Understanding critical quality attributes will help Pfizer develop robust design spaces and, ultimately, achieve real-time release, said Gerry Migliaccio, senior vice-president of network performance for Pfizer Global Supply, according to In-Pharma Technologist. Migliaccio made his remarks at a meeting of FDA’s Advisory Committee for Pharmaceutical Science and Clinical Pharmacology. Using QbD as a basis, and process analytical technology to establish manufacturing controls, Pfizer believes it will be able to reduce quality-control costs, achieve real-time release, and quickly get a return on its investment.

But not all companies are rushing to adopt QbD. Manufacturers of small-molecule generic drugs fear that spending the extra initial time and effort to adopt QbD could prevent them from being the first to file an application for their products. “If you’re not first to file, you may as well be last,” said Yatindra Joshi, vice-president of generics R&D for Teva, at the same FDA meeting. Consequently, some generic-drug manufacturers aren’t willing to gamble that the benefits of QbD will outweigh the profits lost by not being first to file.

If Pfizer and other heavyweights adopt QbD, it could boost patients’ confidence in the safety and efficacy of marketed drugs. But patients would benefit even more if generic-drug manufacturers felt freer to pursue this initiative. By making some elements of QbD mandatory in filings, FDA could “level the playing field,” said Joshi. This idea seems like one plausible solution that could be of advantage to the industry and consumers alike.

For FDA’s evaluation of the QbD program so far, please watch for Pharmaceutical Technology’s September issue, in which CDER’s Helen Winkle and Moheb Nasr analyze the initiative’s present and future.

The session on sequence variants was introduced by Kathleen Francissen of Genentech, who asked, “What is acceptable and what is not”; as analytical methods approach the inherent “error rate” of biosynthetic processes and the actual risk of sequence variants is somewhat unknown, the answer to that question is a moving target.

The first presentation on sequence variants by John Stults, also from Genentech, considered both angles: detection and subsequent risk assessment. Detection of sequence variants, which are unintended amino acid substitutions caused by mistranslation or mutation, is not new. But traditionally, detection has occurred at the cell line development stage during sequence variant screening (if a sequence variant is detected, the cell line is abandoned). Importantly, detection capability is increasing; because of the discovery of a sequence variant late in Phase III development, Genentech implemented earlier systematic sequence variant analysis on both normal and extended cell age samples. If a sequence variant is discovered during extended characterisation, risk assessment is performed by a cross-functional team based on several principals, not least risk of immunogenicity.

There are several issues with measuring immunogenicity risk though. One is the limited scope of in silico assessments or animal models; another is the inability to measure low frequency immune responses in the small patient groups of Phase I/II studies.

So what is the regulatory perspective? Chris Holloway of ERA Consulting Group provided some extreme examples. In one instance, a client was considering the impact of a sequence variant discovered at Phase II. They were told it was certainly a concern – especially as the variant occurred at a level of 45%! He went on to point out though that generally (and presumably at much lower levels!) there was very little experience relating to the actual impact of sequence variants. Whether the risks are real or perceived, impurities are a fundamental quality attribute, and Holloway pointed out the need for batch-to-batch consistency.

In concluding, Holloway stressed the need to start the analytical methodology early on to detect sequence variants, memorably stating, “if only stock prices were linked to analytical method development, we would be a lot better off!” Much laughter ensued. Along with long list of recommendations to reduce regulatory risk, he stated that perhaps the single most important point was the need to fully investigate all factors that could conceivably affect sequence variant levels during process development.

A last key recommendation, backed by a case study, was to secure retained samples for future discoveries; it could alleviate regulatory concerns if a new variant is retroactively discovered in a legacy product.

When asked by a delegate how many batches were required to prove consistency, with reference to the oft-discussed three-batch minimum. Holloway pointed out the fallible nature of human pattern prediction by asking us to consider data from three batches: 20, 40, 30 ppm – ok, looks good. Now consider 20, 30, 40 ppm – is the process drifting? And 40, 30, 20 ppm? The team is improving…! Perhaps three-batch validation really is obsolete…

In the panel discussion that followed, there was more debate yet few solid answers over the risks of immunogenicity. But what everyone appeared to agree on was that if any level of sequence variant is found, extensive investigation is required; regulators will demand that sufficient data is presented to alleviate risks – whether real or perceived.

