Identifying and Resolving GMP Issues for Pharmaceutical Process and Facility Design

Transcription

1 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 42 Identifying and Resolving GMP Issues for Pharmaceutical Process and Facility Design By 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. INTRODUCTION 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 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. Aprocess and facility to manufacture pharmaceutical products can not be put together without considering the people who are going to work with that process, 42 Journal of GXP Compliance

2 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 43 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 April 2007 Volume 11, Number 3 43

3 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 44 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. 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 44 Journal of GXP Compliance

4 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 45 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 Asecond 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. April 2007 Volume 11, Number 3 45

5 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 46 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 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 46 Journal of GXP Compliance

6 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 47 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 DISCOVERY Some Qualification GLP Compliance BULK MANUFACTURING Validation GMP Compliance FINISHING AND PACKAGING Validation GMP Compliance SALES AND MARKETING PRODUCT April 2007 Volume 11, Number 3 47

7 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 48 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. 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. 48 Journal of GXP Compliance

8 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 49 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) RAW MATERIAL SYNTHESIS (3) PURIFICATION AND PACKAGING (4) BULK PRODUCT April 2007 Volume 11, Number 3 49

9 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 50 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 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. 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. Finishing and Packaging 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. Cleanliness FINISHED PRODUCT 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 50 Journal of GXP Compliance

10 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 51 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) FINISHING (2) PACKAGING (3) PRODUCT STORAGE AND SHIPPING (4) April 2007 Volume 11, Number 3 51

11 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 52 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. AHU API CFR FDA GLP GMP HVAC IBC IQ OOS OQ PQ U.S. Article Acronym Listing 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 ACKNOWLEDGEMENT This article was created by IVT 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

12 IVTGXP_April07.qxd 3/19/07 12:59 PM Page 53 The Institute of Validation Technology is pleased to introduce IVT Web Seminars Via the use of high-end web conferencing technology, attendees interact in real time with industry experts worldwide from the convenience of their own home or office. Interactive polling, live questions and answers, and multimedia presentations engage attendees to become active participants in the learning process. Each attendee receives access to takeaway slides in PDF format and has the opportunity to purchase a CD Flash archive of the event that can serve as a permanent resource. Convenient, cost-effective, and time-efficient IVT Web Seminars offer you great educational value for a small investment! SCHEDULED TOPICS INCLUDE: CAPA METHOD VALIDATION FDA INSPECTIONS PROACTIVE COMPLIANCE AND MUCH MORE! The Next Generation in Live, Educational Opportunities. TO LEARN MORE ABOUT WEB SEMINARS AND ALL IVT EVENTS visit