Quality by design (QbD), risk-based manufacturing and process analytical technology (PAT) have become three cornerstones of the U.S. Food and Drug Administration’s effort to modernize pharmaceutical and biotech manufacturing. While FDA has not promulgated an official definition of QbD, there is a general understanding at the Agency of the major elements. According to Moheb Nasr, Ph.D., Director of CDER’s Office of New Drug Quality Assessment, QbD incorporates five ideas:
- A “system” approach, where drug products are designed to meet patient needs and performance requirements.
- Design of a process that is consistently capable of meeting critical quality attributes.
- Thorough understanding of the impact of the starting materials and process parameters on product quality.
- A strategy for identifying, understanding and controlling critical sources of variability are identified, understood, and controlled.
- Process monitoring that enables continuous, consistent quality.
According to this roadmap, the QbD philosophy is identical for biologics and small molecule drugs, although the individual unit operations vary considerably.
Some of these ideas have been in place at top companies for years while some, particularly the “system” approach, is new. The prevailing tack today is empirical rather than system-oriented, with process optimization as the trump card. Through the system approach, the process is designed to meet product criteria, while the product is designed to address clinical needs. Other novelties here: a control strategy for understanding variability and assuring consistency over time, and the acknowledgement of risk and variability. “In traditional processing we avoid variability,” Nasr told Pharmaceutical Manufacturing. “Here we face it as a fact of life.”
To support industry’s adoption of the system approach, FDA has instituted a CMC Pilot Program, managed by the Office of Drug Quality Assessment. The program allows companies to share their QbD experiences through their New Drug Application (NDAs). Most major worldwide pharmaceutical manufacturers are participating. But this program is inherently limited, Nasr says. For industry to realize the full benefit of QbD, it must develop and adopt novel manufacturing platforms, for example continuous vs. batch processing.
Industry is enthusiastically but cautiously testing FDA’s position, attempting to gauge what level of regulatory flexibility will accrue through information-sharing. FDA, meanwhile, promises that if companies are forthright, they will be freer to introduce manufacturing changes without resubmitting the process for regulatory review.
Sufficient examples in pharmaceutical industry lore suggest that industry “talks the talk” with respect to regulatory initiatives to keep FDA happy, rather than adopting the new program on its merits. QbD is apparently not one of these. “The evidence is in their investment in new technologies and platforms. They won’t do that just to make us happy, there has to be a strong business case,” Nasr says.
FDA has already approved an application through its CMC pilot program, but the long-term benefits of QbD are still unknown. “It looks promising, but until we have a number of applications approved this way, it will be difficult to measure the financial rewards.”
In the Beginning
The starting point for QbD in biopharm is the realization that products are heterogeneous mixtures consisting of multiple active and inactive isoforms, plus numerous other proteins and impurities. Bioprocessors tend to worry more about productivity and yield, especially when a product’s heterogeneity is part of its regulatory application. Yield is a more critical factor in supply than isoforms, but some products, notably Immunex’s Enbrel monoclonal antibody for rheumatoid arthritis, depend on very narrow glycosylation patterns for their activity.
Marta Czupryn, Ph.D., Senior Director for Bioprocess Development at Wyeth Biopharma (Andover, Mass.) defines QbD as “achieving acceptable mixtures of product isoforms, such that the product meets purity and other acceptance criteria.”
|A Wyeth BioPharma scientist performs mass spectrometric analysis of a biopharmaceutical product candidate.
Wyeth QbD efforts begin with a defined process beginning with cell line selection and continuing through cell culture and purification. Quality is enhanced by streamlining and defining standardized production methods, all the while applying analytical methods that indicate if the design has led to products that meet specifications. “We’re sometimes surprised,” says Czupryn, “but at least we can detect problems early on.”
One method used at Wyeth is high-resolution mass spectrometry (MS), which easily discriminates among isoforms differing by a single sugar residue. Peptide mapping plus MS, which is applied to digests of protein mixtures, is even more sensitve, according to Czupryn. Where glycosylations represent the only significant differences, it is possible to utilize an orthogonal technique, releasing the sugars and analyzing the peptide backbones for mass and sequence.
MS analysis has been automated in laboratories, to the point where hundreds of samples are run untouched by human hands. But this is still a far-off dream for cell culture, where everything is done offline, some distance from the fermenter. “In a PAT world, this type of analysis would be done inline or at-line,” Czupryn notes, “and if certain isoforms can be correlated with process conditions, one could change bioreactor conditions appropriately. But that’s in future.”