control into the IQ and OQ protocols. For
those controlled by a microchip (e.g., vibrating shaker) or erasable programmable read-only memory (EPROM—not changeable or programmable by
the user), functional testing only is usually an acceptable approach. A slightly
more advanced controller is the electronically erasable programmable readonly memory (EEPROM—which is reprogrammable with another computer program) that could have its functionality tested as part of the unit
operation. An example of this type of unit is a programmable fraction collector. Keep in mind that structural testing is not always possible.
So, what is structural testing or qualification as compared with functional
testing or qualification? Both need to be completed, at least to some degree,
prior to considering the qualification complete.
A definition found in the Pharmaceutical Inspection Co-operation
Scheme (PIC/S) is as follows:
Examining the internal structure of the source code. Includes low-level and highlevel code review, path analysis, auditing of programming procedures and standards actually used, inspection for extraneous “dead code”, boundary analysis
and other techniques. Requires specific computer science and programming
expertise.d
This refers to the software itself. A full structural qualification includes, but
Good Practices for Computerized Systems in Regulated “GXP” Environments, PIC/S 011-3,
Equipment controls and automation
• Source code (for computer programs) review
• Ladder logic (for programmed logic controllers) review
• Structure of the written code
• Annotations in the code
• Review for dead code
• Software version installed
From the preceding text, it is clear that a full structural qualification may be
difficult to achieve on most software. Only software programs that are either
written in-house or by a third party contracted to write the code (BESPEC)
can have a complete structural review. Software purchased from a third party
that is configurable (configurable off the shelf—COTS) usually has a modified structural review. This leads to what is called “gray-box qualification”
As the term indicates, this involves the actual physical testing of the
computer system. Some very simple operating systems, a microchip operating a vibrating shaker (as in the preceding text), cannot have a separate functional test. Testing here would be through the unit itself. On the other hand,
more complex computer system (e.g., running a blender or controlling the
temperature and agitation of a tank) can be functionally tested as a separate
unit and then combined with the process unit. The fact that the computer or
PLC communicates with the agitator or the heat exchanger (heating unit)
has different functions than demonstrating that the tank is able to maintain
temperature or that the agitator maintains correct missing speed.
Both a full structural and a full functional test of the computer system or
control constitute what is referred to as a “white box” qualification. This is
actually not very common today since most software is written by a third
party who limits access to the source code or ladder logic.e There are
two other types of qualification often referred to for computer system qualification. These are “gray box” and “black box.” These are the most common types of qualification today.
The gray-box qualification is a full functional testing and a partial structural testing of the software. In this case the structural testing may constitute
Ladder logic is the equivalent of the source code for a Programmed Logic Controller (PLC).
verifying that the correct software was installed by verifying the software
name and version number. In comparison, the black-box qualification is
often applied to COTS systems or primarily functional testing of the software only. That is, does the software function as expected, and does it meet
the expected user requirements?
Black box, gray box, white box qualifications
From the earlier discussion, it should be clear that there are three types
of full computer system qualification/validation (for systems that are accessible for source code or ladder logic review), that is, computers or PLCs that are
accessible. For those systems that contain computers or PLCs that are not easily accessible (e.g., autoclaves), BLACK-BOX testing is usually acceptable.
For this, one needs only to verify the version of software installed and to perform functional testing to demonstrate that the program performs as expected.
Going up a notch to GRAY-BOX testing, one needs to not only verify the
version of the program installed but also confirm as much code information as
possible. This can usually be performed with source code or ladder logic written specifically for the operation or equipment (e.g., COTS systems).
When WHITE-BOX testing is able to be performed, a full evaluation of
the source code or ladder logic needs to be conducted. This, as described
earlier, requires full access to the source code or ladder logic so that dead
code, annotations, etc. can be evaluated.
IQ/OQ for computer or automated systems
Because of some of the complexity of a computer or automated control system, a procedure has been developed to help assure compliant qualification
and is referred to as the traceability matrix (TM) (Table 1).
Table 1 Basic trace matrix contents
CPP or function
URS location
OQ section
PQ section
This, as seen in Fig. 1, lists the user requirements (URS), the functional
requirements (FS or FRS), and the design requirements (DR or DDS) as
well as the location of the testing to be performed in the IQ and OQ and
or PQ. Fig. 1 gives an example of a TM chart that can be used for computer/automated systems or process equipment. By completing the TM,
it is easier to assure that all functions and operations will be correctly tested
in the appropriate protocol.
