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IVTGXP_April07.

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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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Journal of GXP Compliance

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,

a drum of material sitting somewhere can not be mistaken for a different kind of material. with time. The facility must be sufficiently large for all activities to proceed smoothly. etc. the right people are necessary to run the process. Having written procedures and following those procedures ensures consistency. In this way. For example. The employees must believe in them and adhere to them. how to degown. of course. Employees must be alert to things that are not correct or as they should be. or building must be sufficiently large in order to allow space for operations to be accomplished. Design the facility so as to ensure that these things flow in a way that will prevent confusion and cross-contamination. and produce the planned product. 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. or to unload it. Plan for materials to be moved unidirectionally so that. Quality is about the people who are doing the manufacturing. When the author first considered the subject of this article a few years ago.the facility and the process. Proper people. Quality Quality requires a commitment. Order Consider the orderly performance of operations. Consistency Under GMP. However. At a minimum. Adequate storage and handling space will keep products segregated and avoid contamination or mix-ups. of having adequate lighting and amenities. Adequate Space Regulation 21 CFR Parts 210. This is how consistency is guaranteed. They should be committed to making a quality product and willing to do whatever it takes to make it correctly. In addition to a facility and a process. it is not enough to just have the procedures. they should understand how the operations work. 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. understand completely the operations they are to perform through training and experience. They must know and understand quality. how they interact with each other. Do not crisscross other materials. either to maintain it.qxd 3/19/07 12:59 PM Page 43 Editorial Staff in that facility. discusses the topics of having adequate space within a facility in order to prevent mix-ups and cross-contamination. and of having appropriate accommodations for sewage and trash handling. gown properly. how to run equipment. employees must understand that they must go through the gowning room. move into a room. in another example. The facility should be designed and set-up so that traffic patterns flow in one direction. Employees must be committed to quality. ensure quality. how to walk through the facility. he thought the “people considerations” were probably less important than the other assets . to operate it. For example. Product Protection Unlike work on a vehicle assembly line where manufacturing is exposed in a large hangar-like room. N u m b e r 3 43 . and then move out of the room through another door. he has realized that compliance is all about people. They should. as opposed to static equipment. The same is true of materials. Plan for things to go in sequence. Of course. how to clean equipment. plant. This will prevent mix-ups between materials and crosscontamination. people gown-up. people do not cross-contaminate one another. procedures are required in order to explain everything. material. and specifically Part 211. This is especially important when equipment is to be moved between rooms. such as tanks or IBCs. Plan for product segregation and adequate storage. so that materials being produced move through the operation unidirectionally. how to wash. the people who are putting things together. and they must be committed to that procedure. Consider these regulations when designing the manufacturing facility. They must understand that they may not take short-cuts in order to save time. People must be able to move easily around the equipment as needed. With each procedure comes consistency on how to gown. and equipment flow are necessary to prevent mix-ups. to load it. The facility.IVTGXP_April07. product protection implies processing in 'rooms' or distinct areas in order to manage the A p r i l 2 0 0 7 • Vo l u m e 11 . and they should understand the basic science involved with the process they are working with.

