Historically, the pharmaceutical industry has lagged behind other industries, such as petrochemicals, in the use of process analytical technology (PAT). There are several factors that have contributed to the reticence to adopting this technology by this industry; some real and some perceived. Advances in available PAT technology, heightened business expectations, and recent initiatives by the pharmaceutical regulatory agencies have all begun to modify perceptions that have interfered with employing PAT in pharmaceutical manufacturing. The perceptions that have impeded the use of PAT, the changes taking place that are modifying these perceptions, and the benefits of having a strategic initiative for the use of PAT in pharmaceutical process development and manufacturing are examined.
In August 2002, the Food and Drug Administration announced the Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach [1]. This initiative will be the first major overhaul of the GMP's since they were originally published in 1978. A major impetus to this change was the Process Analytical Technology initiative, which seems to have been launched by a presentation [2] to the FDA's Advisory Committee for Pharmaceutical Science (ACPS) in July of 2001 by Dr. Ajaz Hussain, Deputy Director of OPS, CDER, FDA. This presentation pointed out several issues related to the way that the pharmaceutical industry controls product quality that has led to a less than optimum manufacturing system; a conclusion that was supported in presentations by various FDA and industry consultants at a November ACPS meeting [3,4,5]. Although process analytics has been widely used in the chemical industry since World War II [6] and in several other high tech industries for many years, its use in the pharmaceutical industry has been much less. In general, when the pharmaceutical industry has utilized this technology, it has not been aggressively communicated to the regulatory agencies. Pfizer has referred to this limited communication as "Don't use or Don't tell" [7]. Several factors seem to have contributed to the lack of widespread use of PAT in the pharmaceutical industry, which we will examine.
One of the contributors to the lack of use of process analytics in the pharmaceutical industry seems to be related to the industry's widespread use of batch-oriented manufacturing. This type of manufacturing is very amenable to testing the product off-line after it is produced. In contrast to pharmaceutical manufacturing, the petrochemical industry performs much of its production in a continuous flow mode where being able to monitor and control the quality of the product in real-time is an essential requirement in order to prevent producing large quantities of out of specification product.
Concerns about the technology itself have contributed to the slow adoption of PAT by the pharmaceutical industry. There is a perception within the industry that there is a lack of PAT tools designed for the pharmaceutical industry. These industry specific requirements can be as complicated as needing measurement technologies designed specifically for a unit operation (e.g. near-infrared imaging for blender monitoring) or as simple as sensor designs that are compatible with Clean In Place (CIP) and/or Sterilize In Place (SIP) systems. Whether this is an accurate perception or not, it can impact the more widespread use of process analytics within the pharmaceutical industry sector. The low availability of pharmaceutical industry specific PAT tools can be the result of a "chicken and egg" scenario. Without an established market, instrument companies are going to be reluctant to invest in the development of industry specific instrumentation. Without the availability of industry-optimized instrumentation, the pharmaceutical industry may be reluctant to adapt technology designed for other industries. Contributing to the slow acceptance of on-line analytical measurements is the perception that on-line measurements are not as "good" as laboratory-based measurements, as well as questions including: How will failure of an on-line analyzer during production be handled? and Where will the specialized PAT support capability/expertise come from?
One of the frequently cited reasons for a reluctance to adopt process analytics in the pharmaceutical industry has been regulatory uncertainty. The potential negative impact on the regulatory review process related to the use of new technology in manufacturing has created a situation in the pharmaceutical industry where there is strong encouragement to innovate in discovery and replicate in manufacturing. This can be reflected in quality systems, as well as process systems. The pharmaceutical industry has one of the most technically advanced discovery organizations, but remains more conservative when it comes to using "cutting edge" technology in manufacturing. A major contributor to this conservatism is concern over how regulatory agencies will react to the technology during a facility review. If the technology requires the agency to develop an understanding of the potential impact on the product, this could result in a protracted approval of the facility and thus delay the introduction of a new product to the market.
There are issues specific to the use of PAT that generate additional concerns. These have to do with questions and concerns regarding: analyzer qualification expectations, software validation requirements, acceptance of multivariate statistical techniques by the agency, and acceptance of on-line methods of analysis in place of laboratory-based methodologies. In addition, there has been considerable discussion with the FDA [8] on the interpretation of 21 CFR Part 11 and its application to data generated by on-line analyzers.