Example of a trace matrix
Function/CPP
Adds col 1 and 2
Note: The numbers are arbitrary and do not apply to any real document.
This is a CPP not a computer function.
Fig. 1 Example of a simple TM.
Table 2 IQ considerationsa
▪ Physical equipment
– All components (hard drives, cards, ports, etc.)
▪ Security present
▪ Power requirements
▪ Structural testing
– Audit—experience
▪ Number of users
▪ Input type (alpha or numeric or both)
Includes but not limited to.
Table 3 Generalized OQ considerationsa
– Power limits
– All component functions
– Input limits (boundaries)
▪ Functional testing
▪ Security test
▪ Operation of input and output devices (keyboard, screen, ports, etc.)
▪ Data recovery (local—e.g., hard drive)
– Data recovery after storage
▪ Alarms, locks
▪ Part 11 (audit trail)
Wherever possible the computer control needs to have an IQ and OQ
prepared. Table 2 gives a list of items to be included in the IQ, and Table 3
gives a list of items to be included in the OQ.
It is important to note that there are other tests that need to be performed
on computer systems that do not exist on other pieces of equipment (e.g.,
tanks). Table 4 shows a list of these tests. Two tests are more unique to computer systems qualification than any other piece of equipment. These tests
are the electromagnetic and radio frequency interference (EMI and RFI)
Table 4 Other possible testing
I/O loops
Security—biometric or standard
– Data lines
▪ Data integrity
– Data in versus data out
▪ Robustness
▪ Reproducibility
tests. These tests can be and are usually performed with common equipment
found in the plant. These two tests, using common equipment, for example,
an electric drill (for EMI testing) and the handheld radios used by employees
(for RFI testing), can easily demonstrate that the computer or controller is
free from this kind of interference. These tests are important in order to
demonstrate complete data integrity during working time.
Still another very important aspect of computer qualification is the
question of Part 11f integrity. Does the software act in a way to store or transmit data? An example here is an HPLC system that is computer controlled.
The unit may produce a paper tape of the chromatogram that is inserted into
the laboratory notebook. In addition, the unit may store the chromatogram
in the LIMS system for further analysis (e.g., integration of the peaks). In the
former case, if the paper tape is the final record of the test performed, then
Part 11 is not a requirement; however, if it is the latter case, then Part 11 is
definitely a requirement in the qualification process.
As stated in CFR Part 11 (21 CFR 11.1(b)), this applies to “…records in
electronic form that are created, modified, maintained, archived, retrieved,
or transmitted….” In other words, this applies to anything that has to do
with electronic records or signatures. Electronic signatures pertain to signatures that are included by electronic means. Further guidance on Part 11
requirements can be found in the FDA guidelines on Part 11.g
From the earlier discussion, it should be clear that the qualification of
computer or automated controls for a piece of process equipment is necessary and is not very different than any other qualification. Today, due to the
complexity of the controls and programming, many systems are qualified by
either the Gray- or Black-box approach. If the software is prepared inhouse, then White-box qualification certainly should be completed.
FDA 21 CFR Part 11—Electronic Records; Electronic Signatures.
Guidance for Industry Part 11, Electronic Records; Electronic Signatures—Scope and Application,
Computer systems are nothing to be afraid of. Common sense and an
understanding of what it does (as in with all pharmaceutical equipment) will
enable the necessary testing to complete the qualification. The physical unit
(keyboard, screen, ports, etc.) make up the IQ, while testing these to be sure
that the data are correct and that the computer does what it is supposed to do
(i.e., open/close a valve, start/stop an operation at a specific time, etc.) is
the OQ.
Preparing the protocols: General
According to Merriam-Webster online dictionary, a protocol is “a detailed
plan of a scientific or medical experiment, treatment, or procedure.”a This
means that prior to performing any commissioning or qualification work on
any piece of equipment, a formal protocol needs to be prepared.b Also, this
definition clearly fits with the FDA’s prospective validation/qualification
approach; the tests are predefined, as are the expected results. All protocols
are designed around the needs to the use or process as defined by the users
(operations/production), that is, the user specifications. According to the
FDA, all protocols need to be prepared on using good science and a risk basis
approach.c
Before we look at specific protocols, let’s look at the general path
needed to get a protocol approved for execution. Fig. 1 outlines such a flow.
