Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Siegfried Schmitt

The recognition that the current pharmaceutical industry's manufacturing performance was not as state of the art as other industries has been a key driver behind the increasing adoption of quality-by-design (QbD) concepts. 

 from January 2009 compares the operations performance of the pharmaceutical industry with other industries such as automotive, aerospace, computer, and consumer packaged goods and across a long list of measures, the pharmaceutical industry compares poorly.  

Industry efforts to address these performance issues have focused on Six Sigma/Operational Excellence concepts and, since the issue of new International Conference on Harmonization (ICH) guidelines (i.e., ICH Q8, 9, 10, and 11), on the concept of quality by design. These initiatives have significant implications for pharmaceutical analysts. The desire to improve first-pass yield with zero defects has seen laboratories come under great scrutiny to ensure that all the methods they run work right first time, every time. To reduce inventories and lead times to those typically achieved in other industries, manufacturing planners must know with absolute confidence how long manufacturing and testing will take; rerunning a problem method is no longer an acceptable option. Zero-defect goals have also seen a focus on understanding and improving process capability (i.e., reducing the overall process variation relative to specification), and therefore, there is a much greater focus on truly understanding the variation contribution of the analytical method to the overall process variation.  

QbD concepts described in ICH Q8, 9, 10, and 11 provide approaches that can help achieve the desired improvement in process performance (1

4). ICH Q8(R2) and 11 recognize the importance of effective process development in understanding the relationship between process variables and process performance. ICH Q9 describes how risk-based approaches can be used to determine which variables are crucial to control. ICH Q10 highlights the importance of effective processes for maintaining the control strategy through the lifecycle of the product.   

A major focus of discussion and implementation of QbD has been on the concepts included in the ICH Q8 definition (i.e., product and process understanding and process control). Understanding and control, however, cannot be achieved without a solid foundation of measurement or analytical science. During process development, analytical data are needed to provide the basis for process understanding. Control strategies based on this understanding are increasingly being developed based on recognition of the importance of identifying and controlling variation upstream rather than testing the end product. This control of variation has seen increasing use of process analytical testing (PAT) in preference to or in addition to end product testing, and with it, new technologies to be mastered by analytical scientists. QbD has also seen a focus on understanding and controlling attributes of excipients used in the manufacturing process, with increasing use of physical measurement technologies.  

In addition to affecting what analytical scientists measure, the concepts of QbD, can also be used to enhance the robustness of the analytical methods themselves (5).  One implication of such an approach is that it highlights the potential to re-examine the way that methods are developed and validated, in the same way that application of QbD to manufacturing processes has driven a revision in thinking of how process development and validation are performed (6, 7). 

Taking advantage of the potential improvement opportunities through adoption of QbD concepts, however, does have some challenges. The ability to introduce improvements to analytical methods and to adopt new analytical technologies can be constrained, both through the need for industry to acquire new skill sets and through the challenges associated with making postapproval regulatory changes. These challenges are multiplied many times as a consequence of the global nature of the pharmaceutical business, with many stakeholders (e.g., regulators, pharmacopeias, consensus standards bodies) making harmonization of approaches particularly challenging.  

The introduction of QbD has challenged traditional thinking on pharmaceutical development and manufacturing. There has been a greater focus on developing science and risk-based control strategies based on product and process understanding over the more traditional approach of check-box compliance with reliance often on conventional end-product testing.  

During process development, analysts are being challenged to provide more information on what process and material attributes are truly crucial to process performance. Greater emphasis on understanding the role the physical attributes of input materials play in the process has seen increasing adoption of advanced physical-properties measurement technologies. In-line measurement technologies coupled with multivariate statistical analysis techniques are being used to provide greater understanding of what is actually happening during each of the process steps.  

Risk assessments of processes are increasingly being used to evaluate the need or value of a particular measurement within the control strategy to reduce the risk to product quality. A measurement, for example, may be applied to in-process quality control, or perhaps as an approach to improve detectability of a failure mode examined in a failure mode and effects analysis (FMEA). 

