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Identifying and Resolving GMP

Issues for Pharmaceutical Process
and Facility Design
By Editorial Staff

INTRODUCTION

The absolute, most

important aspects
of GMP are to
remain in control
of the product and
to consistently
make the product
to predetermined
quality attributes.

When considering the design

and building of a pharmaceutical
process and a facility to manufacture pharmaceutical products,
many of the requirements
involved can be found in the U.S.
Good Manufacturing Practice
(GMP) regulations. The actual
specifics will depend upon the
product to be produced.

DEFINE GMPs
Good Manufacturing Practice
(GMP) is a regulation defined in
21 Code of Federal Regulations
(CFR) Parts 210 and 211 and
enforced by the Food and Drug
Administration (FDA). GMP
defines the principles of a Quality
System that, if followed, will
ensure control of the quality of
the pharmaceutical product during manufacture. The principles
of a Quality System are based on
the science of the process; on
the people and the issues associated with the process; and on the
analysis, measurements, and
documentation of the process.
Good Manufacturing Practice is a
quality system that requires good

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science, complete documentation, and responsible people to

carry it out.
Good Manufacturing Practices
have a direct impact on how the
pharmaceutical process and facility should be designed. How will
the facility be constructed, what
sort of utilities will be required?
Consider every part of the
process. How will the process be
put together and what are the
issues involved with the process
that must be addressed in order
to comply with the regulations?
The most important aspects of
GMP are to remain in control of
the product and to consistently
make the product to predetermined quality attributes. It is
essential to know what the product should be and how to make it
day-in and day-out in the facility
using the predetermined process
or processes. These are the
things that must be considered
during the design and building of
the pharmaceutical process or
processes and facility.
A process and facility to manufacture pharmaceutical products
can not be put together without
considering the people who are
going to work with that process,

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in that facility. When the author first considered the

subject of this article a few years ago, he thought
the people considerations were probably less
important than the other assets - the facility and the
process. However, with time, he has realized that
compliance is all about people. Quality is about the
people who are doing the manufacturing, the people
who are putting things together. In addition to a facility and a process, the right people are necessary to
run the process, ensure quality, and produce the
planned product.
Quality
Quality requires a commitment. Employees must
be committed to quality. They must know and understand quality. They must know what a quality product entails and how to work within the building and
the operation in such a manner as to not compromise quality. For example, employees must understand that they must go through the gowning room,
gown properly, and they must be committed to that
procedure. They must understand that they may not
take short-cuts in order to save time.
Employees must be alert to things that are not
correct or as they should be. They should be committed to making a quality product and willing to do
whatever it takes to make it correctly. They should,
of course, understand completely the operations
they are to perform through training and experience.
At a minimum, they should understand how the
operations work, how they interact with each other,
and they should understand the basic science
involved with the process they are working with.
Consistency
Under GMP, procedures are required in order to
explain everything. Having written procedures and
following those procedures ensures consistency.
With each procedure comes consistency on how to
gown, how to walk through the facility, how to degown, how to wash, how to clean equipment, how
to run equipment, etc. All of these procedures must
be in place to guide employees and to ensure that
everyone does the processing or manufacturing in
the same way. Of course, it is not enough to just
have the procedures. The employees must believe
in them and adhere to them. This is how consistency is guaranteed.

Adequate Space
Regulation 21 CFR Parts 210, and specifically
Part 211, discusses the topics of having adequate
space within a facility in order to prevent mix-ups
and cross-contamination, of having adequate lighting and amenities, and of having appropriate
accommodations for sewage and trash handling.
Consider these regulations when designing the
manufacturing facility.
The facility, plant, or building must be sufficiently
large in order to allow space for operations to be
accomplished. People must be able to move easily
around the equipment as needed, either to maintain
it, to operate it, to load it, or to unload it. The facility
must be sufficiently large for all activities to proceed
smoothly.
Order
Consider the orderly performance of operations.
Plan for things to go in sequence, so that materials
being produced move through the operation unidirectionally. Do not crisscross other materials. This
will prevent mix-ups between materials and crosscontamination. Plan for product segregation and
adequate storage. Adequate storage and handling
space will keep products segregated and avoid contamination or mix-ups.
Proper people, material, and equipment flow are
necessary to prevent mix-ups. The facility should be
designed and set-up so that traffic patterns flow in
one direction. For example, people gown-up, move
into a room, and then move out of the room through
another door. In this way, people do not cross-contaminate one another.
The same is true of materials. Plan for materials
to be moved unidirectionally so that, in another
example, a drum of material sitting somewhere can
not be mistaken for a different kind of material. This
is especially important when equipment is to be
moved between rooms, as opposed to static equipment, such as tanks or IBCs. Design the facility so
as to ensure that these things flow in a way that will
prevent confusion and cross-contamination.
Product Protection
Unlike work on a vehicle assembly line where
manufacturing is exposed in a large hangar-like
room, product protection implies processing in
'rooms' or distinct areas in order to manage the
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operations and protect the product, especially near