This flow diagram is a generalized approach. The flowchart shows the
generally expected time and responsibilities for developing a protocol.
(Note: not every protocol needs to follow this path as outlined nor the time
line indicated. This may depend on whether the protocol is prepared inhouse or by an outside firm.)
However, there are some general approaches that have proved successful
over the years.d The first step is that the person assigned to prepare the protocol should be familiar with the intended function of the unit and then to
inquire from the users (if possible) as to the units expected specific function.
https://www.merriam-webster.com/dictionary/protocol.
21 CFR 211.100.
FDA, Pharmaceutical CGMPs for the 21st Century—A Risk Based Approach, Sept. 2004.
https://www.pharmaceuticalonline.com/doc/writing-compliant-iq-oq-pq-protocols-meeting-fdaexpectations-0001.
https://doi.org/10.1016/B978-0-12-817568-2.00006-3
Fig. 1 General flow of a protocol development.
There are several other questions and things to do in order to make the preparation easier and more effective:
• Review the PFD to understand the general process flow.
• Review the P&ID to confirm the system boundaries (Figs. 2 and 3).
• Review the FAT, SAT, and commissioning tests that were performed
and the process development/history (e.g., closely related products being
manufactured on expected similar equipment).
• Determine if any other machines are in use of a similar type.
• Ask if there are any other protocols or products similar to the one to be
manufactured in that unit currently in use that uses similar equipment.
Preparing the protocols: General approach
Fig. 2 Example of a P&ID showing incoming piping for a protocol.
And finally, they should rereview current FDA guidelinese and current
warning lettersf to be sure that all necessary aspects are covered. By understanding the FDA’s expectations as outlined in Table 1, a clear, concise protocol can be prepared.
Once the earlier questions and checks are completed, the author can
begin protocol preparation. Protocols need to have a specific defined structure or format. This format is not as important as content. However, once a
format has been established for the company, do try to maintain this format
for future protocols.
A general table of contents can be seen in Table 2. Certainly, each protocol will have its own unique table of contents where each item or test
Process Validation Guide, others.
https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm.
Fig. 3 Example of a header and footer for a protocol page.
Table 1 General FDA expectations
▪ Written SOPs are available
– IQ needs a list
– OQ needs a draft
– PQ needs them signed
▪ Prepare protocols (review and approve) in ADVANCE
– Use GOOD science
▪ Criteria MUST be measurable
▪ Obtain approved protocol BEFORE executing
▪ Have the final validation report—APPROVED
▪ VALID CONCLUSION FROM THE ACTUAL RESULTS
Table 2 Sample: Table of contents
Title/approval
– IQ—All physical parameters
▪ All persons executing the protocol need to sign or initial their respective
action at the time they perform the task as at the performed by at the bottom
– OQ—All operating needs—full range of operation
▪ Each test is usually a separate page or section and requires a performed by and
reviewed by signature
– PQ—Time testing/stability per specific production use
Each protocol (IQ, OQ, or PQ) has its own layout or configuration.
This is not critical to the actual acceptance of the protocol or unit for its
operation or function in the process. But once a layout has been established,
as stated, it should be maintained as much as possible. Each protocol should
have a header and footer. The header should at least indicate the protocol
name and document number (unique so it is traceable), the identity of
the protocol, the version number, and usually the company name. The
footer should have at least the page number in the format of Page X of
Yg and any other information desired such as file route and date of preparation (Fig. 4). Remember that all pages need to have a unique number and
that when copies are used for execution, they be clearly marked as copies.
The PQ protocol is designed as the IQ or OQ, but more specific tests for the
unit operation for the product are listed not just the operation of the unit.
Another general consideration for protocol preparation is that only one side
of a page is used. This avoids errors when making copies.
21 CFR 211.105 and FDA Guidance for Industry M4: Organization of the CTD.
Fig. 4 Header and footer example.
Another important aspect of protocol preparation is to make sure that
the protocol is designed around what is known as a “stand-alone system.”
Examples of stand-alone systems would be a refrigerator or autoclave.
A stand-alone system means that all valves, piping, instruments, equipment
(tanks, pumps, etc.), etc. that make up the system are included in a protocol.
