Efficient and effective quality systems that incorporate tracking tools are necessary components for compliance with current good manufacturing practices (CGMPs). Strict compliance with regulatory requirements when an out-of-specification (OOS) result is observed preserves the integrity of both the individual data points as well as the overall study. Documentation that is easy to follow, with traceable data entry, is essential to creating an efficient and effective quality system to handle OOS results. The system chosen must incorporate 21 

 Part 11-compliant methods, be well-organized and amenable to user-friendly training, allow easy and flexible configuration changes and updates, and permit ongoing monitoring by quality assurance staff as well as project directors. 

A dependence on paper systems is often problematic. Documents stored in paper files are not quickly searchable. Cross-referencing the initial failure with follow-up corrective and preventive actions (CAPAs) is also difficult with reliance on paper systems. Dual systems may appear to be adequate, but paper documentation and electronic documentation may not be in agreement when capturing relevant data and information pertinent to the compliance failure at issue. Implementing an electronic system with no paper backup ensures that all relevant information is stored in one reliable system and eliminates the possibility of conflicting records. Electronic signature and date capture create traceability for quality assurance management when changes are made to documents in the system. 

A critical first step is the identification of a 21 

 Part 11-capable and -compliant software package. The software package must meet all regulatory expectations as well as any additional requirements that customers or clients may request. Anticipating customer and client needs is difficult; therefore, a software program designed with flexible, validation-ready add-on modules is highly desirable.  

The installation of the software program must be seamless. No changes in source code or company-specific programming should be necessary. The system must be able to manage multiple users simultaneously within the standard time frames expected for current software. Routine maintenance of the software should only require minimal down time and must be achievable during off hours. Revisions and updates should not require any special formatting for implementation. Updates must have been tested under the constraints of full validation of the software package. The installation of any revision or updates also should only require on-site information technology personnel. The involvement of the software vendor's personnel can be kept to a minimal amount of time for a well-documented upgrade for the system. 

 Part 11 necessitates a fully validated system. Validation of the software is expected to occur using off-the-shelf modules prepared by the vendor. Little interaction with the source code is desirable. The vendor can be expected to supply training, support, and service, but validation must be achievable with staff at the work site. In addition, general maintenance and operation of the system should not require extraordinary measures or above-normal training. 

Compliant systems that are not user friendly create additional problems for the end user. Ease of use is often a difficult concept to assess, but it is necessary for efficiency. System users should not be expected to navigate through complex components to enter data, perform searches, or create reports. Searching for original deviations or cross-references to CAPAs, generating reports, and entering data must only require a few quick key strokes for the function to be performed. 

User-friendliness is not only the responsibility of the software vendor, but documentation at the site in the form of well-written, clearly defined standard operating procedures (SOP) also is necessary for efficient usage of the tracking system. A well-defined, step-by-step procedure is crucial for user compliance. The SOP outlines the steps that must be met for initiation of an OOS or deviation. It also must state the parties responsible for data entry, review, and approval of the final document. As in the case of the OOS, customer involvement to resolve and close the deviation is necessary. The software system and SOP must include action items for customer notification, acknowledgement of the OOS status, and inclusion of documentation from the customer or client on the proposed plan.  

Organization of the documentation should include descriptions and definitions of applicable choices, definitions of retest 

 reanalysis, and requirements for supporting records. Prompts for sufficient details must be included to allow complete understanding of the event and subsequent resolution. Justification of retest 

 reanalysis must be adequately provided. Forms within the software program used for data entry must be easy to understand. Including drop-down lists from which the user can choose the appropriate record would contribute to the overall efficiency of the system. Blank areas designed for including suitable comments allow for the addition of supplemental information to the record. During the final processing of initial documentation, the software must prompt the user when inadequate information is present and reject acceptance of the signature until all required information is entered. When supplemental data entry is required after the initial signature(s), audit trails must be in place to document any changes to the record. 

Review by the project manager, project director, and quality assurance staff should occur sequentially. Any questions or observations that arise should be captured electronically. Responses to questions or approval by the project manager, project director, and quality assurance staff also are handled 

 audit trails that include signature, date, and time stamps. 

Training on the acquired systems cannot be excessively lengthy for the average user. Training can occur either in a classroom session or 

 a Web-based program or both. Training can be linked to other software that is 21 

 Part 11 compliant and houses a database of training records. Routine retraining may be accomplished through group classroom instruction or individual sessions through a compliant Web-based program. One benefit of compliant training software is the ease of routine scheduling of required training. 

Analysts, project managers, and project directors can monitor processes for recurrent OOS or deviations. Project directors and quality assurance personnel may use these tools to determine if retraining on a method is necessary for a particular analyst or for all analysts. Tracking tools also can help identify trends that can be handled with advance predictions of the event.  

In the case of cell-based assays, failure to meet acceptance criteria can be highly dependent on the state of the cells at the time of the assay. Differences among analysts have also contributed to variations within assays. Trend analysis can identify predictable events that would lead to assay failure. The use of these tools would allow the implementation of procedures to prevent reaching the failure point and allow uninterrupted manufacturing or testing. Proper documentation with trend analysis is a powerful tool. When used appropriately, OOS results and deviations can be minimized even in cell-based assays. 

Compliant software is a necessity for the GMP environment. Meeting the recommendations and specifications within 21 

 Part 11 will ensure that the software package selected will achieve expectations and requirements. Efficiency and effectiveness are at the root of any good quality system. Without these two components, the benefits of the software system will not be fully realized. A dual system incorporating electronic and paper components may appear to be a good concept in redundant systems; however, the loss in efficiency makes this choice less attractive. Proper training using either classroom-based sessions or compliant Web-based systems will ensure effectiveness of the process. Routine retraining can be accomplished efficiently through the use of group sessions or individual Web-based compliant software.  