the end of the production operation. There are a
number of methods that may be used to protect the
product during the manufacturing process including
use of enclosed processing equipment, or the use
of utilities such as glove boxes and barrier technology. The concept of product protection is a major
aspect of manufacturing pharmaceuticals and properly designed facilities, utilities, and the process
itself can make it happen.
Proper Support Areas
Properly designed and placed support areas are
detailed and required by regulation. Support areas
include showers, utilities, bathrooms, etc.
Cleanability
An extremely important issue regarding manufacturing areas is having the proper finishes in the facility. The finishes should be cleanable and sanitizable. When planning the facility finishes, address
issues such as how the walls and floors are to be
cleaned. The facility, when it is built, should have
rounded corners where the walls and floors meet to
ensure that they can be properly cleaned. The
materials on the walls must be able to withstand
sanitizing agents and high pressure hosing if these
things are necessary according to regulation.
Depending on what is to be manufactured, certain
facilities may require only painted block walls while
others may require very smooth walls, epoxy paint,
etc. It will depend upon the application and the
intended operation.
Cleanability issues can be critical to the designing of a facility. The facility needs to be constructed
so that it can be easily cleaned. For example, if the
rooms are to be hosed down in order to wash the
walls or floors, there must be appropriate drains and
the floors sloped towards the drains to ensure that
all the water used in the cleaning of these rooms will
drain properly.

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UTILITIES
'Utilities' is probably the most critical aspect in the
business of manufacturing pharmaceuticals. Despite
the fact that manufacturing is a process and is
process-driven, the real cost of manufacturing pharmaceuticals is in building the facility. The facility is
usually the most expensive component, in a large
part due to the required utilities, such as the air handling system and the water system.
Air conditioning is the methodology by which, if
you manage the quality of the air in the manufacturing space, you also manage the relative pressurization between the manufacturing spaces. Managing
room pressurization relative to each other and to the
corridor is one of the primary methods of controlling
cross-contamination between products. In a multiple
product, solid dosage facility, for example, dust from
one room must be prevented from getting into
another by relative pressurization between these
rooms and the corridor. This is accomplished by
pressurizing both rooms into a negative pressurization corridor so that nothing from one room goes
into the other. This is achieved by using the air
conditioning systems, also referred to as the airhandling units, AHUs.
Regulations suggest that in cases where there
are materials that are very difficult to clean and
remove, dedicated air-handling units should be
used. Using separate AHUs is also recommended
for materials that pose a certain hazard.
Cephalosporins are one such material. Hormones,
which are high-potency compounds, are another
such material that should be addressed through
air-handling and management.
Water Quality
There is a range of water quality that begins with
municipal water, which is extracted from common
city pipes coming into the plant. This is the least
controlled quality of water. Municipal water has certain criteria that are based on drinking water requirements, but they vary in solids content; they vary in
microbial content. These criteria are not of consistent quality. The quality issue will have to be
addressed through, at a minimum, some filtration;
use of purified water which removes the organics;
all the way to doing water-for-injection (which is
really based on distilling deionized water from which
organics have been removed) for sterile product