Conducted in Basel (Switzerland) in mid-June, the workshop was fully attended, but relatively small, such that it could “foster a feeling of closeness and networking”, according to Richard Levy, senior vice president, scientific and regulatory affairs at the Parenteral Drug Association (PDA). And indeed it did; the numerous coffee breaks were a great opportunity for industry peers and regulators to mix and continue discussions initiated in presentations. Perhaps any bigger, and the sense of relaxed community would be lost… The workshop kicked-off with a wonderfully candid and standout presentation by an assessor from the Danish Medicines Agency, and, as with many of the regulators, it came with a disclaimer: the contents herein are “not a promise of approval!”  The presentation focused on the regulatory perspective of a control strategy in the QbD paradigm, and elicited a number of gasps from the attendees. Not least the statement that shifting quality control upstream as part of a risk-based control strategy could, in theory at least, mean an end to product release testing—something that, the speaker said, would come as a surprise, even to regulators!

There was a call for more openness and transparency in application dossiers. The situation was likened to an iceberg, of which the tip represented release tests (specifications) and the actual contents of the dossier, and where the bulk of the iceberg was hidden underwater: extended characterisation, process controls (procedures, materials, in-process testing, monitoring, validation)—all information and knowledge within the company not routinely included in the dossier and yet some parts of which are accessible at inspections. (A further comical analogy was made to a teenage daughter, the tip being what the daughter told her mother, and the rest being what she was thinking of doing…) Either way, the message was made quite clear: companies cannot provide too much information about process knowledge gained in terms of control strategy.

Another question that raised interest was “how do we determine critical quality attributes (CQAs)” in terms of control strategy. Of course, this has no straight answer, but the message here was that it may change over time as knowledge is gained or if even small changes are made to the production process. From regulatory experience, it seems that the definition and understanding of CQA is clear in the dossier, but the rationale and designation is often lacking or absent.

The second presentation of the day was from Stephanie Schnicke of Roche Diagnostics (unsurprisingly, being in Basel), and also focused on control strategy, putting forward strategic considerations for design. Roche has addressed the difficulty of determining CQAs and non-CQA by assigning an “impact score” to all using a risk-based approach, which took into account four impact areas: pharmacokinetics/dynamics, biological activity, safety and immunogenicity. The latter of which caused debate for the entire conference, and by necessity perhaps the subject of an entirely separate blog post…

Throughout the post-presentation discussions (and to certain extent within the presentations) it was clear that regulatory bodies had limited experience (by their own admission) in QbD applications, put down to the simple fact that so few “full-blown” applications have been seen. European regulators have looked to FDA for advice and example, where the QbD paradigm shift has far more momentum—FDA absence at the workshop was no oversight, however, as it would have “substantially changed the atmosphere” of the workshop, according to Jim Lyda, Senior Science & Regulatory Affairs Advisor for PDA.

Questions over what should or should not be included in dossiers is clearly a sensitive issue for companies who feel the need to protect certain information for future process flexibility, but, as the first presentation concluded very poetically, “Let us, together, find the right balance.”

If a company is authorizing installation of equipment that is not understood by the operating personnel then we have a two-fold problem. 1) Personnel do not understand the basics of the process needs and have installed a wrong equipment, and 2) Authorizing managers have not asked right questions to challenge the expenditure. This is a clear case of “lack of understanding of the fundamentals.” It is a case of trying to climb Mount Everest without understanding the challenge and proper gear.  

Corporate culture has nothing to do with QBD or PAT. Companies have a basic goal (i.e., deliver the expected profit to their stakeholders). They have been able to deliver the profits using inefficient processes. They do not see any need to change. Consumers have paid for these inefficiencies, as they want to extend their life.

Unless we totally understand the fundamentals of active pharmaceutical ingredient (API) manufacturing and API-excipient blending process (i.e., chemical interaction and operating parameters), we will not have command of the process (i.e., first time quality will be elusive). Complete understanding of the interaction and the right instruments will tell us where we have gone “off-course” and how to command the process. Until we have the understanding of fundamentals and use them properly, we will not have a perfect process or close to it that will deliver quality. Innovation will automatically come, as it is a human trait.