Documenting the transfer of knowledge about the SOP is best accomplished through a Web-based system that incorporates short quizzes as a prerequisite to receiving approval for training. Compliant systems to manage OOS results must not require additional programming or manipulation of source code for installation or validation. The use of these off-the-shelf systems will improve adherence to compliance requirements, provide easily traceable databases, and improve the efficiency of the overall quality-management system. 

 is senior manager of cellular technologies with Cardinal Health, 160 N. Cardinal Health Way, Morrisville, NC 27560, tel. 919.465.8522, fax. 919.481.4908, 

Articles

Implementing an electronic system to track out-of-specification results could help ensure compliance with current good manufacturing practices, but the system must be 21 CFR Part 11 compliant and easy to install, maintain, and use.

Out-of-Specification Results and the Quality System Approach to GMPs

The design of pharmaceutical water systems has always been part science and part alchemy, and unfortunately, it is not likely to change in the near future. Daily rhetoric is rife with statements from informed and intelligent people alleging design requirements that do not actually exist. 

The problem is that if you do not have documentation from a reliable source that supports or contradicts these statements, they are nearly impossible to refute. As a result, they are often incorporated into system design. 

Take, for example, the use of bacteria-retentive filtration in a water system. For years, variants of the following alleged statement have circulated verbally: "FDA doesn't allow filters because it considers them to be band-aids on a badly designed system." As a result, many systems were designed without filters, rooted in a fear that the US Food and Drug Administration would disapprove. Meltzer 

 after researching this very subject, wrote that current FDA staffers indicated they would not disapprove a system simply because it contained these filters (1). Was this statement ever really made?  

The answer is a qualified yes, as this author personally heard it numerous times from more than one FDA employee, albeit many years ago. None-theless, it was said in conversation and never written in an approved regulatory document or guide.  

Guide to Inspections of High Purity Water Systems

, one can find comments that, taken out of context, could be interpreted as support for either side of the argument.  

For example, in that Guide, Section "X-Reverse Osmosis," paragraph 6 states, "The systems also contain 0.2 micron point of use filters which can mask the level of microbial contamination in the system" (2). It also goes on in the same paragraph to state, "If filters are used in a water system there should be a stated purpose for the filter, i.e., particulate removal or microbial reduction, and an SOP stating the frequency with which the filter is to be changed" (2). 

Hence, in spite of the urban legend, it does not appear that FDA ever took a definitively negative stance against bacteria-retentive filtration, although some individual inspectors did so, possibly based on a specific system design or set of individualized circumstances. 

The normally accepted design criteria for US Pharmacopeia (USP) water systems (purified and water-for-injection) are neither published by FDA nor are they tabularized in a recognized volume for easy review and discussion, although much is written about them by industry pundits. Nonetheless, most or all of the writings include at least some of the items listed in the sidebar, "Commonly accepted design criteria for USP water systems." Some of the items listed in the sidebar are supported in reliable resources, but many are not, and few confirmations exist in regulatory print.   

Regardless of whether these items are documented in the literature or not, they are very often accepted by owners, engineers, designers, users, validation experts, and operations personnel as rules or laws.  

The good news is that none of these features, properly applied, have ever compromised a water system, although some absolutists have come very close. Consider the example of the engineer who insisted an 1100-ft long, 2-in. line be pitched ⅛ in./ft even though the roof elevation was only 12 ft (it took a contractor with a jackhammer to make the point). 

What is paramount and possibly not obvious is that of the items listed in the sidebar, every one relates either directly or indirectly to microbial control or sanitization of the system. 

The reason for so much focus on sanitization is that achieving the required chemical purity for USP waters (they're basically the same for purified and water-for-injection) is fairly simple with available technologies. Keeping the system under microbiologic control, however, takes finesse. 

Microorganisms are living entities and, hence, they are unpredictable in the sense that we cannot know for certain where or how fast they will grow, or when they will show up in our sample containers to make for an unpleasant day. We do know that heat is an extremely effective sanitant and many in the industry have come to believe in the virtues of ozone. Most often, however, we are unable to maintain sanitization (heated or ozone) limitlessly. 

The best advice any consultant, water expert, or designer can give is to use the KISS principle of design:  keep it simple and sanitary. 

Once you have determined how to treat the water chemically, focus on microbial control. Most likely, you will need to expend at least four or five times more effort than you did for the chemical design. 

Remembering that organisms can occupy the treatment as well as in distribution is critical because the front-end of a system often provides the inoculation that causes long-term problems. 

 Commonly accepted design criteria for US Pharmacopeia (USP) water systems			

Recently, on a job site that had been experiencing significant microbial excursions, it was noted that one environmentally aware individual attempted to reduce waste of pure water by piping the effluent from all of the slip-stream monitors (

 total organic carbon) back into their break tank. As a result, there were dozens of feet of translucent, small-diameter tubing that had been neatly tucked away so as to be inconspicuous. Not surprisingly, the tubes' interior had substantial growth varying from shades of green to black. Once this problem and a few other similar issues were resolved, the system quickly came back under control and returned to reliable operation. (Forgetting microbial issues for a moment, where was their change control?) 

For anyone routinely inspecting systems, this type of situation is a flashing neon sign; however, the personnel at that facility missed this problem entirely and the result was that tens of thousands of dollars were spent on inspection, testing, and cleaning when the original intent was simply and practically to save a few gallons of water each day.  