The more in depth process assessment that is enabled by on-line analytical measurements may lead to an increased number of products failing to meet their release criteria. These same products might not have failed utilizing the current off-line methods of analysis. This situation is created by the more accurate description of the lot's statistical distribution that results from the increased amount of data provided by an on-line measurement technique. This is an issue that needs to be dealt with fairly rapidly in order to encourage the collection of increased data and thus the PAT approach. Several groups [9] have initiated discussions on how product specifications could be redefined to consider the more accurate statistical distribution afforded by the larger amounts of data provided by on-line measurement techniques. This is necessary due to the fact that even a 6σ process will theoretically have 3.4 individuals per million that fall outside the specification limits. There is concern within the industry that the PAT approach could ultimately lead to new regulatory expectations. This concern is compounded by the current lack of worldwide harmonization of regulatory expectations relative to PAT that could lead to PAT being accepted by one regulatory agency while another might not share the same level of acceptance, resulting in quality control strategies that are specific to a given market.
It has been stated that pharmaceutical products are of high quality [3]. If this is true, this leads many to question what the major driver is for the implementation of the PAT approach. From a cost standpoint, there are several issues related to PAT, such as the cost of the equipment, as well as the cost to develop qualification, validation and quality systems for any new technology. Although PAT has been presented as a means of increasing production efficiency, this may not be viewed from a business standpoint as a strong impetus for change due to the perception that the implementation costs may outweigh the return on the investment in some cases.
Given the technology, regulatory, and business issues discussed in the previous paragraphs, have there been changes that will encourage the implementation of process analytical technology? The simple answer to this question is yes. As the chemical industry becomes more mature, process instrumentation manufacturers are looking to expand into new markets. The pharmaceutical market has been cited as a growth area for the near future [10]. As a result, companies that have been traditionally associated with the petrochemical industry are now expanding their instrumentation lines to include features as well as new measurement techniques to make their instrumentation more attractive to the pharmaceutical industry. In addition, the pharmaceutical industry is realizing that the chemical industry offers an excellent resource for process analyzer expertise. This is demonstrated by the recent increased participation by pharma industry and regulatory agency representatives in process analytics conferences such as the International Forum on Process Analytical Chemistry (IFPAC).
The regulatory area appears to be rapidly evolving. The FDA's PAT Sub-Committee, which met 3 times during 2002, provided an excellent vehicle for free exchange of ideas and discussion of issues related to the use of process analytical technology. The agency's PAT initiative was closely followed by the announcement of the 21st Century GMP's in August 2002 [1], which promises to be the first major change in the GMP's in over 25 years. The FDA has voiced its concerns that the current GMP's are not working in spite of increasing regulatory oversight and that a new system is necessary that is based on increased scientific understanding and less on an empirical based approach [11]. To achieve this, the agency is encouraging the use of new technologies, such as PAT, that provide increased process information that will ultimately lead to increased process understanding [12].
The agency has acknowledged the industry's concerns that an increased amount of process data may in fact indicate a problem in a product that meets its current registered release methods. In response to this concern, the FDA introduced the "safe harbor" or "research exemption" concept [11,13]. This is designed to encourage the industry to investigate tools that will provide increased process information without the fear of having a negative impact on the ability to release products that meet all aspects of the company's current registered quality control strategy. Although the PAT initiative has primarily been driven by the FDA, the agency has participated in international conferences as a means of creating harmonization on the PAT approach. OUS pharmaceutical industry groups have demonstrated their support for the PAT concept through the development of opinion papers such as EFPIA's proposal for real-time release of products. These types of activities should also be conducive to harmonization on the PAT approach.
From a business perspective, increasing operational efficiency in manufacturing is clearly of interest. This may occur through cycle time reductions and/or increasing process yields. There is also strong recognition of the value that variability reduction adds by increasing process capability and minimizing the risk of producing out of specification product. All of these identified issues can be positively impacted through the use of process analytical technology. An examination of a typical manufacturing process unit operation will provide additional insight regarding process variability and the resulting consequences on the final product.
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