Innovation has to evolve at the profit making company rather than at an external agency, an expenditure body. Regulatory bodies can demand quality and the operating companies have to deliver quality. However, any expenditure that will reduce their profit margins like now, will meet resistance.

I have to ask a question: “Does anyone really understand QBD and PAT” and if so, can the answer be written in one sentence not exceeding 25 words? If we can, we have simplified the definition of pharmaceutical innovation and we will meet the quality objectives.

Dr. Srinivasan and her colleague Robert Iser, also a team leader at OGD, spoke to the PharmTech audience today about the question-based review (QbR) initiatve started by OGD in 2007 and how it’s being used as a “diving board” into QbD implementation for the generic drug industry. The idea behind QbR is to get a company’s thought process “into the application.” Similar to the messages delivered at yesterday’s sessions, Srinivasan and Iser pointed out that industry needs to change the way it thinks. They spoke about how quality is a life cycle requirement; it shouldn’t start when a failure occurs, which tends to be the traditional pharma industry response.

To date, more than 95% of generic drug applications, or ANDAs, are being submitted to FDA in the QbR format. This is good news, they report, but generic drug applicants still need to spend more time on understanding their manufacturing processes. Just because there is already an innovator product on the market doesn’t mean that information can simply be copied. Although the route of administration and dosage strength may be the same, generic firms still need to look at their own product design, process, container-closure systems, and quality attributes. Comprehensive impurity testing, excipient comparability testing, and scale-up testing are of utmost importance.

This is exactly how QbD can enter the process for generics early on, explained Iser. Working QbD into the product design to help understand what you’re making, the product’s purpose (including the ultimate consumer), and how to make it with upfront testing is key to having a quality-based product. You can’t just tell FDA that your product is equivalent based on certain studies, you have to demonstrate how it is equivalent, you have to justify it, said the speakers. Including any failed bio studies with ANDA submissions—a requirement as of July 15, 2009—will go a long way in this regard.

FDA does foresee QbD being applied to the generic drug industry in the future, said Srinivasan and Iser, but because of the unique timing/patent issues and design space issues, there are additional considerations that need to be worked out. Right now, the QbR format is meant to help the generic industry start thinking about the concepts needed for science and risk-based approaches to product developing and manufacturing. The next stage is to implement these concepts, said the speakers. But the fundamental questions to keep in mind for now are:

• Is your product designed to ensure the desired performance?
• Are you able to scale up and still meet that desired peformance?
• And are you able to manufacture that product within the defined quality paremeters over time?

We’ve all heard that quality by design and science/risk-based approaches to pharmaceutical manufacturing require a paradigm shift among industry. Well, that message was reinforced again today at the 3rd Annual Pharmaceutical Technology Conference in Philadelphia, PA.

Christine Moore, acting deputy director of the Office for New Drug Quality Assessment at FDA, said that industry needs to be more willing to share information with regulators. In the past, industry may have been afraid to share details for fear of receiving more questions from the agency. But with the quality initiatives being undertaken by FDA, said Moore, it’s now okay to say, “There are risks with our product.” FDA just wants to know that you can control those risks, she said.

It’s also important to make sure your company has the financial and management support it needs to implement quality by design and quality systems. You have to be able to colloborate with and work with other departments and functions involved in your product’s life cycle, including with other regions in our growing global pharma market, explained Moore.

Gerry Migliaccio, vice president of quality at Pfizer Global Manufacturing, added to Moore’s point. Pfizer, says Migliaccio, has seen first hand all the benefits that can come from using QbD-based manufacturing, including saved cost and time. But to accomplish this, the company had to change its thinking. For example, instead of approaching a problem with corrective action, they focus on continuous improvement throughout the product’s full life cycle. Instead of analyzing proven acceptable ranges, they focus on design space. Instead of working toward blind compliance (i.e., doing what works to obtain regulatory approval), they work toward science- and risk-based compliance, which satisfies the regulators and can be justified scientifically.

