Laura Bush is a former managing editor of Pharmaceutical Technology and Editor-in-Chief of BioPharm International.

Laura Bush

 released a new guidance covering the content of electronic common technical document (eCTD) submissions. The new 

Guidance for Industry: Providing Regulatory Submissions in Electronic Format-Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications

, updates the August 2003 draft guidance on the same topic. 

The new guidance provides more specificity than earlier guidances regarding the organization of electronic submissions, and it harmonizes the organization and formatting of multiple submission types. The International Conference on Harmonization developed the CTD and the eCTD for marketing approval applications (ANDAs, BLAs, NDAs), but according to the new guidance, they can apply to other submission types such as INDs and master files. More details regarding the ICH eCTD can be found in the ICH guidance document 

M2 eCTD:  Electronic Common Technical Document Specification.

http://www.fda.gov/cder/guidance/6766fnl.htm

Articles

New FDA Guidance on Electronic Common Technical Document Submissions

Oddly for a technical meeting, the Oct. 5–7 AAPS Workshop on Pharmaceutical Quality Assessment focused on words, with an entire session devoted to definitions and countless discussions of meaning and nuance. 

AAPS and FDA convened the joint meeting to examine the agency's plans for overhauling the ways it reviews CMC submissions and regulates manufacturing quality. New key words underlie new key concepts in this approach: 

design space, quality by design, continuous improvement,

. The discussions made it clear, though, that most attendees from industry and even from FDA itself were unsure what, exactly, many of these terms mean. 

That's okay. As any English teacher knows, the best way to give students command of new vocabulary is to have them use the new words and see them in action. Toward that end, attendees met repeatedly in smaller breakout sessions to explore these terms and determine how they would be applied. They used the words in many sentences and, in particular, in many questions. 

One breakout session asked how a new-style CMC submission would be distinguished from the traditional type. "We'll know it when we see it," the group's rapporteur reported. 

"Example is always more efficacious than precept," as Samuel Johnson (the dictionary-maker who defined lexicographer as "a harmless drudge") put it in 

For industry and FDA to master the meaning of this new vocabulary, we must see the concepts in practice. 

 for example, will only truly start to take on meaning after a company applies the concept in a new drug application, and the company and the regulators debate its boundaries and determine the rules around changing it. 

So the new terms, and their definitions, are useful. They provide a framework for thinking about a new approach. But it will take implementation to know what they really mean, and how the new system will work.  

Oddly for a technical meeting, the Oct. 5–7 AAPS Workshop on Pharmaceutical Quality Assessment focused on words, with an entire session devoted to definitions and countless discussions of meaning and nuance.

Defining by Example

 (Singapore) have agreed to collaborate to develop a single-shot vaccine for Japanese encephalitis (JE). Most JE vaccines now on the market require multiple injections. The new vaccine will be developed using OctoPlus’s controlled-release drug delivery technology and the “PER.C6” technology licensed by SingVax from the Dutch company 

 (Leiden, The Netherlands) for manufacturing the inactivated JE virus particles.

OctoPlus has several proprietary controlled-release drug-delivery technologies. For the JE vaccine, the company expects to focus on its modified-dextran system, in which the active ingredient or antigen is encapsulated inside biodegradable microspheres made of modified dextrans (see Figure 1). The crosslinks within the microsphere network are ester bonds that hydrolyze under physiological conditions (37° C and 7.4 pH), causing the microsphere to degrade and release the antigen. The release profile, which can be zero-order or pulsed at a preset time, can be controlled by varying the microspheres’ water content and the number of crosslinkable side chains.

“The ultimate goal is to have at least the same level of immune protection from a single-shot product as you would have from a multiple shot vaccine,” says Gerben Moolhuizen, product director for OctoPlus. 

According to Moolhuizen, one of the advantages of OctoPlus’s technology lies in its manufacturing method. OctoPlus encapsulates the antigen in the microspheres using a double (water-in-water) emulsion, without organic solvents. No physical linkage occurs between the antigen and the microspheres, and the antigen remains intact. “We have one of the few technologies that releases these antigens in fully functional form,” says Moolhuizen. “That is a big difference compared to many other systems that are available.”