An issue of unique concern is cyclic sanitization. Engineers often design using this concept because they believe it will bring the system back to its original condition after each sanitization. Unfortunately, this is far from the truth and results in the biofilm buildup that is difficult to remove. Cyclic sanitization might as well be compared with Russian roulette because the odds are that you will eventually shoot yourself. 

In our haste and to justify our design dictates, we often reference specifications such as 3A, CGMP, FDA, ISPE, and USP along with an endless list of industrial codes, the majority of which most designers are not intimately acquainted. 

One favorite document is the CGMPs, especially 21 

 which provides general counsel regarding the requirements for the manufacture of quality pharmaceutical products. Far too often, designers waggle their fingers at unsuspecting vendors, contractors, and even owners, threatening that failure to install an inane feature they have specified will not comply with CGMP and will result in the wrath of the entire federal government raining down upon them.  

Another often-misunderstood document is the 3A sanitary standards. Originally developed by the International Association of Milk, Food and Environmental Sanitarians under the Dairy Industry Committee of the US Health Service, this set of specifications was developed for milk, cheese, eggs, and other related food products. It was the first definitive specification for the manufacture, finishing, and assurance of cleanability of sanitary equipment. Vendors who were approved to imprint their products with the 3A symbol were accepted more readily by users in the food industry.  

These standards can be extremely valuable in the pharmaceutical arena if properly applied, but for the most part, specifiers fail to understand the implication of including 3A in their specifications. In fact, 3A was the underlying technical resource upon which much of today's pharmaceutical cleanliness was built, including automated cleaning systems, known as clean-in-place (CIP). 

Sanitation remains the common thread throughout the codes, standards, and regulations because adulterated products are potentially dangerous to the public. 

Water-system design requires features that ensure quality and cleanliness and, as a result, will comply with the generalities defined in the regulations. Because, with few exceptions, regulations do not require specific features, this can become a circular exercise. 

A review of the items in the sidebar, "Commonly accepted design criteria for USP water systems" and their associated implications follows. 

This chromium–nickel–molybdenum steel alloy is one of the most corrosion-resistant materials in the original family of 300 series stainless steel; however, 310SS and 317SS are very similar in their capabilities. In addition, more corrosion-resistant, and in some cases less expensive, super austenitic and super duplex stainless steels have been developed. Furthermore, materials such as titanium, hastelloy, and inconel offer far superior corrosion resistance and mechanical strength, albeit at a significantly higher price.  

Are these materials outlawed from use in pharmaceutical product contact? No. As a matter of fact, precedent has been set numerous times for the use of specialty alloys such as hastelloy and AL6XN when warranted by conditions. Conversely, 304SS has been dairies' material of choice for decades.  

Has 304SS (similar to 316LSS but with higher carbon and no molybdenum) been outlawed? It appears not, although the pharmaceutical industry seems to have set 316LSS as the standard in part because USP water systems held at elevated temperatures are notoriously aggressive.  

Sanitary clamp fittings or orbital welds. 

Sanitary clamp fittings and orbital welds are not a panacea. Although they are often recommended, their application is not required. Even published industry guides mention the use of other joining mechanisms. Notwithstanding, many systems have experienced problems caused by poor-quality manual welding as well as from the use of threaded fittings. Although unrelated to water, one threaded system used for processing heart medication is an example of what problems could occur. The piping exploded upon disassembly because nitroglycerine had migrated into the crevices of the threaded fittings. Microbial contamination can certainly do the same.  

Sanitary materials are typically tube outer diameter size. Their tolerances are more strictly controlled, thus making them a more appropriate choice for polished sanitary environments, as confirmed by the food and dairy industries. These more-precise materials lend themselves to orbital welding, thus resulting in improved reliability not only because of an inherent quality advantage, but also because of the rigor that goes hand in hand with their application.  

The mechanical finishing of sanitary components improves their appearance and ostensibly their cleanability. Mechanical finishing may or may not remove surface imperfections, but it invariably damages the passive film that gives stainless steel its inherent corrosion resistance. In addition to providing an attractive and cleanable surface, electropolishing also passivates. Nonetheless, either method of finishing will most likely require preoperational passivation to ensure suitable service.  

The finishing of materials for water system use can be viewed from two perspectives. If the system operates hot, microbial proliferation will be minimal. Hence, polishing, especially to high levels, provides the least added benefit. Nonetheless, heated water is more chemically aggressive such that electropolished material may indeed offer some advantages. Alternatively, cool systems may have greater potential for microbial contamination. Finishing may serve to impede the formation of biofilm and retard organism growth. 

The sloping of lines to drain is an advantage when draining the system for maintenance or rework. For most systems, maintenance occurs 1–2 times per year with outages lasting only hours or a few days. At all other times, except for batch systems, water is continually present, usually circulating. Hence, drainability may not be as great a concern for all systems, especially small systems that could easily be blown dry with clean, filtered air. The requirement for a pitch of ⅛ in./ft is relatively arbitrary and can be relaxed, provided the pitch is measurable and has no obstructions. Such obstructions could include improperly torqued gaskets, incorrectly installed reductions, or mismounted diaphragm valves, all of which could easily cause a problem even if pitched ⅛ in./ft. The requirement for drainability of condensate from steamed systems, usually water-for-injection, is appropriate. The drainability of other systems makes good engineering sense but is not a requirement. 

The recirculation of pharmaceutical water systems is probably the single most common design feature, and is alleged to inhibit microbial proliferation by agitation and constant scouring of the pipe wall while maintaining a flooded condition. Every published document recommends recirculation, although they do not typically consider it a requirement. Stagnation in dead-end systems often results in high bacterial counts. The only suitable alternatives to recirculation are flushing or repeated sanitization.  