The effectiveness of in-process control in assuring product quality has been recognized (8). A number of pharmaceutical companies have developed manufacturing processes where the controls are in process and a control strategy similar to 

 Figure 1: Manufacturing process where the contols are in-process.  

A PAT-enabled process allows increased sampling of the process material to be performed, thereby increasing the information about the process. The increased sampling can, however, increase the risk of failing a zero-tolerance specification found in a uniformity of dosage units test, for example. Pharmacopoeial authorities have recognized this disincentive to the adoption of large sample sizes and responded by proposing alternative approaches (9). 

PAT-enabled processes may also present challenges to the traditional paradigm of batch release based on end-product testing and specifications. The PAT-enabled process may evaluate different attributes or end-points, use multivariate statistical analysis of process data, and also require an understanding of the distribution of data, all of which may affect the determination of appropriate acceptance criteria. 

The implications of these changes include tools that support process understanding (e.g., granule porosity), new technologies and skill sets (e.g., near infrared, imaging, statistics), and new behaviors (e.g., risk assessment vs. check box compliance).    

Application of QbD  concepts to analytical methods

The concepts of QbD as articulated in ICH Q8, Q9, Q10, and Q11 are aimed at improving the robustness of pharmaceutical manufacturing processes and enabling continual improvement. They focus on taking a systematic structured approach to identifying process variables and how these variables relate to the desired process outputs and pharmaceutical products. Such enhanced understanding combined with application of formal risk-assessment processes are used to identify the critical attributes and parameters that should be controlled to assure product quality. Lifecycle knowledge and change-management processes then ensure that control strategies remain effective through the lifecycle. By considering an analytical method as simply a process, it is possible to apply these same concepts to provide enhanced confidence of the robustness of analytical methods. As mentioned above, this increased focus on robust methods is becoming an increasing area of concern for analytical scientists as non-robust methods undermine the ability to plan manufacturing and related quality assurance activities with confidence. Increased regulatory scrutiny on out-of-specification (OOS) investigations and effective root cause analysis of these is another key driver for ensuring method variables are well understood and controlled.  

In 2010, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) jointly issued a white paper aimed at stimulating discussion between industry, regulators, and pharmacopeias on the potential benefits and implications of applying QbD concepts to analytical methods (5).  A number of companies are now adopting this approach as they are seeing benefits in terms of increased method understanding, robustness, and ruggedness. During a Parenteral Drug Association (PDA) workshop, held Mar. 6–7, 2012 in Liverpool, UK, it was acknowledged that there are no regulatory barriers to adoption of a QbD approach for analytical method development and validation; however, it was also recognized that thinking may need to change about approaches to analytical method validation (10).  

A lifecycle approach to method validation has been proposed (11) and indeed some of the concepts behind application of QbD to method development and validation have started to be promoted, particularly by the United States Pharmacopeia (USP) (12, 13) and through ASTM guidance on validation of PAT methods (14).  Recently, USP has established an expert panel to explore whether the chapters on method validation, method verification, and transfer of analytical procedures may become amalgamated into a single chapter describing how methods are assured to be fit for purpose through their lifecycle. Sample replication levels, criteria for agreement between replicates, system performance requirements, repeat testing required for OOS and equivalence testing criteria should all ultimately be able to be linked back to an understanding of the methods performance and the targets for accuracy and precision that are required.  

As noted above, a common understanding between pharmacopeias, regulatory agencies, consensus standards organizations, and industry on the description, application and interpretation of QbD concepts as applied to analytical methods is essential if they are to be more widely adopted. The PDA workshop recognized that alignment of understanding was key and that better clarity was desired on some of the terminology and concepts being used (e.g., method operable design region [MODR] vs. analytical design space [ADS], analytical target profile [ATP] vs. procedure performance acceptance criteria [PPACs]), and participants proposed the development of case studies to better illustrate the concepts. A key point that arose during the workshop that needs further discussion is whether a method is validated to meet a target performance (which is defined from the specification limits) or whether the specification limits are set based on the method capability. 