Under the agreement, SingVax will be responsible for manufacturing the JE virus in Crucell’s PER.C6 human cell line. Using PERC.6 would avoid the purification challenges and concerns about potential protein carryover that have been associated with the mouse-brain–derived vaccine, currently the only JE vaccine available internationally. “There’s been a very big push to get out of mouse brains and into proper cell lines that are well characterized,” says Douglas Thomson, CEO of SingVax. “We believe PER.C6 is a well-tried cell line, and the whole viral particle is a well-accepted antigen for Japanese encephalitis,” he says, noting that these factors influenced the decision to work on JE. “We certainly see a clear path through to get this product at least into the clinic and, hopefully, commercialization.” 

JE is a mosquito-borne arbovirus endemic in various parts of Asia. According to the World Health Organization, the disease is severely under-reported, with approximately 50,000 reported cases each year and 15,000 fatalities. SingVax estimates the market potential for a new JE vaccine at US $250 million, with substantial unaddressed opportunities in Japan, Singapore, Thailand, and Malaysia.

OctoPlus’s controlled-release drug delivery system encapsulates drug or antigen in biodegradable microspheres composed of modified dextrans. (Photocredit: OctoPlus)

Collaboration Targets Single-Shot Japanese Encephalitis Vaccine

In trying to bring pharmaceutical manufacturing regulation into the twenty-first century, the US Food and Drug Administration is doing more than talk. The agency is changing fundamental concepts of regulation and backing those changes up with initiatives to encourage process developers to keep improving their production systems—even after approval. 

As the first article in this series showed, some companies have refused to let outmoded thinking or FDA regulatory filings get in the way of streamlining manufacturing processes (1). Many of these companies are taking a "don't ask–don't tell" approach: through design-of-experiments and advanced real-time analytical methods such as near infrared spectroscopy, they are significantly improving their scientific understanding of their processes. Then, they use that knowledge to monitor operations and make processing decisions, but continue to run the validated test methods at the same time. This way, the company focuses on improving processes instead of on filing manufacturing supplements. 

Adding process monitoring and control elements in parallel with traditional fixed-target analyses, however, can yield only limited gains. Many industry experts believe that significantly improving pharmaceutical manufacturing processes requires a much more flexible regulatory system, in which communication between industry and the regulators is open and fluid, and in which continuous process improvement is an everyday reality.  

FDA already envisions such a world, and  they have christened it 

 (2). The agency has identified the structural problems to reaching that state; now they are trying to pave the road to reach it. Here is what they are doing. 

 recently asked Brian Hasselbalch, a compliance officer in the Division of Manufacturing and Product Quality in FDA's Office of Compliance, "How would you characterize the current industry approach to process validation?"			

His answer was simple: "With the number three."  

Hasselbalch was referring to the three batches that companies typically manufacture at commercial scale before applying for marketing approval of a new drug. If the three batches produced passing results, the thinking went, the process worked, and could be considered validated. The origin of that number lies in FDA's 1993 compliance policy guide on process validation, a document formally directed at agency staff but much read by industry. 

Table I: Types of regulatory filings for scale-up and postapproval changes to approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs).*			

In March 2004, the agency revised the guide, to signal its evolving thinking about process validation (3). In one of the most significant revisions, FDA deleted the reference to three batches at commercial scale as adequate minimum proof of process validity—a number is no longer suggested.  

The other significant change, says Joe Famulare, director of the Division of Manufacturing and Product Quality in FDA's Office of Compliance, was in the way the agency refers to those batches. "We no longer call them validation batches because validation is a life cycle approach and three batches do not represent validation," he explains. 

Hasselbalch says that both industry and FDA have focused too much on the absolute number of replicant runs. "And in doing so I think we've gotten away from the original intent of process validation, which had a strong design and development element to it," he says. "In fact, a careful read of the 1987 guide shows that we intended always that the replication at scale would be preceded by good design and development work."  