Unfortunately with flushing, the waste of expensive, treated water may not be cost-effective or ideal, depending on the system size and the facility requirements. Repeated sanitization also may be problematic because of the expense and time consumed. Additional advantages of circulation can include more-uniform sanitant distribution and more-uniform samples. The velocity of recirculation had been accepted as 3–5 ft/s for many years. Recently, however, several firms have modified specifications to require only turbulent flow. In most instances, this is a substantial departure from past practice, and technical support for this change is incomplete and counterintuitive. 

 Sanitary pumps for water-system application are typically specified with a 45° discharge to avoid any air entrapment in the volute. This specification is reasonable because there is no downside and virtually all sanitary pump housings can be rotated to any position. Casing drains are specified to allow for drainage during maintenance or downtime. As noted previously, the time required for maintenance and service usually accounts for a very small portion of time and hence, may be addressed with alternative measures that cost less than drain fittings with valves, which routinely need service. Nonetheless, if the system is designed with an installed spare pump, drain fittings may be appropriate to ease switchover.  

Drain fittings make housings less likely to be available from stock in an emergency and are substantially more expensive. Neither feature is required by any code, regulation, or guide, however. Many more substantial issues relating to pumps are commonly ignored such as proper seal and seal material selection, ferrite content, and microcavitation. 

Sanitary vent filters are common accessories for water-system storage tanks that filter the air entering and leaving the tank during emptying and filling. Filters allow vessels to operate at atmospheric pressure while eliminating bacteria that might enter during air inrush. Filter maintenance is of concern especially for tanks that are not rated for pressure or vacuum because a plugged filter might cause tank collapse or rupture, especially if other protective devices are not in place. Vent filters on system high points are extremely rare and should be avoided whenever possible because installation and service issues are complicated and difficult.  

Vent filter ratings have ranged from 0.45 μm to the more common 0.20 μm and down to 0.10 μm or lower. Integrity testing may be required and system steaming can pose additional design constraints based on steam collapse during cool down. Issues relating to vent filters associated with ozone applications pose a unique problem because most vent filter elements have an extremely short life in ozone service. Vent filters typically are considered an absolute necessity in spite of the lack of definitive written documentation. 

Use of ball, plug, butterfly, gate, globe, or disk valves. 

Sanitary valves typically come in only two designs, although this is not always the case. The valves most commonly specified and used for water systems are diaphragm-type valves, although most vendors of sanitary components manufacture valves (

 stem valves), which also are qualified as sanitary. Unfortunately, no single standard has been accepted for sanitary water system application. Ball valves, plug valves, and other valves that can trap product in their center are usually not selected because the potential for contamination is high. This, however, is not the case for clean steam systems where ball valves are the valves of choice. In addition, these valves have seats and seals that can be contaminated or wetted as the valve is actuated, and it is alleged that stems can provide for bacterial entry. These criticisms also apply to globe, gate, butterfly, and disk valves in varying degrees.  

Under most circumstances, gate and globe valves obviously will not be suitable for use because of their materials of construction, finish, and connection. Nonetheless, many manufacturers of sanitary components also produce ball, plug, butterfly, or disk valves that might appear to be sanitary because they are constructed in stainless steel and with sanitary clamp ends. These valves are not banned by regulation, but are more difficult to sanitize, require more extensive maintenance on a regular basis, and usually are less robust than diaphragm valves. Typically, only 3A qualifies and differentiates valves. 

Use-point fittings became the norm early in the evolution of water-system design and remain an important component for bringing water as close to the point of actual use as possible. Subsequently, an alternative design using valves that are integrated into the loop has gained in popularity because it minimizes the outlet length or dead-leg. Neither of these options are mandated, and individual preference is normally the deciding factor. Use-point fittings are difficult to fabricate and polish and can be weak near the pull-out, especially for fittings with large reductions. Alternatively, GMP valves are considerably more expensive on an installed basis and are less likely to be available from stock if an emergency occurs. 

The use of drains with air-breaks is overlooked frequently. Equipment in water systems, including use-points that flush to drain, tank drains, and even instrument drains can be easily compromised when the drain piping is extended too far into the drain or hard piped such that a back-up can be siphoned into the system. This problem occurs more often than most people realize, although it is seldom discussed because of the associated embarrassment. The requirement for this commonsense issue is not only rooted in local plumbing codes (although they may not be applicable to process systems), but also implied within the CGMP regulations.  

The discussion of dead-legs began many decades ago and was explored by the sanitarians developing CIP technology for dairy plants. As a result, the 6D rule was created, thereby limiting dead-legs or stagnant distances to six times the pipe diameter. Interestingly, years ago, the pharmaceutical industry adopted an almost identical rule, with little or no documentation.  

Over the years, the rule has seen dozens of iterations and interpretations, however, such that the pharmaceutical industry has virtually no generally accepted limit today. Some organizations require 6D, whereas others demand 4D, or even 2D. Depending on how the dead-leg is measured, these specifications often cannot be met, thus causing frustration for vendors and especially for contractors.  

Water systems require a commonsense approach and good engineering rather than unquestioned acceptance.

Myths, Fantasies, and Rumors about Water System Design

The past few years have been difficult for the pharmaceutical industry. Profit warnings have abounded and products worth billions of dollars failed during late development or were withdrawn because of safety problems (1). Several drugs will lose blockbuster status over the next few years, resulting in  billion-dollar profit losses (2). What is causing these problems? 

