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42 Journal of GXP Compliance

Identifying and Resolving GMPIssues for Pharmaceutical Process

and Facility Design

By Editorial Staff

INTRODUCTION

When considering the designand building of a pharmaceutical

process and a facility to manufac-

ture 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 dur-

ing manufacture. The principles

of a Quality System are based on

the science of the process; onthe people and the issues associ-

ated with the process; and on the

analysis, measurements, and

documentation of the process.

Good Manufacturing Practice is a

quality system that requires good

science, complete documenta-

tion, and responsible people to

carry it out.Good Manufacturing Practices

have a direct impact on how the

pharmaceutical process and facil-

ity 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 predeter-

mined quality attributes. It is

essential to know what the prod-

uct 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 orprocesses and facility.

A process and facility to man-

ufacture pharmaceutical products

can not be put together without

considering the people who are

going to work with that process,

The absolute, mostimportant aspects

of GMP are to

remain in control

of the product and

to consistently

make the product

to predetermined

quality attributes.

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Editorial Staff

43Apri l 2007 Volume 11, Number 3

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 thepeople who are doing the manufacturing, the people

who are putting things together. In addition to a facil-

ity 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 under-

stand quality. They must know what a quality prod-

uct entails and how to work within the building and

the operation in such a manner as to not compro-mise quality. For example, employees must under-

stand 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 com-

mitted 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 de-

gown, 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 thateveryone 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 consis-

tency 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 light-

ing and amenities, and of having appropriateaccommodations 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 unidi-

rectionally. Do not crisscross other materials. This

will prevent mix-ups between materials and cross-

contamination. Plan for product segregation and

adequate storage. Adequate storage and handling

space will keep products segregated and avoid con-

tamination 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-cont-

aminate 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 equip-

ment, 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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Editorial Staff


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 technol-ogy. The concept of product protection is a major

aspect of manufacturing pharmaceuticals and prop-

erly 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 manufac-turing areas is having the proper finishes in the facil-

ity. The finishes should be cleanable and sanitiz-

able. 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 design-

ing 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.

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 phar-

maceuticals is in building the facility. The facility isusually the most expensive component, in a large

part due to the required utilities, such as the air han-

dling system and the water system.

Air conditioning is the methodology by which, if

you manage the quality of the air in the manufactur-

ing space, you also manage the relative pressuriza-

tion 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 intoanother by relative pressurization between these

rooms and the corridor. This is accomplished by

pressurizing both rooms into a negative pressuriza-

tion 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 air-

handling 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 cer-

tain criteria that are based on drinking water require-

ments, but they vary in solids content; they vary in

microbial content. These criteria are not of consis-tent 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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Editorial Staff


manufacturing. All this will depend upon what is to

be manufactured. (In the author's opinion, the mini-

mum water quality for a pharmaceutical manufac-

turer is deionized water.)

Compressed AirUse of compressed air must be consistent with

the operation being performed. For example, if com-

pressed 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 oil-

less compressors or coalescent filters to remove

any hydrocarbons that may be carried in the com-

pressed 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 clas-

sified room, a room that has a certain quality of airof, 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 intro-

duced 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 steril-

ize equipment or implements for example, the relia-

bility 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-in-

place utilities. These are important where the clean-

ing agent is brought to the equipment. This may be

done viaa 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 agentmounted 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 sys-

tem 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 particu-

lar, should the propellers stop because of loss of

power, even momentarily, oxygen starvation couldresult. Therefore, the system demands that power to

the propeller and fermenter not be lost or inter-

rupted.

Other critical utilities include sterilizers or spe-

cialty 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 com-

pliance is that the material used for the manufactur-

ing 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 com-

mon 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 suit-

ability. Is the planned or existing equipment large

enough to do what is planned? If the plan calls forprocessing 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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Editorial Staff


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 cannotbe 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 sanitiz-

able. When considering equipment for the pharma-

ceutical 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 veri-

fied 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 impor-

tant 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 set-

up, how will it be dealt with? Each issue should be

considered and decided upon to complete the pro-

cedure.

Sampling

When considering and designing the process,

recognize that GMP requires a great deal of in-

process 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 sam-

pling. The regulation requires testing of suspected

contaminants and prevention of cross-contamina-

tion. Not only are sampling forks required, the

process should be designed so that there is nocross-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 mate-

rial. Enclosed processing may be necessary to pre-

vent something floating in the air from coming into

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 itmade 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-of-

specification situations. When designing processes,

know what the specifications are and establish analert. 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.

MODELOFA PHARMACEUTICAL

BUSINESS

In the Pharmaceutical Business, there is a dis-

covery component, which is the laboratory. Then,

there is the process development component, which

is basically the pilot plan. There is the bulk manufac-

turing operation, the finishing and packaging opera-

tions, and lastly sales and marketing. In the discov-

ery 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 equip-

ment 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 lab-

oratory, the system will need to be validated. It willalso 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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Editorial Staff


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 devel-

opment? The guiding principle is as follows: when amaterial 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 under-

standing and the documentation as discussed ear-

lier in this article.