if the rooms are to be hosed down in order to wash the walls or floors. dust from one room must be prevented from getting into another by relative pressurization between these rooms and the corridor.qxd 3/19/07 12:59 PM Page 44 Editorial Staff operations and protect the product. The quality issue will have to be addressed through. Managing room pressurization relative to each other and to the corridor is one of the primary methods of controlling cross-contamination between products. 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. which is extracted from common city pipes coming into the plant. Cleanability An extremely important issue regarding manufacturing areas is having the proper finishes in the facility. if you manage the quality of the air in the manufacturing space. This is achieved by using the air conditioning systems. 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 . AHUs.IVTGXP_April07. There are a number of methods that may be used to protect the product during the manufacturing process including use of enclosed processing equipment. Cleanability issues can be critical to the designing of a facility. Proper Support Areas Properly designed and placed support areas are detailed and required by regulation. should have rounded corners where the walls and floors meet to ensure that they can be properly cleaned. etc. the real cost of manufacturing pharmaceuticals is in building the facility. When planning the facility finishes. Hormones. Cephalosporins are one such material. address issues such as how the walls and floors are to be 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. for example. when it is built. which are high-potency compounds. you also manage the relative pressurization between the manufacturing spaces. also referred to as the airhandling units. dedicated air-handling units should be used. The facility needs to be constructed so that it can be easily cleaned. some filtration. Municipal water has certain criteria that are based on drinking water requirements. Air conditioning is the methodology by which. The facility is usually the most expensive component. bathrooms. These criteria are not of consistent quality. at a minimum. This is accomplished by pressurizing both rooms into a negative pressurization corridor so that nothing from one room goes into the other. etc. It will depend upon the application and the intended operation. but they vary in solids content. especially near the end of the production operation. This is the least controlled quality of water. For example. Using separate AHUs is also recommended for materials that pose a certain hazard. utilities. epoxy paint. use of purified water which removes the organics. or the use of utilities such as glove boxes and barrier technology. Water Quality There is a range of water quality that begins with municipal water. 44 Journal of GXP Compliance UTILITIES 'Utilities' is probably the most critical aspect in the business of manufacturing pharmaceuticals. solid dosage facility. Support areas include showers. are another such material that should be addressed through air-handling and management. The finishes should be cleanable and sanitizable. Depending on what is to be manufactured. Despite the fact that manufacturing is a process and is process-driven. they vary in microbial content. The facility. Regulations suggest that in cases where there are materials that are very difficult to clean and remove. certain facilities may require only painted block walls while others may require very smooth walls. In a multiple product. utilities. such as the air handling system and the water system. and the process itself can make it happen. The concept of product protection is a major aspect of manufacturing pharmaceuticals and properly designed facilities. in a large part due to the required utilities.

If a piece of electrical equipment must not stop. i. or with a portable clean-in-place system with tanks for the detergent and rinsing agent mounted on skids.qxd 3/19/07 12:59 PM Page 45 Editorial Staff manufacturing. the tank should be sized to allow the processing of 1000 gallons without a problem.) Compressed Air Use of compressed air must be consistent with the operation being performed. Other critical utilities include sterilizers or specialty gases. Process Suitability A second process consideration is process suitability. utilities such as electricity or steam must be reliable. the equipment that will be used. otherwise. For the same reason. These are important where the cleaning agent is brought to the equipment. A p r i l 2 0 0 7 • Vo l u m e 11 . a portable clean-in-place system may not work as the tanks would have to be too large to move. the results will not be reproducible.e. particulate. All this will depend upon what is to be manufactured. because in much fermentation. if it is of a lesser quality. Other utilities that must be considered include cleaning-in-place and steaming. Should the tanks be sized too small. pressure. if the equipment to be cleaned is large. think of oilless compressors or coalescent filters to remove any hydrocarbons that may be carried in the compressed air. if compressed air is to be used and it will come in contact with the product. to run autoclaves to sterilize equipment or implements for example. the system demands that power to the propeller and fermenter not be lost or interrupted. (In the author's opinion. more exotic alloys may come into play for processing steps involving aggressive materials. and microbial content of the compressed air. then the compressed air should also be at the same quality level. the minimum water quality for a pharmaceutical manufacturer is deionized water. Glass lining is another common material used because it is also inert. which can be brought closer to the equipment. and temperature is critical. and to do otherwise will ruin the product. etc. compressed air is used in a classified room. then the source of that electricity must be reliable. If steam is necessary. 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. If. Therefore. quite a bit of particulate will be introduced into the air. There are a myriad of issues to be well thought out when assessing the utilities needed in a plant or facility. it should not contain oil. When considering use of a compressor. For example. N u m b e r 3 45 . for example. For example. especially when doing fermentation. 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. That is.IVTGXP_April07. Other issues to consider are the water. a filter may be required or the gas may have to be of a certain quality. oxygen starvation could result. Is the planned or existing equipment large enough to do what is planned? If the plan calls for processing 1000 gallons in a tank. They may be critical to the process and must be considered very carefully as to their design and their requirements. should the propellers stop because of loss of power. one hundred particles of less than . This. aerobic fermentation in particular. The manufactured substance must be protected from adulteration at every point of manufacture. say. depends upon the size of the equipment. of course. then the compressed air should be hydrocarbon-free. the reliability of that steam and its quality. are sitting in a utility room and the cleaning agent is piped to the equipment. Not being able to reproduce results will cause problems and consistency will be lost. if nitrogen or another specialty gas is to be used. This may be done via a static clean-in-place system where the tanks with water and detergent. a room that has a certain quality of air of.. the vessels.5 micron per cubic foot. Power Uninterruptible power is a critical requirement. even momentarily. Reliable Utility Systems Depending upon what is being manufactured.or sterilizing-inplace utilities. This is one of the main reasons we see stainless steel 316 as a common material in our business. The materials.