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manufacturing. All this will depend upon what is to

be manufactured. (In the author's opinion, the minimum water quality for a pharmaceutical manufacturer is deionized water.)
Compressed Air
Use of compressed air must be consistent with
the operation being performed. For example, if compressed air is to be used and it will come in contact
with the product, then the compressed air should be
hydrocarbon-free, i.e., it should not contain oil.
When considering use of a compressor, think of oilless compressors or coalescent filters to remove
any hydrocarbons that may be carried in the compressed air. Other issues to consider are the water,
particulate, and microbial content of the compressed
air. If, for example, compressed air is used in a classified room, a room that has a certain quality of air
of, say, one hundred particles of less than .5 micron
per cubic foot, then the compressed air should also
be at the same quality level, otherwise, if it is of a
lesser quality, quite a bit of particulate will be introduced into the air.
Reliable Utility Systems
Depending upon what is being manufactured,
utilities such as electricity or steam must be reliable.
If a piece of electrical equipment must not stop, and
to do otherwise will ruin the product, then the source
of that electricity must be reliable.
If steam is necessary, to run autoclaves to sterilize equipment or implements for example, the reliability of that steam and its quality, pressure, and
temperature is critical.
Other utilities that must be considered include
cleaning-in-place and steaming- or sterilizing-inplace utilities. These are important where the cleaning agent is brought to the equipment. This may be
done via a static clean-in-place system where the
tanks with water and detergent, etc. are sitting in a
utility room and the cleaning agent is piped to the
equipment, or with a portable clean-in-place system
with tanks for the detergent and rinsing agent
mounted on skids, which can be brought closer to
the equipment. This, of course, depends upon the
size of the equipment. That is, if the equipment to
be cleaned is large, a portable clean-in-place system may not work as the tanks would have to be
too large to move.

Power
Uninterruptible power is a critical requirement,
especially when doing fermentation, because in
much fermentation, aerobic fermentation in particular, should the propellers stop because of loss of
power, even momentarily, oxygen starvation could
result. Therefore, the system demands that power to
the propeller and fermenter not be lost or interrupted.
Other critical utilities include sterilizers or specialty gases. For example, if nitrogen or another
specialty gas is to be used, a filter may be required
or the gas may have to be of a certain quality.
There are a myriad of issues to be well thought
out when assessing the utilities needed in a plant or
facility. They may be critical to the process and must
be considered very carefully as to their design and
their requirements.

PROCESS CONSIDERATIONS
Materials of Construction
One of the most important aspects in GMP compliance is that the material used for the manufacturing equipment does not participate in or interfere
with what is being manufactured. This is one of the
main reasons we see stainless steel 316 as a common material in our business. Glass lining is another
common material used because it is also inert.
The materials, the vessels, the equipment that
will be used, must be made of materials that will be
inert to the process and not participate or interfere in
anyway with the physical or chemical properties of
the product. For the same reason, more exotic
alloys may come into play for processing steps
involving aggressive materials. The manufactured
substance must be protected from adulteration at
every point of manufacture.
Process Suitability
A second process consideration is process suitability. Is the planned or existing equipment large
enough to do what is planned? If the plan calls for
processing 1000 gallons in a tank, the tank should
be sized to allow the processing of 1000 gallons
without a problem. Should the tanks be sized too
small, the results will not be reproducible. Not being
able to reproduce results will cause problems and
consistency will be lost.
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Keep in mind that, GMP is designed so that a