The ability to innovate and improve is crucial, not only to ensure the most up-to-date technologies are used to ensure patient safety, but also to improve efficiency and eliminate waste. There have been a number of recent examples of incidents where contamination of drugs has resulted in serious patient harm (e.g., heparin, melamine). These incidents have led to the development and introduction of modern analytical technologies (e.g., nuclear magnetic resonance [NMR]) to help mitigate risks of future occurrences. The pharmaceutical industry has not been quick to adopt new measurement technologies for a variety of reasons such as the significant costs, potential regulatory risk, and resources associated with changing the registered details globally. At the PDA workshop, an example was shown that illustrated the significant cost that a pharmaceutical manufacturer may be faced with attempting to introduce improvements to analytical methodology when products are registered in many global markets. Reducing the barriers to innovation and improvement through better regulation has been a focus of governments through programs such as the UKs Better Regulation of Medicines Initiative (BROMI) or the Executive Order 13563—Improving Regulation and Regulatory Review in the US.  

There are examples from the pharmaceutical industry where flexibility to use any appropriate method is allowed (e.g., FDA's melamine guidance) (15) which states "alternative method or methods can also be qualified for use in screening components for the presence of melamine" and defines the performance required as, "The test method used should be suitable for detecting melamine contamination in at-risk components down to at least 2.5 parts per million (ppm)," or FDA'S Heparin Guidance (16) that again allows alternative methods to be used. Recent proposed changes to the FDA guidance on sterility testing are "intended to provide manufacturers of biological products greater flexibility and to encourage use of the most appropriate and state-of-the-art test methods for assuring the safety of biological products" (17).  

The concepts of comparability protocols/postapproval change management protocols introduced in October 2012 in the US and in Europe may provide a mechanism of facilitating easier postapproval changes. Again, as previously stated, from an industry perspective it is crucial that there be alignment in thinking in this area.  

As highlighted already, it is key for an industry that manufactures and markets globally to have a regulatory framework that also operates globally (aligned and harmonized). In the field of analytical science, the regulatory framework is defined by a number of stakeholders—the regulatory authorities, the pharmacopeias, and other standard setting bodies such as ISO and  ASTM, which may be recognized by the regulatory authorities. With the changes associated with the introduction of QbD, it is important that the thinking and concepts are aligned across these different bodies. The development and publication of ICH Q8, 9, 10, and 11 have played a significant role in motivating alignment among the ICH regions; however, not all the thinking in this area is integrated. It is, however, recognized that the European Pharmacopoeia has already been offering flexibility including the use of alternative approaches for a number of years, which is expressed in particular in the 

 (General Notices section 1.1). Moreover, the European Pharmacopoeia has been playing a leading role in developing thinking on the implications of large sample sizes (9). The USP has been promoting the concept of performance-based monographs and has issued examples of these in a new USP Medicines Compendium as well as a general chapter on how to define performance requirements for methods. USP has also recently established an expert panel that is looking to revise its guidance on method validation and verification. ASTM has been developing guidance on how PAT methods should be validated, while the EMA has issued new draft guidance on use of NIR (18). FDA is promoting thinking on the use of confidence intervals for batch release decisions with reference to ASTM guidance on this topic (19).   

Ensuring global alignment is an extremely difficult goal; however, from an industry perspective it is the key barrier to innovation and effective implementation of QbD.  To advance these concepts, more must be done in this area. It is encouraging to see that pharmacopoeia authorities have agreed to discuss global good pharmacopoeial practices under the auspices of the World Health Organization (WHO).  

The ultimate goal of QbD has been summarized in a statement from Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at FDA, who suggested during a ISPE and AAPS-sponsored CMC workshop on Oct. 5, 2005, that a mutual goal of industry, society, and regulators is "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight." To achieve this goal, it is crucial that we move from a checkbox, compliance-focused culture to one that is founded on a science- and risk-based approach to assure quality and compliance.  

The authors would like to acknowledge the support of the Parental Drug Association and the assistance of Georg Roessling, senior vice-president PDA Europe; Susanne Keitel, director of European Directorate for the Quality of Medicines; and Jean Louis Robert, chair of the EMA Quality Working Party in helping organize and facilitate the workshop.  

Q11 Development and Manufacture of Drug Substances

Guidance for Industry, Process Validation: General Principles and Practices

7. EMA, Note for Guidance on Process Validation (EMA/CHMP/CVMP/QWP/70278/2012-Rev1). 

Guidance for Industry, PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance

10. PDA, Worskshop on Analytical Science and  QBD, Mar. 6–7, 2012. 

11. P. Nethercote et al., PharmaManufacturing 2010, 

www.pharmamanufacturing.com/articles/2010/060.html

13. USP, General Chapter <1033> Biological Assay Validation (2010). 

14. E55.02 WK16888 A Risk Based Guidance for the Validation of PAT Methods – Draft 

 Guidance for Industry, Pharmaceutical Components at Risk for Melamine Contamination

Guidance for Industry, Heparin for Drug and Medical Device Use: Monitoring Crude, Heparin for Quality,  Draft Guidance

18. Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry and the data requirements for new submissions and variations EMEA/CHMP/CVMP/QWP/17760/2009 Rev 2. 

Standard Practice for demonstrating ability to comply with an acceptance procedure

PDA workshop on analytical science and QbD

The Parenteral Drug Association (PDA) organized a workshop, held on Mar. 6–7, 2012, aimed at identifying the role analytical science plays in supporting the implementation of quality-by-design (QbD) concepts and some of the challenges and opportunities QbD creates. The workshop provided a forum for regulated industry and key stakeholders from regulatory authorities (FDA, European Medicines Agency, and the UK's Medicines and Healthcare products Regulatory Agency) and pharmacopeias (European Pharmacopoeia, British Pharmacopoeia) to explore the implications of QbD on analytical science and to assess the future direction and implementation challenges. Diverse representation including analytical scientists and regulatory affairs staff involved in development and manufacturing engaged in an open exchange of ideas during the three topic breakout sessions and the plenary panel discussions conducted over two days. Challenges and issues were identified for topics covering:  

How the critical product and process attributes that are measured change with a QbD approach 

The implications of QbD on specification limits and sampling  

How QbD concepts can be applied to analytical methods development and how this affects method validation approaches  

How implementation of improved and innovative methodologies can be facilitated  

The challenges of global alignment of standards. 

The workshop participants suggested a number of potential actions that might help address these challenges including:  

Agreeing on unique, unambiguous, and well-defined terminology 

Reviewing existing International Conference on Harmonization (ICH) guidelines, and developing a white paper on proposed revisions and potential new guidelines, if any, that would support and enhance the role of analytical methods in QbD

Exploring, during the forthcoming revision to the EU variations guidance, how the Post-Approval Change Management Concept might be used to facilitate continuous improvement and innovation of analytical methodology  

Establishing mechanisms to ensure global alignment of new pharmacopoeial\regulatory texts and guidance in this area (e.g., large sample size guidance and method validation) 

Developing case studies and aligned terminology to ensure consistent understanding of how QbD can be applied to analytical methods and further explore how analytical target profile (ATP) can be presented in regulatory submissions 

Holding further workshops in the US and in Asia focusing on case studies in order to support global alignment of concepts.

Articles

The authors present topics discussed and conclusions that resulted from the PDA QbD workshop.

The Role of Analytical Science in Implementing Quality by Design

There are no two completely identical units in operation anywhere. Even if the difference is only in the version of the operating software, we are always dealing with a unique piece of equipment. Lyophilisers are also one of the few equipment items that are constantly undergoing continuous, and often significant, design changes as manufacturers respond to the evolving needs of customers. In general, there is a global shortage of freeze-drying capacity, which has led to many companies outsourcing this activity. It is not unusual for small-scale production (development to clinical phase II) to be performed at one contract manufacturer, while large-scale (clinical phase III and commercial product) manufacture takes place at another.  

 Diamond Sky Images/Digital Vision/Getty images			

One of the principal issues facing manufacturers is the significant differences that often occur in lyophilisation equipment performance and operation at the development and production stages. Because of this, it is difficult to develop models for process controls linking critical quality attributes with critical process parameter that scale easily, or that can be transposed from one site to another. Quality by Design (QbD) is an initiative that is gaining much attention in the industry. However, so far there isn't much proof of concept for QbD in freeze drying. In the pharmaceutical industry, there have been several QbD submissions, but lyophilisation predominantly applies to biological products and by the end of 2011 there had been no submissions that included a design space for biological compounds, according to a personal communication I had with the FDA's Lucinda Buhse in March 2012 

The fact that freeze drying is mostly used for biological products also creates further challenges. Biologics tend to cost more and there are usually limited amounts of product available. Experiments with the freeze-drying process tend only to be used in early development, and even then they are performed on small scales. One key parameter that must be known is the eutectic point of the formulation, so that the melting point of the frozen product is known. Without this information, the manufacturer will not know when melt back could occur and develop a cycle that has enough safety margin to prevent melt back from occurring. 

There are no two completely identical freeze dryer units in operation anywhere.

The Freeze Drying Challenge

In the early years, trying to champion and implement computer validation was quite challenging. The industry faced the unfamiliar installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) concepts. The common reaction to computer validation back then was quite similar to the Kübler–Ross "Five Phases of Grief" cycle (1). Some readers may have similar recollections and probably have heard some of the following responses: 									

Phase 1, Denial: "Our mission is to implement systems, not to write documents and fill out forms," or "Who says we have to do it, show me the regulations." 

Phase 2, Anger: "We have years of experience in developing and implementing systems, we don't need !@#$*** validation," or "You are joking, you want me to do what?"

Phase 3, Bargaining: "Do we have to do all of those things?" or "Can we do this instead...?"

Phase 4, Depression: "This feels similar to paying a luxury tax," or "This is stressing me out, I don't have the time and resources to do all this work."

Phase 5, Acceptance: "Oh well, fine, if you really want me to do it, I'll do it."

Nowadays, although there are some who are still in the denial stage, the level of grief is more subdued, and the industry is more accepting. For many, computer validation has become a part of daily life, just like accepting and using the mandatory car seatbelt. The road to acceptance was not without its controversies. In the mid 1990s, many varied opinions led to confusion about the scope of computer validation. At one point, a computer's operating system (OS) was thought to be in scope and to require validation, and the OS vendor had to be audited. In another case, a consultant advised that a "change control" must be filed when replacing a printer's toner cartridge (now we know that consumables don't need change control). It was during this period of confusion that "common sense" became the buzz phrase and "it depends" were the first two words that preceded an answer to any computer validation question. 

We have transitioned from the "common sense" and "it depends" environment to a risk-based and risk-management environment, especially since the US Food and Drug Administration is on board with risk management (2). We hope that a risk-management approach will level off the inconsistencies inherent to the "it depends" approach. Only time will tell whether it will be successful. By this transition, however, it seems that along the way we have inadvertently proved Darwin's theory of evolution: we have evolved and transitioned from a less-structured environment to a more technically structured and scientifically minded methodology to computer validation. 

Origins of the computer-validation concept and approach

Although the concept of good manufacturing practices (GMPs) dates back to the early 1900s, current GMP regulations are mostly based on the practices that were revised in the mid-1970s, when the medical-device regulation amendments were introduced. It was during this time period that the manufacturing-validation concept (now known as process validation) was first discussed by FDA officials Bud Loftus and Ted Byers (3). In the late 1980s, the manufacturing-validation concept and approach of conducting IQ, OQ, and PQ were applied to computer validation. This approach was selected in part for the benefit of the relationship between industry and FDA. It was hoped that FDA would accept the computer-validation approach because it was already familiar with and accepting of the IO, OQ, PQ concept. Within the industry, applying  IQ, OQ, PQ to computer validation was challenging at first. This was at a time when validation concepts such as unit testing, module testing, and integration testing in information technology and software engineering already were being practiced. Interestingly, this IQ, OQ, PQ concept has withstood the test of time and is still prominent today, although some may have substituted and intertwined other types of testing into the fold, including unit and integration testing, as well as other variations of testing (e.g., site-acceptance testing and factory-acceptance testing). 

Perspective on regulations and regulatory guidance

Some believe computer validation has been mandatory for only a few years. Most computer validation practitioners believe it started in 1983 with FDA's publication of 

Guide to Inspection of Computerized Systems in Drug Processing

 (known simply as "The Blue Book") (4). FDA documents related to computer systems were published as early as 1976 and 1977, however (see sidebar, "Related FDA documents") (5–7). The 1976 

 provided inspectors with the following guidance (6): 

An understanding of computer operation, and the ability to use a computer, does not require a detailed knowledge of either electronics or the physical hardware construction. An overall view of the computer organization with emphasis on function is sufficient.  

Additional guidance was provided in the 1977 

 "The accuracy and validation of the program is one of the most important aspects of computer control" (7). 

Computer-validation articles published			

Clearly, FDA regulations and expectations have changed since the late 1980s. More detailed documentation is now required to support and verify a system's quality. FDA publications also have become increasingly specific (e.g., in clinical system guidances and those governing the food-processing industry) (8, 9). FDA has a better understanding of the technology and its capabilities as a result of its body of national experts on computer systems, as well as the proliferation of computer and automated systems in the industry. Several other countries also have computer-validation requirements in their GMP regulations (10, 11). 

A discussion about regulations would be incomplete without including 21 

 Part 11 regulations of electronic records and electronic signatures. In 1991, industry and FDA representatives met to determine how to accommodate paperless record systems under 21 

 Parts 210 and 211. Specifically, industry requested FDA's official position on substituting 21 

 Part 211, section 186 "full signature, handwritten" with an electronic signature (12). In response, FDA publshed its progress report 

Electronic Identification/Signature Working Group

 in 1992 (13). The report identified seven key issues: legal acceptance, regulatory acceptance, enforcement integrity, validation and reliability, security, standards, and freedom of information. The final regulation was published in 1997, and although the regulation is now 10 years old, discussions and issues still revolve around most of these points. Former FDA Commissioner David Kessler is believed to have said that he was surprised by the number of experts he found when he searched the topic of Part 11 on the Internet, especially because FDA was still trying to address and develop a better understanding of the implementation and enforcement of the regulation. Even more interesting in hindsight is how the initial request for FDA to address a specific section of 21 

 Part 211 has now evolved and encompassed all other aspects of the GMPs. 

Even now, some uncertainty about Part 11 regulations remains. A contributing factor to this confusion may be the fact that earlier FDA guidelines on the regulation were revoked in 2003 (14) and replaced by a single guideline (15) with the intention of adding other guidelines later. FDA's reasoning behind withdrawing these guidelines (

Docket 00D-1540 in Feb. 2003) was "to avoid loss of time spent by industry in their efforts to review and comment on Part 11 issues that may no longer be representative of FDA's approach under the new GMP initiative." Since then, no additional guidelines have been issued, but FDA is working on a Part 11 amendment (16).  

While FDA published its official regulations and guidelines, the industry also was actively addressing computer validation. In the late 1980s to the early 1990s, the Pharmaceutical Manufacturers Association (PMA, now Pharmaceutical Research and Manufacturers of America, PhRMA) Computer System Validation Committee (CSVC) led by Ken Chapman was the industry's main forum to discuss computer-validation issues. One series of discussions about system-development life cycle (SDLC) methodology resulted in the selection of the waterfall life cycle model (see Figure 1). In the mid 1990s, a variation of this waterfall model, the V model, became more popular (see Figure 2) and is still the model of choice. Looking back, there is no significant change in the computer validation SDLC. This is rather surprising because in some cases, using other methodologies might be advantageous (e.g.,

rapid prototyping methodology, which involves configuring how software should operate first, then documenting the final configuration and functional operation, followed by the software's operational verification). 

Figure 1. "Waterfall" life cycle method.			

PMA also published other computer validation related articles, mainly in 

, which has published more than 40 articles about computer validation. Historically, this publication played a key role in shaping and spreading understanding of computer validation in our industry. Even individuals from FDA published articles in the journal back then (17). Sadly, this is no longer the case because, for better or worse, FDA is now stricter about allowing its employees to publish. (A list of computer validation–related articles is online at 

Figure 2: "V model" life cycle method.			