There are two basic ways to achieve stand-alone conditions:
1. All piping, instruments, etc. entering the unit (following a valve that can
isolate the unit) are to be included with the unit’s protocol (Fig. 2).
2. The other way is to include all piping, instruments, etc. leaving the
unit as part (up to a valve that can isolate the unit) of the unit’s protocol
No other component is needed for its function (other than possibly a utility
such as electricity). Developing “system boundaries” is the means to achieving this stand-alone state. Using the P&IDs, one can draw with colored
markers (or others) lines to demark the components to be included or
excluded from a given protocol. This will assure that all components (piping, valves, pumps, etc.) are accounted for in a protocol (it doesn’t matter
which protocol). Keeping this in mind, each protocol set (IQ/OQ/PQ)
should be specific for the unit being qualified.
A totally generic approach to preparing a protocol (e.g., all tests or sections are identical for all equipment) is not usually acceptable. Thus, having
the same sections and/or tests for all IQs or OQs may not actually test or
verify the unit as carefully as it needs to be tested. This said, each protocol
needs to be as specific and unique to the unit tested as possible.
Table 3 Acceptance criteria
Comparisons of clinical materials (i.e., bio-batch, impurity profile, and R&D)
Capable of controlling process parameters within acceptable ranges
Variability assessed using SPC methods during development
Acceptance criteriah
Acceptance criteria for all protocols need to be quantitative and measurable (as expressed in Table 3). For example, when turning on a unit and
the indicator light changes from RED to GREEN is a measurable, quantitative result. Another important aspect of acceptance criterion is that they
should be expressed as a range. For example, the temperature of the solution
reaches 45°C  2°C. As compared with saying that the temperature goes up
or down, one needs to know how much. It can say it goes up at least X°C or
not more than X°C or even not less than X°C nor more than X°C. However, the set point can and should be a definite value, for example, 45°C,
which is the target for that particular operation.
All protocols will need to be reviewed and approved not only by the
author but also by others. This leads to the signature requirements on the
protocol. There are two signature pages found on all protocols. The first signature page is the preapproval page that indicates that the items (tests or specifications and acceptance criteria) in the protocol are acceptable to those
signing. The signature page at the end of the protocol is by the same persons
or groups that signed the preapproval page and indicates that the results are
acceptable and true.
So, who needs to sign a protocol? The author certainly needs to assume
credit for the protocol, so they sign as the preparer. Then, depending on the
protocol type and the unit function, usually, someone (a manager or supervisor level person) from operations, engineering, and possibly maintenance
will also review and approve. These reviewers review the document for
their expertise only. That is, the engineering person will attest that the unit
21 CFR 210.3(20).
can operate at the conditions specified (e.g., speed, temperature, pressure, or
vacuum.). The operation person will attest that the test criteria and acceptance criteria include those needed for production. If there are safety items
(e.g., interlocks), then the safety group should also sign and affirm that the
unit can meet the requirements of safety required. The last person or group
to sign both the preapproval and postapproval page is always the quality unit.
They review the protocol for compliance to corporate standards of writing,
FDA requirements for protocols, and other in-house or specific requirements for the protocol. Their review is based on meeting both corporate
and regulatory requirements. This is done for both the preapproval page
of the document (it certifies that the protocol meets the requirements of
all parties concerned with the correct operation of the unit(s)) and the postapproval page (the same departments review the data to assure that they are
accurate and meet the acceptance criteria set forth).
Each test section needs to have a space for the person(s) executing the
protocol and the person reviewing each section and a comment area. This
review is not to be confused with the approval pages. It is to indicate primarily that all spaces on the document were filled in, that the data appear
correct, and that the acceptance criteria were either met as understood by
the reviewer. This review should be performed as soon as possible after
the execution so as to be able to correct any errors or answer any questions
(refer to Chapter 10).
With the basic understanding of preparing a protocol (Chapter 6), it is now
necessary to consider some of the specific protocols needed for a full qualification program. These include the Factory Acceptance Testa (FAT), the
Site Acceptance Test (SAT), and the Commissioning Protocols. Table 1
summarizes the key events of the equipment life cycle for all types of equipment starting with establishing the need and ending with the unit being
taken off line and sold or discarded (even if it is a used piece of equipment).