product of predetermined quality attributes may be
made consistently. Therefore, the equipment must
be suitable to the process. For example, if a solution
is to be filtered to remove solids, equipment
designed for filtration must be used. A sieve cannot
be used. The right tool must be used for the right
results. Problems will result, because the equipment
was not designed to do that job.
The equipment must all be cleanable and sanitizable. When considering equipment for the pharmaceutical business, it should always be easy to clean,
easy to reach every corner, and every element able
to be taken apart. This is called sanitary equipment.
Sanitary piping and sanitary equipment can be
taken apart and cleaned completely. All parts of the
equipment should be able to be sanitized and verified to be clean.
There should be a method for record keeping
and processing these items. Batch sheets, and how
they are developed, are critical. Spots for keeping
the batch sheets are important to design. It is important to decide where to put the batch sheet, how the
batch sheet will be set-up, and where the operator
will work with it. Will it be an electronic batch sheet
or a paper batch sheet, where is it going to be setup, how will it be dealt with? Each issue should be
considered and decided upon to complete the procedure.
Sampling
When considering and designing the process,
recognize that GMP requires a great deal of inprocess testing. This will require proper sampling
for testing. Sampling mechanisms will be needed;
ways of obtaining samples without interrupting the
operation. This is a part of designing processing
equipment and setting-up the processes.
Cross-contamination is a critical aspect in sampling. The regulation requires testing of suspected
contaminants and prevention of cross-contamination. Not only are sampling forks required, the
process should be designed so that there is no
cross-contamination; that no material can flow from
one tank to another when it is not supposed to.
Check valves or the proper isolators must be
installed to prevent cross-contamination of the material. Enclosed processing may be necessary to prevent something floating in the air from coming into
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the process.
The regulations require that the equipment is
properly cleaned and that it is demonstrated that it
is clean. For example, a teratogen the author was
processing could not be analyzed at a very low level
for its existence or presence. It was decided that it
made no sense to clean the equipment and use it
for another process because it was impossible to tell
with 100% accuracy that it was cleaned. As a result,
it was used as dedicated equipment. If a potent
material involved in the designed process is unable
to be analyzed at very low levels and there is a
place where it is not possible to demonstrate that
the equipment is cleaned, it is best to use dedicated
equipment for that operation.
Always be prepared to investigate for out-ofspecification situations. When designing processes,
know what the specifications are and establish an
alert. Define the alert precisely so that operators will
quickly recognize an out-of-specification condition or
a deviation. Validate the process. In designing the
process and specifying the equipment, ensure that
the design and process information is in place so
that a proper validation can be conducted.

MODEL OF A PHARMACEUTICAL
BUSINESS
In the Pharmaceutical Business, there is a discovery component, which is the laboratory. Then,
there is the process development component, which
is basically the pilot plan. There is the bulk manufacturing operation, the finishing and packaging operations, and lastly sales and marketing. In the discovery component, some qualification will be needed.
This is where Good Manufacturing Practice (GMP)
and Good Laboratory Practice (GLP) requirements
dictate that some level of qualification of the equipment is needed. See Figure 1. For example, if an
autoclave is used in the research organization, the
autoclave should be qualified. It should be a validated
system. If water of a certain quality is used in the laboratory, the system will need to be validated. It will
also be necessary to be GLP compliant, which is
really a documentation and methods validation issue.
During process development, the equipment and
system must be qualified. Some of the systems may
need to be validated. For example, if a specific
water is required in the process development or pilot

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plan, it is necessary to validate the water system to

ensure that the quality of the water is established.
And, of course, all GLP and GMP requirements
must be complied with. Why are we required to
comply with GMP requirements and process development? The guiding principle is as follows: when a
material is to be used in humans, then it should
comply with GMP requirements. That is, the Quality
Systems must be in place along with the understanding and the documentation as discussed earlier in this article.
In bulk manufacturing, of course, total, complete
validation is required. GMP compliance is a requirement that should be addressed as you go along. In
the finishing and packaging, validation and GMP
compliance is required. In sales and marketing, the
issues are really in the documentation associated
with how the product is sold.

VALIDATION
The normal or the well-known definition of validation is that there is documented evidence that the
product can be made consistently, which means
there are predetermined quality attributes. Process
validation is documented evidence that gives a high
degree of assurance that the product can be made
consistently at the desired quality attributes. In order
to achieve this, the desired outcomes must be
known in advance.
Methods Validation
Methods validation is an analysis or an analytical
methodology that is developed in place. These new
methods should be validated to demonstrate that
the method can consistently give a reading as to the
characteristics of the material being analyzed. In
cases where a methodology has been published,
whether in the pharmacopoeia, the compendia, or in
articles and literature that have been demonstrated
to work well, there is no requirement to validate the
method. But in many cases it will be necessary to
demonstrate that these methods still work for specific cases, and that they do not suffer due to interference from other components that may be in the

Figure 1
GMP/GLP Requirements

PROCESS
DEVELOPMENT
Qualification
Some Validation
GLP/GMP Compliance

BULK
MANUFACTURING
Validation
GMP Compliance

FINISHING AND
PACKAGING
Validation
GMP Compliance

DISCOVERY
Some Qualification
GLP Compliance

SALES
AND
MARKETING

PRODUCT

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material being analyzed, especially if different compositions are being used.

What is a Validation Protocol?
Validation protocols are procedures that explain
how to validate, how to run the validation study.
They also are the repository wherein all of the data
may be kept. A validation protocol is first and foremost documentation. At the end, it is the documented evidence. The validation protocol is a significant component of the validation effort or of
building, managing, and running a facility for manufacturing pharmaceuticals.
Once the protocols are in place, there are a number of regulatory imperatives. These are things that
must be done from a regulatory point-of-view. First is
validation. This is not an option. It is a requirement.
In order to validate, a validation protocol is required.
The equipment must be carefully designed and
selected. The rationale for the design and equipment
selection should be documented. There must be a
procedure to prevent contamination. It must be
demonstrated in the design of the processes and
facility that the procedures will prevent contamination. Criteria for initiating and performing Out of
Specification (OOS) investigations must be established. These are the critical criteria that will indicate
when to initiate an OOS investigation.
There must be validated procedures for reprocessing. It is necessary to establish the idea that
revalidation should take place when specific
changes occur. Reprocessing is a common occurrence in the manufacturing of pharmaceuticals.
When something does not quite meet the quality
attributes or when it is anticipated that this could
happen, there must be some way to rework the
material to bring it within quality standards. These
procedures must be in place and validated. Along
with these systems and procedures, a change control procedure i.e., a system in place to manage any
changes to these validated systems and facilities, is
necessary.

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How Do We Conduct Validation?

Critical Systems
Once the facility has been designed and built,
what is critical and what is not must be defined. For
example, a critical utility, such as the HVAC system,
the water system, the clean steam being used, or
the compressed air system must be validated. What
are non-critical utilities that do not need to be validated? Those would probably include the air conditioning for the office space within the facility, for
example; the potable water being used in the bathrooms; the plant steam coming from the boiler
house; or the effluent handling system (the sewer
system). These are not critical systems, and they do
not need to be validated.
The first thing to do is to define what is critical
and what is not from both the process point-of-view
and the utility point-of-view. In most cases, all utility
equipment, and all process equipment are critical to
the process. If they were not, then they would not
be needed. Once identified and defined, it must be
ensured that the right pieces of equipment have
been installed correctly. Then, it must be verified
that this equipment is going to do what it is supposed to do. For example, was a mixing tank with a
motor that is capable of giving you 150 rpm for the
mixing shaft purchased? If so, then ascertain that
the motor is capable of doing that. The motor must
perform adequately within the limits established for
the process. This is called Operational Qualification
(OQ).
Qualification
The first part, where it was ascertained that the
right piece of equipment was purchased, is called
Installation Qualification (IQ). When it is verified that
the parts of the process are working correctly, this is
called Performance Qualification (PQ). The parts
that are more critical are challenged to ensure that
they are working correctly. Then it must be determined that the entire process works correctly and
produces the product of the quality planned. Finally,
the results are summarized and assurance provided
that once validated, they will remain in a validated
state.

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Process Steps
What are the types of pharmaceutical processes
that we deal with? There are bulk processes, which
is a synthesis and it is done either via chemistry or
biologics, through fermentation or cell culture. Then
comes finishing, which can be either sterile or nonsterile. Last comes storage. The bulk process starts
with the raw material, which is stored. The raw material is prepared, i.e., derivatized and dissolved or
something is put in a solvent. When the material is
synthesized, other materials besides the material of
interest appear. Now, the material must be purified,
and normally, dried, and packaged. The results are
what is called bulk product. See Figure 2.
Issues of Importance
In raw material storage, warehouse space that
gives these materials adequate room is a necessity.
Good record keeping is also a necessity. The warehouse has to be clean. That is why rodent and
insect traps are used in these facilities. These traps
ensure that these areas remain clean and are not
contaminated.
There is usually a need for a proper sampling
facility within the warehouse. Sampling is needed
because side reactions must be monitored along

with the progress of those reactions, the formation

of impurities, etc. A sampling room should be established where the samples can be taken. A laboratory
on the side to do quick tests of the raw material as it
comes in may be desirable. These are important
aspects to be considered when establishing the
warehouse.
Materials and product must be segregated.
Enclosed areas are necessary where rejects can be
kept in a quarantined area and where approved and
released products can be kept. These needs will
dictate how to set-up a warehouse and how to
space things. There should be limited access areas
and tampering prevention precautions. All of these
considerations should be addressed in procedures
for dealing with raw material storage.
In the preparation of the raw material the quality
of the solvent must be considered. For example, if
solvents are to be recycled, the quality of the recycled solvent must be addressed to ensure that it
does not retain contaminants from previous
batches. The ability to clean the equipment and use
of sanitary equipment is a requirement. In the synthesis step, an understanding of the chemistry of
each process is necessary.

Figure 2
Bulk Manufacturing

PREPARATION
OF RAW
MATERIAL
(2)

STORAGE
(1)

SYNTHESIS
(3)

PURIFICATION
AND
PACKAGING
(4)

RAW MATERIAL

BULK PRODUCT

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Yield Reproducibility

Finishing and Packaging

The regulation indicates that yield from various

steps is critical and that it must be tracked. In many
cases the product consistency is measured by
obtaining the same yield from the same steps consistently. Therefore, a means to calculate and measure the yield is necessary. The water quality and
the material construction are other issues that
should be considered in the synthesis.

Controlling the atmosphere in the packaging

room is critical. Humidity may affect the product,
and the packaging material may affect the packaging process. Having the correct level of humidity in
the packaging room is necessary. Particulates in the
packaging room may contaminate the material of
interest or the bulk that is being packaged. So care
must be taken regarding the environmental controls
in the packaging area.
After the bulk has been extracted and purified, it
is time to make it into tablets or into a sterile
injectable, etc. At this point, the bulk and excipients
(which are the additives) are brought in and stored.
Next comes formulation and dosage. Finishing is
complete. The product is packaged in bottles or
ampules, etc., and the packaged product is stored
and shipped. See Figure 3.

Purification
There are many ways of purifying. It is important
to understand the various steps used to purify material, whether crystallization, filtration, or distillation.
Chromatography is used in the purification of protein, etc.
Crystallization
Oftentimes, when doing crystallization to remove
the product of interest, mother liquors are left upon
removing the crystals. These usually have more of
the material of interest, so it is desirable to recycle it
in order to obtain that material. While extracting the
material of interest, impurities are being concentrated in the mother liquor. It is important to ensure
that the impurities are not concentrated to a point
that the purpose of the crystallization is defeated.
Although recycling of mother liquors is a common
way of processing purification, it also has its pitfalls
and needs to be carefully performed.
Dryer Recycling
There is a critical aspect of drying a large
amount of material that has been synthesized that
must be considered. Much of the material dried on
drum dryers is taken, but some is left behind. Usually the leftovers are dissolved on the dryer, and
dried again with the next batch. Unfortunately, as
the material 'cooks' over and over on the heated
drum, impurities are generated. It is extremely
important to be aware of this and process materials
carefully as you recycle dryer material.

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FINISHED PRODUCT
Cleanliness
Let us look at some of the issues relative to the
finished product. At this point, we have segregation
issues. When making a sterile product, other finishing aspects include the quality of the air in the
rooms. We must have the correct labeling of the
various storage areas and the various materials that
come into storage. Cleanliness now becomes even
more critical because this product is not all chemicals or sacks of material. These are little drums of
very close to being final product. These are active
pharmaceutical ingredients (APIs) and excipients.
The important aspect to think about in finishing is
that, normally, no further cleaning or purifying is
done. Purification occurs in the bulk manufacturing,
but in most finishing phases and in the packaging of
final product, not much more purification is done. At
this point, it is very important not to contaminate the
product, because there are no further steps to clean
it. Extreme caution must be used to prevent crosscontamination, in maintaining the cleanliness of the
product, and in dealing with the product during storage and staging.
Cross-contamination must be considered again.
Since the product is not going to be purified any further, it is critical to ensure that the equipment is
clean, can be maintained in a clean state, and that
people do not contribute to the contamination of the