Updating the process validation guideline

The 1987 guide Hasselbalch mentions is the 1987 

Guideline on General Principles of Process Validation

 (4), often confused with the compliance policy guide on the same topic. When FDA released the revised compliance policy guide, it also announced its intention to update the much larger 1987 guideline. Although FDA will not comment in detail on the revision until the draft is made public (possibly before 2006), Hasselbalch says the agency plans to reflect more of a "life cycle approach" to validation. 			

"The design, development, and verification of the process capability has to factor in the information gathered during routine production," says Hasselbalch, because even well-designed and well-developed processes sometimes need adjustment. "Processes may need to be optimized to improve yield or to reduce margins of quality," he says. 

So there's hope that the new guideline  will make it easier for manufacturers to improve their processes after approval. In the meantime, can changes in the drug filing system also help? 

PQAS: New CMC review systems ease postapproval changes

FDA also is considering ways to give manufacturers flexibility by changing the way the chemistry, manufacturing, and controls (CMC) information is submitted in new drug applications—both NDAs and ANDAs. 

In Sept. 2004, the Office of New Drug Chemistry announced that it is developing a new system for quality review, to replace the existing CMC review process (5). Through the new "pharmaceutical quality assessment system" (PQAS), the office wants to receive more information in new drug applications about pharmaceutical development, manufacturing science, quality-by-design and its implementation in unit operations, and the scientific rationale behind a sponsor's proposals. 

The promise of this new system is that by having companies submit appropriate information about the scientific underpinning of their processes, FDA will be able to grant companies more latitude to make postapproval changes. 

The new system also will include a new quality overall summary (QOS). Moheb Nasr, PhD, director of FDA's Office of New Drug Chemistry, says the QOS will prompt companies to carefully review the critical aspects of their applications before submitting them, thus improving the quality of the submissions and saving reviewers time. "Now, we get tons of information without a coherent summary or description of what the application is about," he says, which makes it difficult to identify the critical CMC issues. The old system, he says, was like doing graduate research and handing in your laboratory notebooks; the new system is more like writing a manuscript to summarize and analyze the findings. In this way, he says, "the assessment of the CMC submission starts at the sponsor before it comes to us." 

 To pave the way for the PQAS approach, the agency is conducting a pilot CMC program (6). Through the pilot, FDA hopes to obtain additional information from companies that will help the agency develop and implement the new review system.  

The agency is seeking 12 pharmaceutical companies to volunteer to participate in the pilot program by submitting original NDAs. The announcement was made in mid-July; by the end of August, the agency had received five applications and several inquiries, Nasr says. 

"The CMC pilot program provides an opportunity for industry ... to share with us, in an open manner, the kind of scientific information they currently have, and provide the justification to allow for regulatory flexibility," says Nasr.  

For example, if a company uses design-of-experiments to study the effects of particle size distribution on a drug product's performance, it may be able to prove to FDA that particle-size distribution within a wider range will not significantly affect the performance of the drug product. "So when we set specifications, that specification would be a wider particle-size distribution, since we have the scientific evidence of its impact—or lack of impact—on the performance of the product," Nasr explains.  

This approach contrasts with the existing system, in which manufacturers typically submit limited data, based on a single particle size or a very narrow range. "So if you do a single experiment, and you carry it through manufacturing, that specification will be set around the information we have from that single experiment," he says. "When they come to us with a single point, what other choice do we have?" 

The international scene: ICH Q8, Q9, and Q10.			

Nasr notes that some companies already conduct the experiments needed for such justification, and he believes the pilot, and the new system, will encourage firms to share that data with FDA. "The data ... will result in fewer supplements and provide more freedom to manufacturers to continue to improve their processes," he says. 

				The new concept of "design space". 		

 The concept underlying this approach—of leaving companies in control of a limited set of changes within a certain set of parameters—is the idea of 

 which has been defined in the International Conference on Harmonization's (ICH) Q8 document on pharmaceutical development (7) (see sidebar, "The international scene: ICH Q8, Q9, and Q10"). 