From this table, it can be seen that there is a lot to activity prior to
testing the unit. This all needs to be documented. The FAT and SAT testing
are the forerunners to commissioning. After the unit is ordered and the
(qualified/approved) vendor is ready to ship to the client, the FAT protocol
is usually run. The FAT protocol is usually prepared by the vendor; however, the client company can also prepare the protocol. The FAT is prepared
mostly for large items such as an autoclave. Even so, smaller units (e.g., glass
washer or a V-blender) may be initially tested on the vendor site before it is
shipped to the client. The company, prior to the start of any FAT testing,
should review the FAT and approve the protocol and add their own specific
requirements if necessary. This is because the vendor will probably prepare
the FAT protocol so that the unit will pass. Thus the company should have
prearranged agreement with the vendor to be able to add, or change, any of
the tests so as to best evaluate the unit’s operation as required by their specific
process. It is also advisable for a representative of the contracting company
(company) to attend the testing to witness the testing and to be sure that any
changes to the FAT that were required by the company are included and that
the testing meets manufacturing needs. Once the FAT is completed and
approved, the unit is shipped to the company.
http://carelabz.com/what-factory-acceptance-testing-how-fat-done/.
https://doi.org/10.1016/B978-0-12-817568-2.00007-5
Table 1 General equipment life cycle
Process engineers determine design specifications
Design specifications are reviewed by operations and sent to purchasing
Order equipment from a qualified vendor
Vendor submits drawings/specifications with bid
Bid is reviewed for company requirements
Perform Factory Acceptance Test (FAT)
Perform Site Acceptance Test (SAT)
Commission the unit
Qualify the unit (Chapter 8)
Use the unit
Decommission when not to be used
Upon completing the FAT and receiving the unit on-site, a SAT
should be conducted. Even those that do have the FAT will undergo a
SAT to assure that everything is intact and nothing was lost along the
way in shipping. Certainly, those items shipped without a FAT will often
have a SAT. Even if the vendor is across the street from the company,
damage may be incurred during shipment. Instruments get bumped,
joints may loosen, or parts may fall off or get lost if they were shipped
separately. In any case, units undergoing a FAT should also have a SATb
to assure that all components are still in place and functional. These tests
are also conducted via a written protocol. This protocol also needs to be
reviewed and approved by the manufacturing company prior to starting
Upon receipt of the unit the receiving (manufacturer) company verifies
the unit as per the purchase order requirements. The manufacturing company then prepares and approves the SAT protocol for both small and large
units (often the same basic tests as performed in the FAT). The SAT is used
to show that the unit that has been received was not damaged during shipment and that all components are still intact. The SAT while similar to the
FAT is usually a simpler test protocol just to assure the unit is intact and not
damaged during shipment. The commissioning comes next.
So, what is a commissioning protocol?
https://learnaboutgmp.com/good-validation-practices/the-difference-between-a-fat-and-a-satvideo/.
Commissioningc
Following the FAT/SAT portion of the equipment purchase and
installation, the unit can be commissioned. Understanding the use and
the how and why of commissioning is another critical step in setting up
an effective equipment qualification program. Commissioning is “bring
(something newly produced, such as a factory or machine) into working
condition.” By this definition, all equipment to be used in a pharmaceutical
plant use should be commissioned, at least to some degree. Commissioningd
is a ubiquitous operation that is very often overlooked even in our daily
lives. For example, when we purchase a car, the dealer commissions the
car for us. Here, for example, the dealer fills the gas tank, checks the windshield fluid, and checks tire pressure. Likewise, when a new piece of process
equipment is purchased and installed, after the FAT/SAT, commissioning
needs to be done to make the unit ready for use. According to industry
standards, commissioning is a preplanned, documented, and managed
approach to assure that the equipment is ready for use as intended. All major
components need to be verified, flow rates need to be adjusted, temperatures need calibration, preventive maintenance may also have to be
As with any item we purchase, whether an item purchased in a store or
ordered from an on line vendor, the first thing anyone does is inspect the
package. Any defect in the package may indicate a possible defect in the
product. This is also true of pharmaceutical equipment. The next thing
we usually do is to open the package, inspect the unit for damage and decide
to accept it or return it to the vendor. This is easier for home items that pharmaceutical equipment, however, if there is evident damage the vendor is
contacted and rectification of the issue is made.