The regulation requires testing of suspected contaminants and prevention of cross-contamination. All parts of the equipment should be able to be sanitized and verified to be clean. and lastly sales and marketing. If water of a certain quality is used in the laboratory. the finishing and packaging operations. There is the bulk manufacturing operation. See Figure 1. During process development. It is important to decide where to put the batch sheet.IVTGXP_April07. When considering equipment for the pharmaceutical business. This is where Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP) requirements dictate that some level of qualification of the equipment is needed. Some of the systems may need to be validated. Always be prepared to investigate for out-ofspecification situations. the process should be designed so that there is no cross-contamination. Validate the process. know what the specifications are and establish an alert. Therefore. which is the laboratory. if a solution is to be filtered to remove solids. A sieve cannot be used. It should be a validated system. It will also be necessary to be GLP compliant. There should be a method for record keeping and processing these items. the autoclave should be qualified. Then. This is called sanitary equipment. Batch sheets. Problems will result. GMP is designed so that a product of predetermined quality attributes may be made consistently. some qualification will be needed. ways of obtaining samples without interrupting the operation. MODEL OF A PHARMACEUTICAL BUSINESS In the Pharmaceutical Business. Sampling When considering and designing the process. Sanitary piping and sanitary equipment can be taken apart and cleaned completely. if a specific water is required in the process development or pilot . and every element able to be taken apart. 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. how will it be dealt with? Each issue should be considered and decided upon to complete the procedure. and how they are developed. Cross-contamination is a critical aspect in sampling. the equipment must be suitable to the process. how the batch sheet will be set-up. This will require proper sampling for testing. Define the alert precisely so that operators will quickly recognize an out-of-specification condition or a deviation. The equipment must all be cleanable and sanitizable. there is a discovery component. Check valves or the proper isolators must be installed to prevent cross-contamination of the material. Sampling mechanisms will be needed. easy to reach every corner. Spots for keeping the batch sheets are important to design. which is basically the pilot plan. are critical. and where the operator will work with it. recognize that GMP requires a great deal of inprocess testing. it was used as dedicated equipment. Not only are sampling forks required. 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. the equipment and system must be qualified. if an autoclave is used in the research organization. that no material can flow from one tank to another when it is not supposed to. Enclosed processing may be necessary to prevent something floating in the air from coming into 46 Journal of GXP Compliance the process. When designing processes. This is a part of designing processing equipment and setting-up the processes. it is best to use dedicated equipment for that operation.qxd 3/19/07 12:59 PM Page 46 Editorial Staff Keep in mind that. For example. there is the process development component. it should always be easy to clean. equipment designed for filtration must be used. For example. Will it be an electronic batch sheet or a paper batch sheet. In designing the process and specifying the equipment. The right tool must be used for the right results. where is it going to be setup. a teratogen the author was processing could not be analyzed at a very low level for its existence or presence. The regulations require that the equipment is properly cleaned and that it is demonstrated that it is clean. the system will need to be validated. For example. In the discovery component. which is really a documentation and methods validation issue. For example. As a result. because the equipment was not designed to do that job. ensure that the design and process information is in place so that a proper validation can be conducted.

validation and GMP compliance is required. there is no requirement to validate the method. total. And. it is necessary to validate the water system to ensure that the quality of the water is established. of course. which means there are predetermined quality attributes. But in many cases it will be necessary to demonstrate that these methods still work for specific cases. VALIDATION The normal or the well-known definition of validation is that there is documented evidence that the product can be made consistently.qxd 3/19/07 12:59 PM Page 47 Editorial Staff plan. then it should comply with GMP requirements. In sales and marketing. That is. the issues are really in the documentation associated with how the product is sold. 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. all GLP and GMP requirements must be complied with. In the finishing and packaging. the desired outcomes must be known in advance. the Quality Systems must be in place along with the understanding and the documentation as discussed earlier in this article. whether in the pharmacopoeia. In cases where a methodology has been published. or in articles and literature that have been demonstrated to work well. GMP compliance is a requirement that should be addressed as you go along. N u m b e r 3 47 . Process validation is documented evidence that gives a high degree of assurance that the product can be made consistently at the desired quality attributes. 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.IVTGXP_April07. the compendia. In bulk manufacturing. complete validation is required. Methods Validation Methods validation is an analysis or an analytical methodology that is developed in place. of course. In order to achieve this. 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 A p r i l 2 0 0 7 • Vo l u m e 11 .

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. In order to validate. A validation protocol is first and foremost documentation. In most cases. The parts that are more critical are challenged to ensure that they are working correctly. Criteria for initiating and performing Out of Specification (OOS) investigations must be established. then ascertain that the motor is capable of doing that. For example. it is the documented evidence. how to run the validation study. When it is verified that the parts of the process are working correctly. The validation protocol is a significant component of the validation effort or of building. a system in place to manage any changes to these validated systems and facilities. At the end. The equipment must be carefully designed and selected. the plant steam coming from the boiler house. Once the protocols are in place. It must be demonstrated in the design of the processes and facility that the procedures will prevent contamination. especially if different compositions are being used. the clean steam being used. These are not critical systems. Along with these systems and procedures. it must be ensured that the right pieces of equipment have been installed correctly. 48 Journal of GXP Compliance How Do We Conduct Validation? ➣ Critical Systems Once the facility has been designed and built. managing. It is necessary to establish the idea that revalidation should take place when specific changes occur. These procedures must be in place and validated. For example. 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. what is critical and what is not must be defined. then they would not be needed. Finally. a critical utility. This is not an option. What is a Validation Protocol? Validation protocols are procedures that explain how to validate. When something does not quite meet the quality attributes or when it is anticipated that this could happen.qxd 3/19/07 12:59 PM Page 48 Editorial Staff material being analyzed.. or the effluent handling system (the sewer system). the results are summarized and assurance provided that once validated. this is called Performance Qualification (PQ). there are a number of regulatory imperatives. There must be a procedure to prevent contamination. These are the critical criteria that will indicate when to initiate an OOS investigation. The motor must perform adequately within the limits established for the process. is called Installation Qualification (IQ). such as the HVAC system. it must be verified that this equipment is going to do what it is supposed to do. Then it must be determined that the entire process works correctly and produces the product of the quality planned.e. they will remain in a validated state.IVTGXP_April07. a change control procedure i. There must be validated procedures for reprocessing. . ➣ Qualification The first part. where it was ascertained that the right piece of equipment was purchased. These are things that must be done from a regulatory point-of-view. or the compressed air system must be validated. the water system. If they were not. The rationale for the design and equipment selection should be documented. Reprocessing is a common occurrence in the manufacturing of pharmaceuticals. and all process equipment are critical to the process. Once identified and defined. the potable water being used in the bathrooms. was a mixing tank with a motor that is capable of giving you 150 rpm for the mixing shaft purchased? If so. a validation protocol is required. all utility equipment. It is a requirement. This is called Operational Qualification (OQ). and they do not need to be validated. Then. there must be some way to rework the material to bring it within quality standards. First is validation. is necessary. They also are the repository wherein all of the data may be kept. and running a facility for manufacturing pharmaceuticals. for example.

The results are what is called bulk product. Figure 2 Bulk Manufacturing PREPARATION OF RAW MATERIAL (2) STORAGE (1) SYNTHESIS (3) PURIFICATION AND PACKAGING (4) RAW MATERIAL BULK PRODUCT A p r i l 2 0 0 7 • Vo l u m e 11 .. etc. through fermentation or cell culture. dried. For example. The bulk process starts with the raw material.IVTGXP_April07. the formation of impurities. All of these considerations should be addressed in procedures for dealing with raw material storage. There should be limited access areas and tampering prevention precautions. and packaged. Materials and product must be segregated. Last comes storage. These needs will dictate how to set-up a warehouse and how to space things. the material must be purified. Sampling is needed because side reactions must be monitored along with the progress of those reactions. Good record keeping is also a necessity. i. These are important aspects to be considered when establishing the warehouse. Now. which can be either sterile or nonsterile. The raw material is prepared. an understanding of the chemistry of each process is necessary.e. Enclosed areas are necessary where rejects can be kept in a quarantined area and where approved and released products can be kept. The ability to clean the equipment and use of sanitary equipment is a requirement. In the synthesis step. There is usually a need for a proper sampling facility within the warehouse. other materials besides the material of interest appear. Then comes finishing. These traps ensure that these areas remain clean and are not contaminated. A sampling room should be established where the samples can be taken. which is a synthesis and it is done either via chemistry or biologics. A laboratory on the side to do quick tests of the raw material as it comes in may be desirable. See Figure 2. warehouse space that gives these materials adequate room is a necessity. N u m b e r 3 49 . derivatized and dissolved or something is put in a solvent. which is stored. When the material is synthesized. That is why rodent and insect traps are used in these facilities.qxd 3/19/07 12:59 PM Page 49 Editorial Staff ➣ Process Steps What are the types of pharmaceutical processes that we deal with? There are bulk processes. the quality of the recycled solvent must be addressed to ensure that it does not retain contaminants from previous batches. In the preparation of the raw material the quality of the solvent must be considered. ➣ Issues of Importance In raw material storage. if solvents are to be recycled. The warehouse has to be clean. and normally.

Purification There are many ways of purifying.. At this point. Therefore.IVTGXP_April07. in maintaining the cleanliness of the product. The important aspect to think about in finishing is that.qxd 3/19/07 12:59 PM Page 50 Editorial Staff Yield Reproducibility Finishing and Packaging The regulation indicates that yield from various steps is critical and that it must be tracked. filtration. Since the product is not going to be purified any further. other finishing aspects include the quality of the air in the rooms. It is extremely important to be aware of this and process materials carefully as you recycle dryer material. ➣ Crystallization Oftentimes. Chromatography is used in the purification of protein. It is important to ensure that the impurities are not concentrated to a point that the purpose of the crystallization is defeated. mother liquors are left upon removing the crystals. can be maintained in a clean state. The water quality and the material construction are other issues that should be considered in the synthesis. We must have the correct labeling of the various storage areas and the various materials that come into storage. whether crystallization. and dried again with the next batch. Humidity may affect the product. After the bulk has been extracted and purified. These are little drums of very close to being final product. the bulk and excipients (which are the additives) are brought in and stored. and the packaging material may affect the packaging process. ➣ Dryer Recycling There is a critical aspect of drying a large amount of material that has been synthesized that must be considered. and that people do not contribute to the contamination of the . Cross-contamination must be considered again. Particulates in the packaging room may contaminate the material of interest or the bulk that is being packaged. so it is desirable to recycle it in order to obtain that material. Although recycling of mother liquors is a common way of processing purification. because there are no further steps to clean it. Finishing is complete. Next comes formulation and dosage. or distillation. In many cases the product consistency is measured by obtaining the same yield from the same steps consistently. it also has its pitfalls and needs to be carefully performed. etc. The product is packaged in bottles or ampules. etc. 50 Journal of GXP Compliance FINISHED PRODUCT Cleanliness Let us look at some of the issues relative to the finished product. Cleanliness now becomes even more critical because this product is not all chemicals or sacks of material. While extracting the material of interest. impurities are being concentrated in the mother liquor. At this point. it is critical to ensure that the equipment is clean. These are active pharmaceutical ingredients (APIs) and excipients. Unfortunately. but in most finishing phases and in the packaging of final product. Usually the leftovers are dissolved on the dryer. when doing crystallization to remove the product of interest. but some is left behind. These usually have more of the material of interest. as the material 'cooks' over and over on the heated drum. no further cleaning or purifying is done. When making a sterile product. Purification occurs in the bulk manufacturing. See Figure 3. normally. Much of the material dried on drum dryers is taken. and the packaged product is stored and shipped. and in dealing with the product during storage and staging. etc. it is time to make it into tablets or into a sterile injectable. So care must be taken regarding the environmental controls in the packaging area. Extreme caution must be used to prevent crosscontamination. impurities are generated. it is very important not to contaminate the product. It is important to understand the various steps used to purify material. At this point. we have segregation issues. a means to calculate and measure the yield is necessary. Having the correct level of humidity in the packaging room is necessary. Controlling the atmosphere in the packaging room is critical. not much more purification is done.