For one, products are becoming more complex. Because of advances in molecular sciences and technology, pharmaceutical companies can, in theory, develop drug–device–diagnostic hybrid products, healthcare packages for patients with specific disease subtypes, and targeted treatment solutions (

 individualized medicine). But these products, which are complex, delicate, and difficult to manufacture, are beyond the reach of most pharmaceutical companies at the moment. 

Another factor is that the US Food and Drug Administration has raised the bar on regulations. Janet Woodcock, deputy commissioner for operations at the US Food and Drug Administration, said in a 2003 

 article: "Production techniques were outmoded, and that just refining procedures and documentation wasn't going to change that" (3). Compliance now requires a quality-systems approach that begins with quality by design during development and ends with scientific process control in manufacturing. 

In addition, reported quality performance improvements are somewhat misleading. Although the absolute number of recalls is down (from 471 in 2000 to 254 in 2005 [4]), the ratio of development-to-manufacturing issues has doubled during this period, thus indicating the true source of poor quality performance. Although quality improvements have been made, they have been attained by increased efforts in "testing-to-document quality." This approach is costly, superficial, unsustainable, and simply not feasible for new, complex products coming down the pike. 

Joiner and Gaudard sharply summarized the difference between quality by inspection, the industry norm now, and quality by design: "Depending on inspection is like treating a symptom while the disease is killing you. The need for inspection results from excessive variability in the process . . . Ceasing dependence on variability means you must understand your processes so well that you can predict the quality of their output from upstream measurements and activities" (5). 

Building on Deming's principles, FDA's vision for modern pharmaceutical manufacturing (6) can be summarized in five statements: 					

product quality and performance are ensured by effective, efficient manufacturing processes;

product specifications are based on a detailed understanding of how formulation and process elements affect product performance;

continuous "real-time" assurance of quality;

regulatory policies and procedures are tailored to the level of scientific knowledge required for product applications, process validation, and process capability.

risk-based regulatory scrutiny relates to the extent of scientific understanding of how formulation and manufacturing processes affect product quality and performance and the ability of process control strategies to prevent or mitigate the risk of producing a defective product.

In other words, pharmaceutical development and manufacturing will be synonymous with quality by design, scientific manufacturing, and risk-based regulatory oversight in the future. No longer can the industry afford to be ruled by a "cause no problems" mentality focused on getting enough manufactured product through extensive quality controls to meet market demand. 

If pharmaceutical companies are to meet FDA's challenge to improve the predictability of their drug development and manufacturing processes (see Figure 1), they must create a risk-based framework for identifying, developing, and manufacturing drugs, and acquire the scientific knowledge and technological skill to create and deliver increasingly complex products (6). To achieve these goals, pharmaceutical companies will face a myriad of complex questions: 					

Which products should be retained, unlisted, or redeveloped?

Which technologies should be phased out, acquired, or monitored for impact on quality?

What is the right sequence of investments, where should investment be focused, and over what time period should investments be deployed? 

 Figure 1: FDAÃÂ´s challenge is three-fold: to improve innovation, efficiency, and predictability in drug development and manufacturing.										

Based on industry research and the authors' extensive experience with clients in the pharmaceutical industry, we believe companies should take a "value-driven compliance" approach to these questions (see Figure 2). This plan consists of five steps: risk diagnosis, business refactoring, transforming industrialization, compliance-centric business architecture, and compliance-centric IT architecture. 

Figure 2: IBM value-driven compliance approach.			

 The first step is risk diagnosis, which involves identifying root causes of failure, quantifying product risk, and then translating the results to dollars. 

By analyzing batch records, deviation reports, out-of-specification reports, nonconformance reports, and customer complaints, the root causes of failure can be identified and indeed attributed to inherent characteristics of products, pharmaceutical technologies, and good manufacturing practices (GMPs) systems. 

Using advanced statistical analysis techniques, it is then possible to assign a probability to each root cause and to derive the cumulative "beta" factor for any given source. By adding revenue projections to the equations, it is further possible to derive a probability density distribution that represents the company's revenue at risk over a particular time horizon. 

Next, companies should engage in business refactoring in which they prioritize, schedule, and cost-justify the best set of actions to reduce and manage the risk profile. 

Once a company has calculated the beta factors and figured out its potential effect on future revenue, it must decide what to do to reduce the root causes of failure and reduce the potential revenue impact. 

One method, developed by IBM's business consultants and academic researchers, uses a mixed-integer linear program to calculate a company's revenue at risk based on the computed beta factors for its products, technologies, and GMP systems, and its projected product revenue streams. The method then determines the best course of action by accounting for the capital cost of every risk mitigation option, the actual risk reduction these options are expected to achieve, and the company's goals and constraints.  

The model has been tried in a pharmaceutical environment with 18 months of data on 3500 batches from 13 product families manufactured at three different sites. The root causes of all nonconformance incidents were identified, quantified, and classified in more than 90 categories. The information then was used to calculate the beta factors for all 13 product families and seven technology platforms. The output was used to simulate five future scenarios, including the sequence of actions required to reach the desired end state. One scenario was chosen for further analysis. 

Business refactoring not only helps to comply with the FDA's vision for pharmaceutical manufacturing, but it also provides the business case for change, together with the sequence and timing of actions. 

Third, companies should build quality into products and processes using science, systems, and technology to reduce risk. 

FDA's vision requires significant collaboration across the scientific disciplines (

 development, quality, and manufacturing) and functions (

 review of chemistry, manufacturing, and controls as well as current GMP [CGMP] investigations) incident to pharmaceutical quality. This collaboration is needed to develop an understanding of the systematic factors affecting quality and performance. The enablers of this collaboration are data, information, and knowledge management. 

(PLM) is a concept for managing product data throughout a drug's lifecycle from early development to retirement. PLM is the electronic backbone that facilitates the flow of data on products and processes between development and manufacturing, which are presently far too disconnected. It provides an integrated framework for regulatory compliance, strategic sourcing, product specification and data management, manufacturing and corrective actions, and product safety and quality control. The two-way data flow (

 passing data back from manufacturing to development to inform the design of new products and processes) is crucial, particularly as products and processes become more complex. 

Compliance-centric business architecture.

 Next, companies should make a cultural revolution to embed quality into everyday operations and reduce compliance costs. 

 for FDA staff about drug manufacturing inspections, the 

harmonizes a company's development and manufacturing operations with its GMP systems;

manages its activities by a set of standardized quality and compliance macroprocesses;

controls these activities through business-performance management (BPM) and supporting BPM technologies (7).

The key to moving to a systems-based approach is the definition, ownership, and execution of a quality plan for each GMP system. This strategy helps to ensure each system has clearly defined objectives, quality and regulatory requirements, resources, training needs, performance standards, controls, and targets for continuous improvement, regardless of which department "owns" the GMP system. 

Defining and instituting a set of standardized processes to manage quality and compliance across operations improves the consistency and quality of execution, standardizes training needs, and helps instill quality and compliance. Once these processes are harmonized and the information content is standardized, BPM and other technologies can play a role in ensuring process conformance, assessing process performance, and delivering process excellence. 

Compliance-centric information technology architecture (CCITA). 

Finally, companies should provide the visionary architecture to enable value-driven compliance and show feasibility. 

Finally, every pharmaceutical company must move toward CCITA. This plan provides a "topology" of systems functionality to support integrated quality, manufacturing, and compliance processes, and a service-oriented technical design that uses existing IT solutions and provides services to the quality and compliance macroprocesses. 

The functional architecture identifies the system functionality required to support quality by design and scientific manufacturing. Focusing on functional components (

 product-data management or enterprise-risk management) instead of on specific applications helps to ensure that the architecture suits the needs of the business rather than those of the applications vendors. 

The final dimension of the CCITA is the technical architecture, which facilitates business integration and supports the functional needs of the organization. It has multiple layers (

 infrastructure, data, application, service, integration, and interaction), each of which can be instituted and modified without affecting the others. To work, it must be designed according to the principles of open standards, common specifications, and a service-oriented architecture (

 a structure that functions as a collection of services that communicate with each other, either to pass data or to coordinate two or more activities). 

Companies that embrace the new five-element manufacturing paradigm can cut internal failures from 16% to less than 1%, reduce the cost of goods sold from 20% to 17%, and attain process performance levels of 4.5 sigma. For the top 30 pharmaceuticals companies alone, savings of nearly $10 billion are possible. Greater production effectiveness can speed time-to-peak-sales by as much as two years, generating additional revenue of $600 million per year for a drug with peak sales of as much as $1 billion per year (2, see figure 3). 

Figure 3: Process understanding can accelerate time to peak sales by as much as two years.			

Companies that quantify their quality and compliance risks and then plan the strategic actions to mitigate those risks while building a foundation for quality by design and scientific manufacturing will likely be rewarded with business certainty, operational efficiencies, reduced regulatory oversight, and, most important of all, the freedom for real process and product innovation. Those companies that do not might not be around for the next revision of the GMPs.  

 is the global Value Driven Compliance lead in the life sciences and pharmaceuticals practice at IBM Global Business Services, 

is the global lead in life sciences and pharmaceuticals at the IBM Institute for Business Value, 

*To whom all correspondence should be addressed. 

Companies must create a risk-based framework for developing and manufacturing drugs, and acquire the scientific knowledge and technological skills to create more complex products.

From Quality by Inspection to Quality by Design: A Roadmap for Success

According to its final report in September 2004, 

Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach

, the US Food and Drug Administration's guiding principles now include risk-based orientation, science-based policies and standards, integrated quality systems orientation, international cooperation, and strong public health protection. Per the guidance, FDA reviews include risk-based approaches, quality-systems approaches, enhanced internal regulatory coordination, international collaboration, and a strong analysis of current good manufacturing practices (CGMPs) requirements. Because "sterile drug products are a major component in FDA's risk-based inspectional program, FDA hopes to facilitate the application of good science and modern technology, and thus eliminate avoidable risks from aseptic operations" (1). 

This approach is found in the agency's recent draft publication, 

Guidance for Industry INDs: Approaches to Complying with CGMP During Phase I

 (2). Recommendations for compliance include suggestions for personnel, quality control functions, facility and equipment, control of components, production and documentation, laboratory controls, container closure and labeling, distribution, and record-keeping. Many of these recommendations are useful for supporting all phases of pharmaceutical manufacturing because the structure required to implement and support these recommendations for Phase I products is beneficial for all CGMP activities in the production of quality and efficacious pharmaceutical products. 

 The proper application of CGMPs requires more than following a set of rules to ensure a drug product is of adequate strength, purity, quality, and efficacy. CGMPs are an overall approach in both theory and practice that must permeate the entire process. CGMP regulations should never be viewed as extensively as roadblocks or as simply as documentation practices. They should be viewed as a mindset or the best method to produce quality pharmaceutical products. 

The interpretation and application of CGMPs are problematic for any pharmaceutical company. They are especially challenging in the world of a contract manufacturing organization (CMO) where processes are not always well defined and requirements vary based on the stage of the product in question (

 toxicological material, clinical trial material, Phases I, II, III, registration, or commercial).  