The next step is to place the unit in place (kitchen shelf, night table, etc.).
For pharmaceutical equipment it may be necessary to have made special provisions for the unit to be installed. This may include things like a thicker
cement pad, a vibrations absorbing pad, a noise-reducing environment, or
other specific requirements for the correct operation of the equipment.
Commissioning and Qualification of Existing Facilities and Systems, J. Butterfield, R & D Magazine, 2005
(https://www.rdmag.com/article/2005/07/commissioning-and-qualification-existing-facilities-andsystems).
ISPE Baseline Guide Vol 5, “Commissioning and Qualification” March 2001.
Following the placement of the unit into its proper location we are often anxious to start it up. While this may be possible for a toaster, or an alarm clock it is
not so easy with a piece of pharmaceutical equipment. A forklift, crane, or
other large piece of equipment is often needed to move or place a unit in
its proper place. Care must be taken using these devices as well.
Now that the unit is in place, at home we try it out, in the pharmaceutical industry we need to do some further work. It needs to be fixed in place
(except for portable units) according to the manufacturers specifications
(i.e., distance from the wall, floor or ceiling, level, etc.) While it may be easy
to refer to the installation instructions alone, or to have the machine manufacturer perform the installation this is not the accepted way of doing
things. A protocol has to be written and executed.
This verification is accomplished with a commissioning protocol. The engineering group usually prepares the commissioning protocol since they are
often the ones who are responsible for the installation of the unit. In some
cases the company producing the equipment will install the unit according
to the manufacturing company’s requirements and their own specifications.
This protocol while similar to the IQ and OQ protocols discussed in
Chapter 8 does have some major differences (see Table 2). First of all, as
defined, it is intended to get the equipment ready for use as compared to
testing it to be sure it meets the required specifications.e That means changes
can be made without going through the change control procedures (note: is
some cases the quality unit does want to sign the protocol, thus making it a
GMP document and thus may be subject to the change control program).
The reason to keep this part of the qualification program as a separate item is
to allow the engineers, the operation staff, or the vendor to make the necessary changes, according to predetermined testing, following a written set
of procedures so that all changes or modifications that are made to the unit
are correctly recorded and these changes will be incorporated and verified in
the IQ and/or OQ protocol. The commissioning protocol can be as simple
as a checklist (e.g., unit has two blades; motor is 2 HP) or more complex as to
having defined specifications to be met (e.g., flow rates and RPM
Some examples of commissioning changes can be seen in Table 3.
Commissioning—Key to Project Success, D. Owings, Pharmaceutical Manufacturing, Sep./Oct.
2002, 22:5.
Table 2 Commissioning versus qualification
Check sheet/protocol
Corrections made as necessary
Not necessarily a GMP document
Changes made need to be documented
Purpose is to get equipment ready for use
A GMP activity
Specified versus actual
Preapproval of the protocol is needed
Purpose is to prove usability for a specific function
Required if there is any product contact
Summary report needed
Table 3 Examples of some commissioning steps
• Adjusting the rate of ozone flowing in a purified water system
• Changing a stuck gauge for a comparable working one
• Changing a gauge to a more sensitive scale (i.e., the original gauge reads from 0 to
100 psi, but the pressure needed for the system only goes to 25 psi, so a gauge
reading from 0 to 50 psi is more appropriate).
I/O checks (loop checks)
Verifying polarity of electric outlet
Bumping the pump (check for rotation and speed)
Verifying distance from wall, floor, and ceiling
Verifying utility connections
Checking (adjusting as needed)
 Flow rate(s)
 Pressure(s)
 Temperature(s)
 Speed(s)
The commissioning protocol needs to check the operation and range of
the gauges, flows, temperatures, etc. based on the process information produced during the development stage for the process. All changes made during the execution of the commissioning protocol are to be carefully
documented and approved by the corresponding authority. This means that
a change in a valve size needs engineering approval while a change to flow
rate of the product would require approval by the production or operation
Using commissioning data
While getting the equipment ready for use is the main purpose of commissioning, there is another advantage to having a well-defined, welldocumented commissioning program in place. This advantage is that some,
if not all, of the commissioning tests may be used to support or replace testing
that would have to be tested in the IQ or OQ. This is at the discretion of the
quality unit. For example: