MasterControl Deviations Management Software helps ensure FDA compliance.
During the research and development phases of a product’s life cycle, pharmaceutical companies that use paper-based or hybrid systems can wind up paying many times more than what it would have cost to install a centralized, electronic system for managing product discrepancies. According to an article titled, “Deviation Controls in Pharmaceutical R&D” (printed on the Genetic Engineering and Biotechnology News website):
There are numerous examples of products that took many years to research, develop, get approved, and finally, marketed, due in part to inadequate controls during the R&D phases. Products have been approved but could not be marketed because they could not be manufactured reproducibly according to the conditions of approval. Review of data from preclinical, clinical, and other product studies and investigations into discrepant results from laboratory and clinical studies revealed wide variations in product formulation, handling, manufacturing, and testing [italics inserted]. 1
The “wide variations” in product formulation, handling, manufacturing, and testing, and the “discrepant results” from preclinical, clinical, and other product studies and investigations cited above may well be due to the fact that it is very difficult to be consistent in identifying and categorizing deviations using manual or decentralized electronic tools. This underscores the importance of having an effective system for managing deviations in place during the beginning phases of product development, so that products can be manufactured reproducibly according to their conditions of approval. The challenges faced by companies with paper-based or hybrid systems are summarized below.
Challenge #1 – Lack of a Uniform ResponsePharmaceutical (as well as biotech †) companies that use manual or hybrid systems for managing deviations can find it difficult to provide a uniform response to discrepancies that may be related to similar events. In part, this is because the focus is on single rather than multiple events. As a result, patterns and trends often go unrecognized, making it difficult to identify and categorize deviations so that these companies can respond in a uniform manner. The situation is further aggravated by the fact that there may be hundreds of testing and manufacturing activities going on simultaneously during a relatively short timeframe. In addition, testing and manufacturing activities may be “contracted out,” which throws another potential monkey wrench into an already challenged system.
† Pharmaceutical and biotech companies are similar in overall mission, product development, and regulatory challenges, according to Ayse Kocak, a former marketing director for Pfizer, and currently the VP of Marketing for a small biotech company. 2
Challenge #2 – Bottlenecks that Result in Poor TurnaroundIt is not unusual for companies with paper-based or hybrid systems to wind up with piles of paperwork accumulating on someone's desk. In a sequential process, this can result in debilitating bottlenecks, excessive downtime, and poor turnaround in identifying/ resolving deviations. According to Ajaz S. Hussain, Deputy Director, Office of Pharmaceutical Science, CDER, FDA, the “critical path is becoming a serious bottleneck to delivery of new medical products.” 3 (The critical path is the sequence of activities that must be completed on schedule for the entire project to be completed on schedule.) In addition to slowing the time to market, and hence the delivery of new medical products, bottlenecks and poor turnaround result in higher production costs, potential sacrifices in quality, and decreased profits.
Challenge #3 – Poor Deviation Tracking
Another challenge is that of tracking deviations during the course of a product’s development using a manual or hybrid system is extremely difficult. According the article cited previously in Genetic Engineering & Biotechnology News:
Too often, it is virtually impossible to accurately trace the progression of a product’s development from initial phases of research, through multiple development phases, and finally, to the product submitted for approval and proposed for marketing. Sadly, since the review of product development typically occurs long after the work is completed, problems are identified late in the product life cycle and can result in redoingmultiple
Obviously, identifying problems late in the product life cycle and having to redo earlier studies in order to determine the cause(s) of divergence or deviation from the conditions of approval is extremely time-consuming. It also leads to a double-jeopardy type of situation, whereby the same inefficient system is being used to try to correct the very problems it created.