Each client has a unique set of requirements for the successful manufacture and release of its product. These requirements range from process scale-up assistance and batch-production record assistance to lyophilization cycle development and analytical-method validation. Moreover, every client has a unique level of experience with its product and with CGMPs. Some clients are virtual companies that rely heavily on consultants with varying degrees of experience to provide guidance. Still others are from large pharmaceutical companies with a specific set of expectations for quality assurance and documentation practices. Complicating the process further is a range of experience levels and multiple client styles with varying interpretations of CGMPs in the client/product life cycle. 

Given the complexities involved, a strong project-management system is the best way to provide individual customer service while maintaining a reasonable level of infrastructure, meeting required deadlines, and fulfilling all CGMP requirements. It is essential that the project management system be robust with decision power at all critical levels. It must also be well maintained and work simultaneously with timely and consistent communication. 

Project-management systems work most effectively with equal participation between the client and the CMO. Multidisciplinary project teams from each company must meet frequently and have a working communication style and decision power that moves the project forward. To meet aggressive timelines associated with contract manufacturing, the level of communication required may include information sharing between consultants or third-party laboratories. 

A project-management system developed by contract manufacturer HollisterStier meets clients' multifaceted needs by acting as a framework for the manufacturing process. This system is most effective when executed with precision. All projects have multiple moving parts, thus making it challenging to meet time frames. Moreover, integrating CGMPs into each cycle of production in a uniform manner is complicated. Using a well-defined set of project-management guidelines that outline a successful project widens the opportunity for success. It is helpful to identify the following criteria before beginning the project: 					

required project documentation adequate to facilitate future communications with customers, equipment maintenance and trouble-shooting, and facility modifications.

It is important to create a multidisciplinary team with representatives from business development, validation, regulatory affairs, engineering, and manufacturing. The team should include representatives from quality assurance, quality control, and product development departments to ensure project accuracy. These team members should meet weekly as needed with a corresponding client project team 

A team leader is established as the contact point on both sides of the equation. All communication flows through the team leaders. When required, team members from the client team and the CMO team may communicate with each other for specific project needs. These needs include quality control for analytical method support. The project leader should be copied at all times. 

The project leader is responsible for team-meeting minutes and project record-keeping. A project binder is maintained throughout the project and may be passed to a new project leader, should the need arise. This is especially helpful when a project changes scope during the project life cycle. For example, a project may require the building of a specialized facility. In this case, an engineer is often the best choice to lead the project for this phase. Once the building is complete, a process development representative may be better suited to lead the project. When the change occurs, the project binder is simply passed to the new leader for a seamless transition. 

Finally, once a project is completed, a closeout meeting is held to assess the project's success. Updated project guidelines ensure lessons learned are passed along to the next project. 

Creating a timeline to support CGMP documentation requirements

 Timelines are closely managed by Microsoft Project and customized databases with communication to senior management on a daily basis in morning production meetings. A monthly project meeting also is held to provide project updates during an informal question-and-answer session. In support of this meeting, project leaders provide detailed updates to a project database and present status reports to upper management. 

 Support groups that are well trained in CGMPs feed the project-management engine. They provide the project leader with background information by giving guidance when necessary.  

A well-established Contract Manufacturing Documentation Requirements checklist serves as guidance for the project leader when communicating with clients. This checklist covers all areas affecting the project, including general information such as material safety and waste requirements, sterilization, lyophilization, manufacturing, validation, quality control, quality assurance, regulatory issues, engineering, maintenance, metrology, and business development.  

Recommendations in the checklist are based on the following guidelines: CGMP 21 

International Conference on Harmonization of the Technical Requirements for Registration of Pharmaceuticals (ICH)

). Relying on these resources and previous manufacturing and regulatory filing experience are critical. They support the checklist, thereby providing a means for both the client and the CMO to be on the same page. The entire process depends on the communication process to keep teams informed and the project on track. 

Trusting and flexible client–CMO relationships. 

Mutual trust and flexibility are integral to the process. A CMO can supply support and guidance to customers based on strong regulatory history and audit experience. Agency, customer, and internal audits provide assurance that a CMO is compliant and provide the opportunity to improve the process constantly. For example, since 2000, HollisterStier has hosted more than 100 client audits, seven preapproval inspections (PAI) audits, and eight general agency facility audits, including FDA, European, Japanese, and other international regulatory agencies. These audits support all regulatory needs, including product-flow diagrams; drug master file authorization; chemistry, manufacturing, and control;and PAI support. Customer notification is distributed through an automated database system, thereby allowing for timely and accurate project and product information delivery. 

Risk management: component and excipient identification

In addition to a regulatory notification system, each client and the facility should be protected by the fundamental practice of identifying every component or excipient that enters production areas. This procedure is not only a good manufacturing practice, but it also protects clients and CMOs from possible contamination that could take much longer to address than issues arising with known substances where cleaning methods are established. Applying the practice of using dedicated or disposable equipment for product-contact equipment and parts saves time and energy with cleaning validation. 

The following case studies describe a variety of project challenges and successes. The studies demonstrate the adaptation and application of several CGMPs in a project-management system, including the corresponding support systems to provide customers with timely and quality service. 

Case study 1: communication in proper equipment handling. 

Client A had a new process requiring a state-of-the-art facility with more than 40 aseptic connections. This project required a highly specialized compounding–filling suite. A project team was assembled and set to work. Six months from the project's start date, the facility was ready and the process transfer began. The process, however, was fraught with problems because scale-up and process development modified the scope of the project several times. CGMP regulations dictate: 

				Appropriate equipment (is required) that will not contaminate the product or otherwise be reactive, additive, or absorptive with the product and that is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals following written procedures (1).			