Design space is a multidimensional space that defines the parameters and acceptable ranges of a process. Its boundaries are the limits of interrelated specifications, including time, within which product quality will still be maintained. Companies that develop and define their design space would have the opportunity for continuous improvement or optimization within the bounds of their design space, without the need to file CMC supplements or reports. In this scenario, postapproval continuous improvement would be managed within a company's quality system and subject to FDA's inspectional oversight for compliance with current good manufacturing practices (CGMPs). "The design space concept was intended to change the definition of change itself, saying movements within the design space are not changes," says Ajaz Hussain, PhD, deputy director of FDA's Office of Pharmaceutical Quality.  

Of course, granting companies such flexibility requires that the company be able to demonstrate a high level of process understanding. "[T]he information we will receive from the sponsor, [will] help establish the design space," says Nasr. "We will provide industry the opportunity, using their own existing robust quality systems, to manage manufacturing within that design space." And that design space can be large, he says, if the company has data to show that product quality will be maintained in a large space. 

					New FDA postmarketing division to support postapproval changes. 				

 To make the revamping of the quality assessment system work, Nasr is restructuring his office. Key changes include establishing a new branch for assessing manufacturing science and hiring staff with expertise in areas such as pharmaceutical development, pharmaceutical engineering, and physical pharmacy to complement the chemistry experience the office already had. And in the new system, each submission will be handled by a team of reviewers with varied expertise, rather than by the current single reviewer.  

After the restructuring, separate branches will handle premarket submissions (INDs and NDAs) and postmarket submission (CMC supplements). This will accelerate new-drug reviews by allowing one set of reviewers to focus their time and attention on INDs and NDAs without interruptions to review supplements. Second, it will streamline the review of postmarket changes. Currently, the review of postmarketing changes is scattered among 19 chemistry teams in 15 clinical divisions. "Now it would be consolidated to only one division, within our office," Nasr says.  

Third, the new postmarketing division will have a greater ability to evaluate the types and frequency of postmarketing supplements. This change, Nasr believes, could allow the agency to develop strategies and guidances related to what kinds of supplements could be eliminated and what kinds of changes could be down-regulated to less-onerous filing categories. 

				Question-based review for generic-drug filings. 				

 At the same time that this new review system is being developed in the Office of New Drug Chemistry, the Office of Generic Drugs is also developing a Question-based Review (QbR) system, that promises manufacturers regulatory relief if they submit more-complete product and process development data. In the current system, ANDA sponsors do not submit product development information or a quality overall summary. 

				"We will have more information about the way the product was developed and the way the process was developed," says Gary Buehler, director of FDA's Office of Generic Drugs (OGD).			

"With that additional information, we will be able to allow certain regulatory relief with respect to supplements." For example, a change that would normally require a company to file a prior approval supplement may only require that the company file a change-being-effected supplement. Thus, the Office of Generic Drugs is applying the concept of design space. 

Lawrence Yu, director for science at OGD, says that the office can even go beyond the design space submitted by the sponsor. FDA reviewers have a lot of accumulated knowledge, which they can apply when reviewing drugs. So in some cases, even if a manufacturer has not submitted data for a broader specification range, the agency may be able to grant some flexibility, based on its own knowledge. "We can make decisions based on the sponsor's data and our own internal knowledge base," says Yu. Buehler emphasizes that the agency would not use any proprietary information to allow other applications to get approved. "It's basically the information in the literature and the information that's accrued over the years that is available to us," he says. 

OGD hasn't worked out the details yet. Buehler says he expects the increased flexibility to be stated in the approval letter, although he doesn't know what kind of wording will be used. 

One way or another, the agency will find a way to make it easier for manufacturers to improve their processes. "We don't want to stand in the way of pharmaceutical innovation," says Buehler. "We don't want to stand in the way of companies being able to modify their process and make the process better." 