Challenge #4 – Difficulty Trending Deviations
Another challenge that manual and hybrid systems face is that of trending deviations. Because there can be multiple variables involved in the occurrence of a single deviation, it is important to look for trends. According to the article in Genetic Engineering & Biotechnology News, it is not uncommon, once FDA approval is finally achieved, for companies not to be able to determine the causes of a variability (or deviation from the conditions for approval). This is because there have been so many events that might have gone wrong:
In some cases, there have been so many issues to consider that causation of variability in study results could not be determined. In other cases, the lack of adequate documentation prevented any meaningful review or investigation because an accurate history of R&D could not be reconstructed. 1
Thus, in addition to being able to efficiently track deviations, it’s important to be able to trend them, or categorize them according to when, where, and how they occurred, and it’s important to have solid documentation of the causes for deviations. There needs to be the ability to filter deviations by product, manufacturing line, raw materials, supplier, etc., and to create reports and analyses that provide a feedback loop for evaluating, isolating, and quickly identifying problems. Not surprisingly, biotechnology and pharmaceutical companies that rely on manual (or decentralized electronic and partially manual) systems for managing discrepant events typically lack the ability to efficiently filter and trend deviations.
Challenge #5 – Lack of Integration with Quality Processes The FDA requires companies involved in the development of pharmaceutical or biotech products for human use to establish and maintain procedures for ensuring quality products. The ability to quickly respond to, track, analyze and trend deviations, as we have seen, can facilitate quality processes by helping companies determine the causes of deviations in a time-efficient manner. Knowing what the problem involves, however, is only half of the equation. A company must also be able to respond to deviations effectively, at times on a number of different levels. This can involve the need to change manufacturing processes, initiate corrective and preventive actions, recalibrate equipment, retrain employees, etc. Companies that rely on paper-based or hybrid systems, which are inherently time-consuming and cumbersome, can be significantly hampered in their efforts to respond effectively on the multiple levels that may be required to correct a problem.
SummaryPharmaceutical and biotech companies that depend on paper-based or hybrid systems to identify and respond to deviations during the R&D and manufacturing phases of a product’s life cycle face significant challenges. First, neither manual nor hybrid systems are very efficient at responding to deviations in a uniform manner. This is because paper-based and hybrid systems are designed to look at single events, rather than multiple events that occur over time. As a result of this inherent “shortsightedness,” much more time is required to analyze the causes of deviations, resulting in bottlenecks and poor turnaround. The problem is that paper-based and hybrid systems lack the ability to filter deviations by product, manufacturing line, raw materials, supplier, etc., and create reports and analyses that provide a feedback loop for evaluating, isolating, and quickly identifying problems. This leads to poor deviation tracking and poor trending. Finally, once the problem or problems are identified, companies that use paper-based or hybrid systems encounter essentially the same difficulties during the resolution process that they faced during the identification process: slow, disconnected processes, susceptibility to human error, and unreliable documentation. In a centralized (which entails a web-based †) electronic system, with software designed specifically for managing deviations, the problem—once it is identified, and even if it involves multiple variables—can usually be quickly resolved via software for corrective and preventive action, change control, planned deviations, recalibrating equipment, managing suppliers, retraining employees, etc.
In short, pharmaceutical and biotech companies that use paper-based (or hybrid) systems for managing deviations are extremely vulnerable to (sometimes huge) time-to-market delays. Looked at from a broader perspective, this affects the pharmaceutical/biotech industry as a whole in terms of productivity gains. As FDA Commissioner Mark B. McClellan is quoted as saying:
Other high-tech industries with essentially no tolerance for errors or impurities, such as the semiconductor industry, have achieved enormous productivity gains in manufacturing in the last 25 years. We should expect nothing less from the pharmaceutical industry. 4
† Because testing and manufacturing operations are frequently “contracted out,” particularly during product development, a centralized, electronic system entails a web-based system that can be accessed from any location.
- Deviation Controls in Pharmaceutical R&D. (2006 May 15). In: Genetic
Engineering & Biotechnology News: 26-10. Retrieved September 24, 2007, from http://www.genengnews.com/articles/chitem.aspx?
- “Marketing from Big Pharma to Start-Up Biotech.” Retrieved September 30,2007, from http://www.ngpharma.com/pastissue/article.asp?art=
- Hussain, AS (2004). Critical Path Initiative: Challenges and Opportunities. Office of Pharmaceutical Science, CDER, FDA. Retrieved online September 25, 2007 from http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm076689.htm
- McClellan, M.B. (2003, March 28). Speech before PhRMA. Retrieved September 24, 2007, from http://www.fda.gov/oc/speeches
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