In this case, the primary CGMP challenge was taking equipment from several locations around the country and literally putting the pieces together on-site. Discussions began by determining how to ship each piece of equipment, transfer them down the hallway, and complete proper installation, operation, and performance qualifications. The project teams from the client and CMO worked very hard to resolve the problems and manufacture the product aseptically within CGMP guidelines. The client was on-site for several months as this project took place.  

Key to this successful project was timely and consistent communication. Many process development steps were fine-tuned within the Contract Manufacturing Documentation Requirements checklist during this project. 

Case study 2: label crunches and temporary staff. 

Client B had a commercial diluent project. At first glance, this project was simple. But, 13 product lots needed to be produced over a three-month time frame. Labeling became the critical path for this project.  

Because of the aggressive timeline and label-vendor supply issues, CGMP labels were not available as quickly as required. When the labels became available, the packaging and release of the product lots (nearly 2 million vials) were completed in one month. This project was completed with a skilled staff and effective use of local temporary employees. The 21 

 211.130 (a) "Packaging and Label Operations" and 211.25 "Personnel Qualifications" guidelines both apply in this case and the support thereof was critical. Efficient and specific CGMP training programs provide CMOs the ability to use temporary staff when specialized nonroutine projects arise. 

Case study 3: multiple projects for the same client with different originating sites. 

Client C had several small clinical trial material projects run by three different groups or sites in its large pharmaceutical company. Because one can interpret and implement CGMPs in many ways, the project was a true test of the project-management system's consistency. Several small, yet very important, projects with different client project leaders (each with different styles) and short timelines tested the system's ability to repeat the process with overall project uniformity and application of Subpart I-Laboratory Controls (21 

 A solid pattern was established for transfer requirements, but flexibility in applying the pattern was the key to providing support for the client's individual project leader's needs. A management oversight committee was established to meet routinely to discuss successes and possible improvements. This client appreciates the well-defined documentation system, the project-tracking system, and the CMO project team's preparedness at weekly teleconferences. As a result, multiple projects have been completed successfully. In this case, flexibility fostered a great working relationship and ensured continued business. 

Case study 4: method transfers from non-CGMP facilities. 

Client D had a very aggressive timeline for a project with underdeveloped analytical methods from a non-CGMP facility. According to 21 

 211.165 "Testing and Release for Distribution" (e): 

The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with 211.194(a)(2). 

Meeting this specific requirement often becomes a critical path for many projects. After redefining the project scope, developing assays, and writing the validation protocol, the method was validated at an outside laboratory. To complete the validation in time for scheduled batches, the contract laboratory used the CMO's validation protocol. This demonstrates a need to meet customer requirements by having several CGMP-compliant contract laboratories qualified to perform on-demand outsourcing requirements. It also shows that sharing information may be the best course of action to complete a project on time. 

Case study 5: third-party laboratory transfers. 

Client E, a virtual company, required a complicated analytical method transferred from a third-party laboratory where communication was extremely challenging. Differing opinions in the application of validation criteria and CGMP timing requirements (method validation must be complete before stability-study commencement) were the primary challenges. The method included extensive system-suitability criteria with secondary standards. It also required in-house, laboratory-prepared molecular weight markers using eight chemicals and more than 36 hours of hands-on labor. Patience, persistence, and several three-way technical conference calls were required to complete this transfer. Once transferred, an excellent laboratory training system allowed this method to be performed by four scientists in support of final container and stability testing requirements. 

Client G had a unique problem: bringing back a product that had been off the market for more than 20 years. This project encompassed antiquated methodologies and processes, lost product historical information, and different raw material suppliers. In addition, there were a huge regulatory risk and multiple issues requiring the redefinition of the project's scope. Ultimately, applying CGMPs to this project required a complete change in approach, timeline, and the addition of clinical trials demonstrating that producing a quality-compliant product comes first. 

Client H presented its project with a very aggressive timeline. Nonetheless, the client's project and regulatory strategy had not been thoroughly examined. As the project was defined, the client allowed the CMO to draw on the prior expertise of the CMO's project team.  

More than 1.5 million vials for a large Phase III clinical trial were produced in time to begin the associated study, thus saving the client time and money. Although basic in nature, the 21 

 211.22 responsibilities of the quality control unit apply in this case. The key to success with this project was willingness on the part of the client to learn, understand, and accept the CMO's quality systems.  

Without a strong quality unit and well-established systems in place, the client would not have trusted the CMO to the extent necessary to complete the project within the desired timeframe. Together, CGMP issues were identified, discussed, and applied using CMO-established systems. A long-standing relationship has ensued with many additional projects completed at the CMO. 

A successful contract manufacturing organization (CMO) must clearly identify the goals of a project, establish a plan, and then effectively execute accordingly. Knowing that each project includes diverse companies, personalities, phase requirements, and a large variety of products helps project leaders decide what communication style can most successfully move the projects forward. CMOs that empower their project teams by providing them with decision-making authority and direct access to senior management result in teams that operate quickly and with flexibility. Using the aforementioned strategy with a uniform application of current good manufacturing practices, allows CMOs to continue their role of producing high-quality and efficacious pharmaceutical products. 

 is the senior manager of quality control at HollisterStier Laboratories, LLC, 3525 N. Regal, Spokane, WA 99207, tel. 509.489.5656, 

A contract manufacturing organization must clearly identify the goals of a project, establish a plan, and then effectively execute accordingly.

Pharmaceutical Technology-09-01-2006

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