Comparability protocols—because we learn about processes as we go 

But what happens if a company doesn't have that much data available at the time of submission? That happens often. Because delayed approval of new drugs can cost millions of dollars, pharmaceutical companies typically don't want to delay filing by conducting extensive manufacturing studies. Later, through commercial operations, manufacturers often gain experience that would allow them to make process improvements. 

FDA has proposed comparability protocols for postapproval CMC changes. In its Feb. 2003 draft guidance, the agency described a way for companies to reduce the paperwork for postapproval changes by showing that what a company intends to change is comparable to what was in the original filing (7). Through such protocols, a change that normally would require a prior approval supplement could be down-regulated, so that it only requires  a changes-being effected filing. Similarly, other changes would move down a level from their standard filing requirements. 

The problem, industry experts say, is that the comparability protocols guidance focuses on discrete changes and recommends that companies don't combine too many changes in one comparability protocol application. This limits the usefulness of comparability protocols. "This is a step in the right direction, but I think for a true process understanding process change system to work, it has to be holistic," says Richard G. Whitfield, PhD, senior director and team leader of Global Quality Technical Services at Pfizer.  

Nasr says the agency understands those concerns and is revising the comparability protocols guidance to try to make it a more useful tool. "We are simplifying and streamlining the process," he says. But he quickly adds that the amount of regulatory relief provided by the agency must be proportional to the level of scientific evidence companies provide about their processes. "The better you understand your process, the more we are comfortable as regulators that you can operate within the design space without a problem. We have the responsibility to assure the safety and efficacy of the product, and we would be reluctant to let go [of control] without such scientific assurance." 

More flexibility up front; more accountability later

What this flexibility means is that more responsibility for compliance and maintaining quality shifts from FDA to the company.  

"It is not losing control; it's basically making industry more responsible for the product," says Nasr. "We at the agency do not discover drugs, do not develop drugs, we do not manufacture drugs. So what's our responsibility? Our responsibility it to make sure that the drugs, before they come to the market, [are controlled for their] critical quality attributes, to assure their safety and efficacy. And that means we have to evaluate information coming to us to provide that assurance without creating an environment that prevents or delays approvals or continuous improvement." 

Hussain agrees that regulatory flexibility won't mean a lack of regulatory control. Freedom to make low-risk changes in well understood processes without filing CMC supplements, he says, would be balanced by control over compliance with current good manufacturing practices. In other words, regulatory scrutiny would be applied through inspections for CGMP compliance. "It's not that continuous improvement change control is not regulated," says Hussain, "In fact, our regulatory hammer for penalizing somebody who doesn't do things right is higher on the GMP side than on the CMC review side." 

For years, pharmaceutical manufacturers have complained that federal regulations impede process improvements. Now, FDA is trying to do something about it.

FDA Lowers Barriers to Process Improvement

The translator strives for quality, for a flawless re-setting of ideas from language to language. It is precise, painstaking work, making sure that all the concepts are there, that the grammar and syntax are correct, that the register (the formality, the emotional and social tone) is accurate, and that the text reads smoothly.  

Translated literature, from the Bible to García Márquez, moves individual hearts and molds whole societies. Reading a translation, though, most of us think only of the product, and forget the process that brought it to us. Only in recent decades has academia deemed translation worthy of study. Even today, translating (in writing) and interpreting (in speech) are still somehow second-class pursuits (witness hospitals that ask the janitor to interpret in the emergency room). 

Yet growing numbers of people now realize the importance of understanding the key steps of translation: analyzing the original, transferring the concepts to the other culture, and restructuring them to fit the framework of another language. The translator asks many questions: Does this point hinge on culturally bound concepts that readers from other cultures won't immediately grasp? Was that metaphor an everyday expression in the source language, or a creative invention of the writer?  

Pharmaceutical industry professionals go through their own translation steps, as they transfer formulations into manufacturing processes, ultimately converting scientific concepts and raw materials into finished products. Yet pharmaceutical manufacturing, like translation, has long suffered secondary status. Pharma manufacturing, too, has focused on the final product, not the process that produced it.  

Today, however, all this is changing. Manufacturing scientists are shifting focus and FDA regulators are modifying rules to embrace dynamic models, trying to understand what the process does, not just what it produces.  