This shift in process and thought is not expected overnight but it is taking over the industry. Moore reported that FDA is now receiving more QbD-based applications than it received during the CMC pilot program, which began in 2005. But, added Migliacchio, more culture changes are pending. With fading blockbusters, increasing costs, and additional IP challenges and safety concerns, industry also needs to be rethinking its full supply chain and examining it in ways it never has before. For example, said Migliaccio, Pfizer is now sending its ICH Q8 managers on site to ensure that suppliers are using and following a quality system. The company is also working to monitor pricing and supply gaps and working to help emerging markets that have immature regulatory systems to learn how a process and quality management system should work.

FDA and industry worked together the past several years to draft, approve, and implement the ICH quality guidances, Q8, 9, and 10. But today, much more work is outsourced to markets outside of the ICH region, such as India and China. It’s up to industry, says Migliacchio, to train the companies we outsource to. And if they don’t comply, we have to avoid buying from them or contracting with them. This requires yet another cultural change among pharma. But all of these changes—this re-education if you will—are critical to keeping our supply chains and products safe.

The quality trio guidances aren’t meant to teach industry about quality, said Dr. Cappuccino, industry has been manufacturing quality products for years. The guidances are meant to help industry address quality issues. Quality isn’t supposed to be “tested,” it’s supposed to “built in,” explained Dr. Cappuccino, who provided the following example of a traditional quality approach compared with today’s enhanced approach.

A traditional product approach might include these steps:

• Gain market input
• Develop API
• Formulation
• Develop process
• Implement finished product control, including submitting any changes via a regulatory supplement.

The enhanced approach, discussed in ICH Q8, 9, and 10, proposes these steps instead:

• Create a target product profile
• Conduct a risk assessment
• Complete API studies as well as formulation studies (this is where design space enters the process)
• Conduct process studies and develop a control strategy
• Control  process
• Real-time release
• Note that any changes or improvements within the design space do not require regulatory supplement filings.

The overall benefit of compiling more information in the beginning and understanding more about the process is that manufacturers have more flexibility and less regulatory oversight, said Dr. Cappuccino.

Additional quality sessions are being held later today and tomorrow at the PharmTech conference. Stay tuned for more blog posts. And also stay tuned, says Dr. Cappuccino, for potential ICH guidance revisions. Being considered by the steering committee are changes to Q3A/B and Q6A/B in light of Q8, 9, and 10. Also coming soon from ICH are a third group of Q&As that address the quality trio guidances. Two groups of Q&As are already on the site at www.ich.org.

In his plenary address, Jim Thomas, PhD, vice-president of the process and product development group at Amgen, spoke about the benefits and challenges of QbD principles in biologicals. He set the scene by quoting a recent article that predicted that in 2014, 7 of 10 top selling drugs will be biologicals. Moreover, biotechnology drugs will account for 50% of the top 100 drugs in 2014, compared with 11% in 2000 (versus conventional drugs). But, said Thomas, the challenges were many. The costs of drug development and treatment are high. Intellectual property issues and the growth of follow-on biologics will have to be addressed. In addition, he listed at least 25 major attributes of molecules that, if modified, would have an effect on a molecule’s pharmacokinetics. “We need to pay attention to these attributes because of concerns over safety, efficacy, and stability,” said Thomas. The long-term solution, he said, is innovation, specifically in formulation, better production methods, and in deliverying protein therapeutics. “Innovation will be key to future success,” said Thomas, who then discussed in detail Amgen’s work in antibodies, peptibodies, and avimers as examples.

Amgen is working with the US Food and Drug Administration and other companies to understand how to apply the philosophies of QbD in they way they develop protein therapeutics, particularly “based on a fundamental understanding of the science of building quality into the molecule.” The process, said Thomas, starts with a core design knowledge (”what works and what doesn’t”), which must then incorporate what he referred to as “systematic learning” or “buckets of information” that include analytics (including top-down mass spectrometry), biological aspects, and the process itself. The keys are trying to link an knowledge of the molecule with analytics and then linking the analytical characterization of the molecule to the biology to define the critical quality attributes.

The main challenge in doing this, says Thomas, is that there will be a significant initial investment to apply QbD to biologics, but these costs should decrease for platform modalities. The application of QbD to nonplatform molecules will be much more costly. An investment in high-throughput technologies is necessary, he said. Other challenges include the need for sophisticated knowledge of antigen systems, linking molecular structure to biological attributes, and applying risk-management tools to help define the design space. Thomas said Amgen is taking “gradual steps” in applying QbD in it’s processes and will “soon” have evidence of QbD in its regulatory filings.