The PMA CSVC was dissolved in the mid 1990s, and the US Parenteral Drug Association (PDA) became the industry's main forum. Part of PDA's computer-validation committee efforts focused on software-supplier audit and the creation of an audit repository center (ARC) (18). The ARC concept, however, has had varying success. Currently, the repository is managed by Syntegra. Since the late 1990s, the main industry forum for computerized systems validation has been the ISPE good automated manufacturing practice (GAMP ) group. The GAMP guideline is widely considered to be the 

 pharmaceutical-industry standard in computer validation. The current GAMP 4 version introduced the risk-management concept into computer validation in 2001, aligning with FDA's effort on GMPs for the 21st century. Currently, GAMP is working on version 5, which is slated for publication in late 2007 or early 2008. It is important to note that GAMP 4 explicitly excludes 21 

 Part 11, although a separate guideline has been produced. 

The healthcare industry has actively addressed Part 11 regulations. ISPE/GAMP and PDA both have published guidelines on Part 11, hoping to help clarify the implementation and compliance to the regulation. As discussed previously, there was much confusion about the implementation of Part 11 when it was initially introduced. Accordingly, PDA arranged a public FDA conference about Part 11 in June 2000 (19). The conference reinforced the public's concerns about Part 11, and based on industry's reaction, FDA issued the final guidance on Part 11 in August 2003 (15). FDA also scheduled a Part 11 public hearing in June 2004, again allowing the public to voice concerns and suggestions about Part 11. Unfortunately, President Ronald Reagan's funeral fell on the same day as the scheduled public hearing date, and the day was declared a federal holiday. The meeting was therefore cancelled and never rescheduled, prompting industry, as a "21 

 Part 11 Coalition" to file a public petition letter in September 2004 (20). Since then, there has been a semblance of calm on the topic as FDA considers rewriting Part 11 and industry adjusts to a risk-based approach. The resulting decline in the number of Part 11 483s may be related to the fact that FDA is citing the predicate rule directly, rather than Part 11. Until the new amendment is issued, FDA is indeed showing enforcement discretion regarding the implementation of Part 11. It should be noted, however, that Warning Letters with severe consequences were sent to Able Labs, MDS Pharma, and Ranbaxy, and the warnings related to electronic records, even though Part 11 was not mentioned. 

Perspective on enforcement and observations

We can understand FDA concerns about computer systems as we look at the following examples. The "Therac-25" medical-device software went awry between 1983 and 1987, overdosing patients with X-rays (21). FDA stopped the use of the device. According to the recollection of the authors, Wyeth Laboratories Inc. is believed to have received the first computer validation–related 483 from Center for Drug Evaluation and Research (CDER) in October 1983 for a lack of documentation for the validation of a computer system used for the statistical analysis of data. In the late 1980s, the generic-drug scandal caused concern because data had been falsified. One of the authors served as a witness in a grand jury investigation of the generic-drug scandal. Interestingly, Phil Piasecki, a former FDA official who later worked in the industry, once told one of the authors of an observation he made on computer systems. He noticed that the red light of a dehumidifier in a data center was on. After inquiring about the dehumidifier's purpose, he cited the company for not having a standard operating procedure (SOP) for its use and maintenance. 

These examples illustrate the wide range of enforcement actions and levels of impact on patients' safety (from serious to limited and indirect impact). Since the mid 1990s, we have also seen numerous observations relating to computer-validation issues, ranging from "the system is not validated" to "the SOP is not followed." Since the early 2000s, however, it seems the number of observations has decreased. Between 2000 and 2005, the number of Warning Letters issued decreased by 50% (22), perhaps resulting from a shift in FDA's focus after the 9/11 attack in 2001 to homeland security and food safety (23). At the same time, FDA faces a decrease in budget spending (24). 