And like translators, the pharmaceutical industry and the regulators are discovering that quality is the journey, not the destination. 

 She is certified by the American Translators Association as a Spanish-to-English translator.

The translator strives for quality, for a flawless re-setting of ideas from language to language. It is precise, painstaking work, making sure that all the concepts are there, that the grammar and syntax are correct, that the register (the formality, the emotional and social tone) is accurate, and that the text reads smoothly.

Preserved in Translation

In 1987, when the US Food and Drug Administration issued its 

Guideline on General Principles of Process Validation,

 a young FDA reviewer asked her supervisors, "What does this term 

Much has changed in the past 18 years. So much has changed, in fact, that the current concept of process validation, once a fresh idea in quality control, and which later became accepted dogma, may now be ready for the trash bin. With companies achieving new levels of process understanding, what does it mean to validate a manufacturing process? Industry leaders and FDA are now examining that question and looking at new models to follow. 

				Although the 1987 guideline did not introduce the concept of validation, it did plant the notion firmly in industry. It defined validation as: 

establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes (1).			

That seems logical enough. The problem, many experts say, is that over time validation activities have become centered on documentation instead of on ensuring quality. "It's a forest for the trees situation," says Russell E. Madsen, president of The Williamsburg Group (Gaithersburg, MD, 

). "A whole industry grew up around process validation. It has resulted in a proliferation of validation protocols, validation reports, and validation documentation; but you still have processes out there that don't work." We've lost sight of the goal, Madsen says, "which is to demonstrate the process reliably does what it's supposed to do. It's as simple as that."  

 The continuous quality verification model 			

			Fernando Muzzio, PhD, a professor in the Department of Biochemical Engineering at Rutgers University (Piscataway, NJ, 

) says the main problem underlying the traditional approach to validation is that that we don't understand our manufacturing processes very well. And if we don't, our validation activities are essentially meaningless. "How can we agree to validate a process we don't understand?" he asks. "You know the old tale about the emperor's new clothes? Well, that's validation. Validation is, and always was, a fantasy." 			

The second key problem with the traditional approach to validation, Muzzio says, is it presupposes that if you don't change anything from the validation batches, everything will remain the same. But this assumption is false, he says, because neither ingredients nor processing conditions remain fixed. "There will be lots of little changes over time that operators will introduce, or equipment will be moved from one place to another, where room moisture may be higher or lower. We will get a new supplier for a given material, and the new material may be within specifications, but it could be different in terms of its particular morphology, flow, or one of 60 possible variables. It was never real that you could keep everything the same." 			

The fixed validation model also has a third major problem: It's based on an approach to quality control that relies on discarding bad lots to keep quality high. That makes for inefficiency.  

Philippe Cini, PhD, a principal at Tunnell Consulting (King of Prussia, PA, 

) explains it in terms of the Six Sigma approach to quality. "Right now, pharmaceutical products on the market meet a high quality standard—about 5.5 Sigma. So we have very, very few defects reaching patients or in the distribution pipeline," he says. But average industry manufacturing capabilities are at about 2.5 Sigma. "Today we close the gap from 2.5 Sigma to 5.5 Sigma by deploying quality management systems that screen out bad product once it's been made," he explains. "That's a very, very expensive way of manufacturing." 			

Ironically, the ingrained practices of validation, intended to ensure quality, have become an impediment to quality improvements. One of the first things any industry newcomer learns is that pharmaceutical manufacturers avoid altering an approved process—even to improve it— because any change requires regulatory filing, which can take a long time and involve a lot of paperwork. 

But the problem goes beyond that. Quality assurance staff have been afraid to even generate new data about manufacturing, much less submit them to FDA, for fear of giving the regulators the impression that they didn't understand their processes well.  

"Twenty years ago, when I was trained, I was told, 'Never generate data if you don't know what you're going to do with it,'" says Gerry Migliaccio, vice-president of Global Quality Operations at Pfizer (New York, NY, 

). "There's been a huge fear that if you have data about your processes and you can't explain it, you're setting yourself up." 