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product. Personal cleanliness of employees as

regards contamination of product must be
addressed in the packaging of the final product.
Labeling
More than 90% of recalls are caused by the mislabeling of product. In the packaging of the final
product, label control is an important aspect. Controlling the labels, counting them, making sure the
correct label is applied to the correct material, are all
important aspects of labeling the product. Final
inspection of the product must be done online.
Temperature Control, Storage
Final product is the material that will go to the
user or to the patient. This material must be stored
and properly segregated. Inappropriate materials
cannot be put together; for example, aspirins with
steroids. Ensure the correct temperature and humidity controls within the space so that the product
does not deteriorate during storage. Finished products may be temperature-sensitive so the warehouse, unlike the warehouse in bulk manufacturing,
may need some temperature control. It may need to
be kept cold or at a more comfortable temperature
or at lesser humidity than the warehouse where the
bulk is stored. Control what is outgoing.
Consider how to ship this material, or product.
Shipping issues are increasingly more important.

Shipment by truck is common in the United States,

and environmental conditions may vary widely.
Trucks can get very hot when they sit out in the sun
at a truck stop, or very cold at night should the
trucker stop somewhere and fall asleep. The conditions within the truck are significant and must be
managed.
Product File
Record all the complaints and problems that
occur once the product is sold. Adverse event
recording, reporting, and management are
extremely important aspects of pharmaceutical
manufacturing that must be dealt with ongoing.
Training
The overall consideration is that the processes
and the entire operation are validatable to ensure
that the systems put in place will be in control and
give the consistent results expected at all times.
Another critical component is the training requirements of personnel which must be addressed.
There are many 483s and Warning Letters that
have been based on a lack of proper training for
personnel and operators, which makes this issue all
the more important.

Figure 3
Finishing and Packaging

EXCIPIENTS
BULK

STORAGE AND
STAGING
(1)

PRODUCT

FINISHING
(2)

PACKAGING
(3)

STORAGE AND
SHIPPING
(4)

A p r i l 2 0 0 7 Vo l u m e 11 , N u m b e r 3

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Editorial Staff

Cost
All of these GMP issues add cost to the manufacture of the product, but these are not frivolous
issues. Proper construction of processes and the
facility, training and education of personnel, along
with the proper documentation of all procedures and
policies, although adding cost, also render a much
higher quality product, which reduces risk to the
patient, and that is a significant gain to the corporation. No one wants their patients to experience
adverse events because the quality of their product
is substandard.
Attending to these issues also increases profits,
because the equipment lasts longer, there is
reduced down-time along with reduced errors and
rework. These savings usually reflect crucial positive
returns on these investments. Attending to these
issues reduces the number of errors, because there
is an understanding of how things are to be accomplished. This results in a much higher quality product; therefore resulting in fewer complaints, fewer
returns, and fewer recalls, all of which are an
absolute cost savings. And, of course, safety numbers increase, because personnel understand the
processes and operations much better, so they are
safer and they work safer.
Although there are costs associated with incorporating GMP requirements, they are 'the lesser of two
evils' when the costs involved in ignoring them are
considered, which would be reflected in the costs of
recalls, 483s, Warning Letters, and possible fines
and penalties, not to mention other business-related
expenses that show up in costs of employee
turnover, absenteeism, errors, rework, etc.

ACKNOWLEDGEMENT
This article was created by IVT Editorial Staff in
collaboration with Cindy Green, RAC, with reference
to a teleseminar held June 13, 2006, presented by
Gamal Amer, Ph.D.

52

Journal of GXP Compliance

Article Acronym Listing

AHU
API
CFR
FDA
GLP
GMP
HVAC
IBC
IQ
OOS
OQ
PQ
U.S.

Air Handling Unit

Active Pharmaceutical Ingredient
Code of Federal Regulations
Food and Drug Administration
Good Laboratory Practice
Good Manufacturing Practice
Heating, Ventilation, and Air
Conditioning
Intermediate Bulk Container
Installation Qualification
Out-Of-Specification
Operational Qualification
Performance Qualification
United States

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