In bulk manufacturing, of course, total, complete

validation is required. GMP compliance is a require-

ment 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 valida-

tion 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 highdegree 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 spe-

cific cases, and that they do not suffer due to inter-

ference from other components that may be in the

Figure 1

GMP/GLP Requirements

PROCESSDEVELOPMENT Qualification Some Validation GLP/GMP Compliance

DISCOVERY Some Qualification GLP Compliance

BULKMANUFACTURING Validation GMP Compliance

FINISHING ANDPACKAGING Validation GMP Compliance

SALESAND

MARKETINGPRODUCT



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Editorial Staff


material being analyzed, especially if different com-

positions 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 fore-

most documentation. At the end, it is the docu-

mented evidence. The validation protocol is a signifi-

cant component of the validation effort or of

building, managing, and running a facility for manu-

facturing pharmaceuticals.

Once the protocols are in place, there are a num-

ber 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 contamina-

tion. Criteria for initiating and performing Out of

Specification (OOS) investigations must be estab-

lished. These are the critical criteria that will indicate

when to initiate an OOS investigation.

There must be validated procedures for repro-

cessing. It is necessary to establish the idea that

revalidation should take place when specific

changes occur. Reprocessing is a common occur-

rence 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 con-

trol procedure i.e., a system in place to manage any

changes to these validated systems and facilities, is

necessary.

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, orthe compressed air system must be validated. What

are non-critical utilities that do not need to be vali-

dated? Those would probably include the air condi-

tioning for the office space within the facility, for

example; the potable water being used in the bath-

rooms; 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 utilityequipment, 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 sup-

posed 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 deter-

mined that the entire process works correctly and

produces the product of the quality planned. Finally,

the results are summarized and assurance providedthat once validated, they will remain in a validated

state.



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Editorial Staff


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 viachemistry or

biologics, through fermentation or cell culture. Then

comes finishing, which can be either sterile or non-sterile. Last comes storage. The bulk process starts

with the raw material, which is stored. The raw mate-

rial 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 ware-

house 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 estab-

lished 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 thewarehouse.

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, ifsolvents are to be recycled, the quality of the recy-

cled 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 syn-

thesis step, an understanding of the chemistry of

each process is necessary.

Figure 2

Bulk Manufacturing

PREPARATIONOF RAW

MATERIAL(2)

STORAGE(1)

SYNTHESIS(3)

PURIFICATIONAND

PACKAGING(4)

BULK PRODUCT

RAW MATERIAL



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Editorial Staff


Yield Reproducibility

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 con-

sistently. Therefore, a means to calculate and mea-sure the yield is necessary. The water quality and

the material construction are other issues that

should be considered in the synthesis.

Purification

There are many ways of purifying. It is important

to understand the various steps used to purify mate-

rial, whether crystallization, filtration, or distillation.

Chromatography is used in the purification of pro-

tein, etc.

CrystallizationOftentimes, 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 concen-

trated 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. Usu-

ally 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.

Finishing and Packaging

Controlling the atmosphere in the packaging

room is critical. Humidity may affect the product,

and the packaging material may affect the packag-

ing process. Having the correct level of humidity in

the packaging room is necessary. Particulates in thepackaging 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.

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 finish-

ing 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 chemi-

cals 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 cross-

contamination, in maintaining the cleanliness of the

product, and in dealing with the product during stor-age and staging.

Cross-contamination must be considered again.

Since the product is not going to be purified any fur-

ther, 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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Editorial Staff


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 mis-labeling of product. In the packaging of the final

product, label control is an important aspect. Con-

trolling 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 withsteroids. Ensure the correct temperature and humid-

ity controls within the space so that the product

does not deteriorate during storage. Finished prod-

ucts may be temperature-sensitive so the ware-

house, 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 condi-

tions within the truck are significant and must bemanaged.

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 ensurethat the systems put in place will be in control and

give the consistent results expected at all times.

Another critical component is the training require-

ments 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

STORAGE ANDSTAGING

(1)

FINISHING(2)

PACKAGING(3)

STORAGE ANDSHIPPING

(4)

BULK

EXCIPIENTS

PRODUCT



11/12

Editorial Staff


Cost

All of these GMP issues add cost to the manu-

facture 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 andpolicies, although adding cost, also render a much

higher quality product, which reduces risk to the

patient, and that is a significant gain to the corpora-

tion. 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 thereis an understanding of how things are to be accom-

plished. This results in a much higher quality prod-

uct; therefore resulting in fewer complaints, fewer

returns, and fewer recalls, all of which are an

absolute cost savings. And, of course, safety num-

bers increase, because personnel understand the

processes and operations much better, so they are

safer and they work safer.

Although there are costs associated with incorpo-

rating 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.

Article Acronym Listing

AHU Air Handling Unit

API Active Pharmaceutical Ingredient

CFR Code of Federal Regulations

FDA Food and Drug AdministrationGLP Good Laboratory Practice

GMP Good Manufacturing Practice

HVAC Heating, Ventilation, and Air

Conditioning

IBC Intermediate Bulk Container

IQ Installation Qualification

OOS Out-Of-Specification

OQ Operational Qualification

PQ Performance Qualification

U.S. United States



12/12

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