The truth is, when manufacturers launch a new product, usually they 

 know that much about their manufacturing processes. Most companies don't want to delay filing for drug approval by spending a long time developing the commercial manufacturing process, because every additional day a product is on the market can mean thousands of dollars in sales. So it's not until 

 approval that a manufacturer generates large volumes of data about the process—from its commercial operations.  

Today, however, the mentality is changing, and some companies are willing to spend time and effort studying and improving their processes. 

New technologies, and a change in thinking, are working hand-in-hand in this shift. The pharmaceutical industry is starting to catch up to other industries in the use of online monitoring technologies such as near infrared (NIR), Raman, and acoustic spectroscopy to gather more in-depth data about processes. FDA's guidance on process analytical technology (PAT) was important in encouraging the adoption of these technologies (2). The PAT guidance also was important in another way, because in it FDA addressed industry's fear of scrutiny. The guidance expressly states that FDA will not examine manufacturing data collected for research purposes. This guidance spurred some companies to study their processes. It also brought out of the closet process improvements that quality control managers were already making but not talking about. 

A poll conducted last year showed that only 11% of respondents felt their companies had a high level of understanding of PAT, but more than 60% felt PAT could assist with quality control concerns such as identifying critical sources of variability and preventing scraps and rejects (3). There are several strategies for bringing more sophisticated process models into the manufacturing floor. AstraZeneca, Genentech, and Pfizer all have programs, for example, but each illustrates a different approach to different goals.  

Changing without filing: fixing broken processes

Pfizer's primary focus is on studying older, problematic processes, with the aim of reducing variability.  

In one example, Pfizer had high failure rates for a reaction step in the manufacture of an active pharmaceutical ingredient (API), at a cost of more than $125,000 per batch. When the quality control team applied spectroscopic methods all along the process, it traced the problem to an unsuspected failure of an earlier reaction step which formed an intermediate ingredient, Precursor A. Studies from NIR monitors revealed that about half the time, the Precursor A formation reaction never occurred. The application of new technology was required to discover this. 

"Because this was a cryogenic process, occurring at –20 °C, we didn't have an effective way to sample it," says Laurie St. Pierre Berry, PhD, a senior development scientist with Pfizer's Process Development Laboratories in Groton, Connecticut. "When we starting using NIR monitoring, we were able to see what was going on."  

Berry and her team discovered that variations in a moisture-sensitive raw material were causing the problem. Now the team is working to try to understand and control the raw material variations. In the meantime, Pfizer can now monitor the Precursor A formation reaction and scrap batches earlier in the manufacturing process, before they reach API synthesis. This saves money, and it saves time. 

Tim Marten, PhD, vice-president of global compliance at AstraZeneca (London, UK, 

), says his company also applies spectroscopy to reduce variability in difficult processes for currently marketed products. First, the manufacturing team uses probes and sensors to gain a better understanding of the critical variables. Now, with this increased understanding, the quality control staff collects and analyzes data online and uses them to monitor and control process steps. 

"We've managed to increase our throughput of successful batches quite considerably, by not having products sit around waiting between stages—because instead of doing the analysis 

 we've finished, we've done the analysis 

 the processing," says Marten. "That's made an enormous difference to both pass rates and lead times."  

The usual response to examples like these is, What do the regulators require to allow companies to replace laboratory tests with online monitoring? But Pfizer and AstraZeneca aren't letting regulatory filings inhibit their quest for process understanding. Instead, they are continuing to run their standard laboratory analyses even as they gather data with modern analytical techniques and apply that data to  process monitoring and control.  

"Pfizer's program is really about process understanding," says Migliaccio. "Some companies are working hard toward real-time release, but for Pfizer, that's a tertiary goal. Our priority is to reduce the number of deviations, to get to definitive root cause, to reduce cycle times." Migliaccio says the reason is limited resources. "We believe the biggest gain is eliminating deviation, rather than eliminating finished-product release testing." 