An afternoon session in process analytical chemistry echoed much of these challenges and future benefits of implenting QbD. In a session titled “What can the Biopharmaceutical Industry Learn from the Use of QbD in Small Molecule Production,” Mel Koch, PhD, of the University of Washington’s Center for Process Analytical Chemistry (CPAC) reviewed the fundamental principles of QbD and how the advancements in measurement science (miniaturization, new materials, data processing, etc.) have helped trigger the need for implementing these principles in bioprocessing. Areas of interest, said Koch, include the characterization of media, nutrient quality, sampling, and microfermentation for optimizing bioprocesses.

A keen eye on science and built-in quality … biotechnology is indeed on the verge of great innovation.

Janeen Skutnik, chair of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) and director of quality and regulatory policy, global regulatory CMC at Pfizer, spoke of the importance of QbD. IPEC-Americas has formed a working committee, the Quality by Design Product Development Committee, to consider issues relating to excipients and QbD. She emphasized that the goal of QbD is to enhance process understanding, which includes understanding the variability of raw materials such as excipients in a specific formulation and manufacturing process. She underscored that QbD involves building robust formulations and processes that can adapt to this variability while maintaining the performance and quality of the pharmaceutical product and does not simply mean creating tighter and tighter specifications for excipients. “QbD does not equal tighter specifications for excipients,” she said, but instead she said that QbD is used to facilitate the understanding of the functionality of an excipient in a given formulation and manufacturing process.

As discussed by Skutnik, enhancing excipient user–supplier collaboration is an important aspect of building the shared knowledge that is critical to developing the deeper understanding required in QbD. This symbiotic relationship between excipient user and supplier not only produces technical benefits, but is also at the center of a productive business relationship, a point emphasized by Alex Pena, purchasing manager at Schering-Plough, who spoke on business and operational excellence in materials supply. He discussed the importance of building a “win-win” relationship in which both suppliers and the pharmaceutical customer benefit. He emphasized the value in building collaborative business models to meet the increasing complexity of a global pharmaceutical supply chain.

What these issues—QbD and optimizing supply-chain practices—tell us is that the relationship between excipient suppliers and pharmaceutical-company users will continue to evolve to meet these ongoing challenges.

Applicable to both large- and small-molecule drugs as well as APIs (but not medical devices), the new draft guidance takes FDA’s quality-by-design and life-cycle approaches by the horns and aims to steer industry even farther down this new track of pharmaceutical manufacturing.

The draft guidance, expected to be finalized by the end of 2009, says McNally, breaks down process validation into three stages: process design, process qualification, and continued process verification. This third area focuses on what industry has often referred to as “revalidation,” but FDA is trying to get out of that mindset and no longer use that term. Gone are the days where three batches of qualified product meant it was time to go to market. Rather, “reproducibility” and “periodic evaluation” are critical, said McNally. “The three batches aren’t important…it’s what you’re looking for in those batches that’s important,” she said.

The overall message behind the draft guidance, she explained, is that companies need to have enough data—and the right data—to feel confident about their product and to be able to justify to FDA and patients why their process and end product will be safe and effective time and time again. FDA’s goal is for manufacturers to better link process development to their commercial process so that a true life-cycle approach is carried out (QbD, PAT, and the ICH quality guidelines really come into play here).

Some webinar participants questioned whether the draft guidance applies to legacy products. “There’s no need to go back to five-year-old DOE records or open new studies and processes,” said McNally. But most companies who are concerned about quality are reviewing their products and processes at least once a year and when companies go through this activity, they may want to keep the draft guidance’s third stage in mind, she said.

Other concerns arose from participants regarding potential conflicts with other existing guidelines such as ICH Q7A and the aseptic processing guidance. McNally said that the new draft guidance is not meant to conflict with any current standards, but that any foreseen problems should be submitted to the agency as part of the review-and-comment process.

Of note, said McNally, the comment period is being extended by 30 days from Jan. 20 to Feb. 20, 2009 to allow industry more time to provide feedback. Comments can be submitted electronically at www.regulations.gov.