FDA's presentation titled "Data Integrity, Another Looming Crisis," revealed its recent enforcement has focused on record integrity (25). The presentation made it clear that based on recent inspection findings, FDA would refocus on the integrity of e-records and train inspectors in this topic. Despite challenges that FDA faces, it has increased significantly the understanding and knowledge of computer systems in the industry. The agency actively participates and has a Computer System National Expert representing FDA in industry forums (e.g., GAMP), as well as providing computer validation training courses internally and through selected providers. Hence, although we are now seeing fewer computer-validation 483s, partly because FDA is citing predicate rules instead of Part 11, these 483s are more meaningful and should not be interpreted as a reflection of relaxed enforcement. 

Perspective on computer-validation practices

The Standish Group's "Chaos" reports, indicate that "incomplete requirements and specifications" and "changing requirements and specifications" are two of the top three "project challenged factors" for computer-system projects (26). This assessment seems to hold true in today's computer-validation practices. An informal poll conducted by the authors indicates that user requirements are the main challenge when validating a computer system. User requirements have been a factor since the early years of computer validation. Nonetheless, the general understanding about how to conduct computer validation in the industry has increased since the 1990s, and most companies now have groups or departments dedicated to computer validation. Since the introduction of the Sarbanes–Oxley financial regulations for a publicly traded company, more and more information technology (IT) departments have established compliance groups. It is generally accepted now that IT infrastructure must be qualified to meet growing regulatory requirements across the business. 

FDA has published more than 30 documents related to computer systems and computer validation, and the term 

 is no longer foreign to the industry. Computer-validation practices and regulations are evolving and reaching the maturity stage of other validation disciplines, even if more recently it seems that the efforts on computer validation and Part 11 compliance are less apparent than before. This complacency might be a result of the wait-and-see attitude toward what the new Part 11 regulation amendment might bring and may also result from the perception that computer validation–related 483 observations have decreased in recent years. 

The intent of Part 11 regulations was to allow businesses to be more efficient, to enable automation, and to generate less paper documentation. Yet, these goals have not been fully realized. Most companies addressed how to meet and comply with the Part 11 regulations, but they did not necessarily develop business strategies to take full advantage of what the regulations allow the companies to do. 

As technology evolves, computer validation also will change. We will see what the next 10–30 years bring. Could we see programmable drugs based on nanotechnology? For example, one article suggests that nanodiamonds could be useful in biological applications such as carriers for drugs (27) or perhaps as bioerodible implants with programmable drug release (28). Computer validation will need to be continuously simplified, standardized, and automated while reflecting the growing complexity of designed and engineered drugs and delivery systems. 

The authors thank Alan Kusinitz, managing partner of SoftwareCPR, and George R. Smith Jr., FDA consumer safety officer at CDER's Office of Compliance, for their input and review. 

 is the computer validation manager at Boehringer-Ingelheim Chemicals and a member of 

 is the director of computer system quality assurance at Wyeth. 

 is a compliance expert at Agilent Company. 

 is manager of manufacturing systems and process automation at Bristol-Myers Squibb. 

, is the quality director at GE Healthcare Global IT. 

is the life sciences manager at Business & Decision. 

*To whom all correspondence should be addressed. The scope of this article is specific to the healthcare industry and to the view of the authors or FDA, which may not necessarily reflect the view of the companies where the authors and reviewers are employed. 

Rory: "I was in the UK, going to school." 

www.businessballs.com/elisabeth_kubler_ross_five_stages_of_grief.htm

 3. IVT Proposed Validation Standard VS-2, Computer System Validation, IVT 3 (2002). 

Guide to Inspection of Computerized Systems in Drug Processing (

ITG Subject: The Computer in FDA-Regulated Industries (

www.fda.gov/ora/inspect_ref/itg/itg23.html

ITG Subject: The Computer in FDA-Regulated Industries Part II Computer Hardware (

www.fda.gov/ora/inspect_ref/itg/ itg29.html

Guidance for Industry: Computerized Systems Used in Clinical Trials (

www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

This article provides a historical review of computer validation in the pharmaceutical industry within the last three decades, evolving from the early years' initial concept and approach to today's current practices. Also included is how the regulations and industry have progressed in addressing the topic of computer validation.