			AstraZeneca also is running its online analysis in addition to its laboratory tests, and Marten is pleased with the benefits they have achieved by reducing variability. He would like to take the use of these technologies further, however, to eliminate end-product testing. "Ultimately, quality control analytical testing at the end should be a thing of the past. In the long-term future, we would expect that good process understanding and good monitoring of the parameters during processing will assure us that the product we make is the one we want to make. We won't do quality control testing in the end, because it will add nothing—we will already know this is the right product." (See Sidebar, "A dynamic approach to quality control"). 

) has taken a different approach. Its focus has been on applying design of experiments to gain a thorough understanding of a new product's manufacturing process before filing for FDA approval. With one of its latest drugs, "Avastin" (Bevacizumab, a recombinant monoclonal antibody for treating metastatic colon and rectal cancer), Genentech used carefully designed, statistically valid experiments during the development stage to quickly zero in on which process parameters were critical to ensuring product quality. 

Although one would expect such studies to delay the product's release to the market, Ron Branning, vice-president of commercial quality at Genentech, says this approach actually saved them time.  

"In using these methods, you save time because you know what the critical process parameters are much more quickly than by using any other technique." He explains that in using a design-of-experiments strategy, developers may start with 20 or 30 parameters that could be critical. A set of well-designed, statistically valid experiments might then indicate that only a few of those factors are critical, in a very narrow range. Then, one can repeat just a small number of the experiments to confirm the results, focusing on the key factors, instead of conducting 30 or 40 runs to gather the same amount of data with the same statistical validity.  

"That's a lot faster than doing a very large number of experiments and then trying to correlate data," says Branning. "I believe this approach helped us with a rapid review and approval of Avastin." 

What about the cost of doing all this manu-facturing science? Clearly, the manufacturers most visible in this effort are Big Pharma companies with the greatest resources. But in some cases, the benefits have been shown to outweigh the costs. FDA cites figures that the costs associated with pharmaceutical manufacturing can far exceed those for research and development operations (4). Others point to the cost of noncompliance: Ask any company with a consent decree how much it has spent on remediation.  

Migliaccio also sees the investment as time and money well spent. Pfizer has a policy of treating projects to improve manu-facturing as a research investment; anyone who proposes such a project does not have to submit a return-on-investment analysis. As a result, Migliaccio can't attach a cost savings number to the company's work on process understanding, but he thinks the allocation of resources is beneficial. "We're looking at problematic processes that we were already throwing a lot of resources into anyway, because of the time and effort spent trying to resolve deviations and find root cause. We have certainly shifted the amount of time our quality control staff spends resolving problems to more fulfilling work in proactive quality improvement." 

With Avastin, Genentech decided not to rush to file with incomplete data, and the company feels this strategy paid off in several ways. Branning says the submission was easier for FDA to understand, leading to rapid review and approval; the development of batch records was easier; and it reduced the amount of validation work, because fewer parameters had to be validated. "And we had ironclad, statistically valid data to base those decisions on," he says.  

Since approval, the company has also found the ongoing monitoring and control of the manufacturing process easier. "We find that we have fewer discrepancies and investigations, and when we have those, they're easier to resolve," Branning says. 

So where do the industry and the regulators go from here? Focusing on good science is imperative. "It doesn't need to be exhaustive science," says Branning. "It just needs to be good science, that focuses on the issues at hand. We need to get people to understand that that's the fundamental necessity." 

Muzzio agrees, and thinks that the leaders will bring the rest of the industry with them. "Over time, whenever a higher quality standard becomes clearly achievable, it becomes part of the expectation. The bar rises naturally."  

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

3. D. McCormick, "PAT Survey Reflects Optimism, Uncertainty," 

Innovation and Continuous Improvement in Pharmaceutical Manufacturing. Pharmaceutical CGMPs for the 21st Century 

(FDA, Rockville, MD, Sept. 2004), p. 8; available at http://

www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

In 1987, when the US Food and Drug Administration issued its Guideline on General Principles of Process Validation, a young FDA reviewer asked her supervisors.