which makes this issue all the more important. The conditions within the truck are significant and must be managed. may need some temperature control. are all important aspects of labeling the product. Final inspection of the product must be done online. Temperature Control. or very cold at night should the trucker stop somewhere and fall asleep. This material must be stored and properly segregated. Shipment by truck is common in the United States. 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. 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. Personal cleanliness of employees as regards contamination of product must be addressed in the packaging of the final product. Controlling the labels. label control is an important aspect. for example. Another critical component is the training requirements of personnel which must be addressed. Control what is outgoing. counting them. and environmental conditions may vary widely. Ensure the correct temperature and humidity controls within the space so that the product does not deteriorate during storage. aspirins with steroids. Storage Final product is the material that will go to the user or to the patient. Finished products may be temperature-sensitive so the warehouse. 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 . making sure the correct label is applied to the correct material. Labeling More than 90% of recalls are caused by the mislabeling of product. Shipping issues are increasingly more important. Consider how to ship this material. unlike the warehouse in bulk manufacturing. Trucks can get very hot when they sit out in the sun at a truck stop. reporting. or product. Adverse event recording.qxd 3/19/07 12:59 PM Page 51 Editorial Staff product.IVTGXP_April07. and management are extremely important aspects of pharmaceutical manufacturing that must be dealt with ongoing. Product File Record all the complaints and problems that occur once the product is sold. In the packaging of the final product. Inappropriate materials cannot be put together. There are many 483s and Warning Letters that have been based on a lack of proper training for personnel and operators. N u m b e r 3 51 .

along with the proper documentation of all procedures and policies. all of which are an absolute cost savings. because the equipment lasts longer. because personnel understand the processes and operations much better. and fewer recalls. 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. but these are not frivolous issues. fewer returns. No one wants their patients to experience adverse events because the quality of their product is substandard. errors. rework. presented by Gamal Amer. safety numbers increase. and possible fines and penalties. therefore resulting in fewer complaints.qxd 3/19/07 12:59 PM Page 52 Editorial Staff Cost All of these GMP issues add cost to the manufacture of the product. not to mention other business-related expenses that show up in costs of employee turnover. Warning Letters. Air Handling Unit Active Pharmaceutical Ingredient Code of Federal Regulations Food and Drug Administration Good Laboratory Practice Good Manufacturing Practice Heating. And. with reference to a teleseminar held June 13. Ventilation. there is reduced down-time along with reduced errors and rework. Attending to these issues reduces the number of errors. etc. 52 Journal of GXP Compliance Article Acronym Listing AHU API CFR FDA GLP GMP HVAC IBC IQ OOS OQ PQ U.IVTGXP_April07. Attending to these issues also increases profits. and Air Conditioning Intermediate Bulk Container Installation Qualification Out-Of-Specification Operational Qualification Performance Qualification United States .D. Ph. This results in a much higher quality product. absenteeism. Proper construction of processes and the facility. also render a much higher quality product. ❏ ACKNOWLEDGEMENT This article was created by IVT Editorial Staff in collaboration with Cindy Green. of course. because there is an understanding of how things are to be accomplished. although adding cost. Although there are costs associated with incorporating GMP requirements. training and education of personnel. so they are safer and they work safer. and that is a significant gain to the corporation. 483s.S. 2006. which reduces risk to the patient. RAC. These savings usually reflect crucial positive returns on these investments.

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