FDA seeks volunteers for QbD pilot with biotech drugs; CDER officials outline benefits at DIA.

FDA's Office of Biotechnology Products is seeking drug companies to volunteer for a quality-by-design (QbD) pilot, this time on defining "clinically relevant attributes for complex products and linking them to the manufacturing process," according to a July 1 Federal Register notice.

According to the notice, the pilot also will "consider quality by design approaches to unit operations in supplements" and "explore the use of protocols," describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect for specified types of manufacturing changes on drug safety, purity and potency.

In the notice, comparability protocols were suggested since they have been used for single manufacturing changes. FDA wrote:

"Protocols based on quality by design submission will focus on critical quality attributes to chemistry, formulation and process design. Such will be referred to as Expanded Change Protocols," which will describe the QbD risk based approach linking attributes and processes to product performance, safety and efficacy.

FDA's Office of New Drug Quality Assessment conducted a pilot in 2005 for QbD in chemical drugs.

According to the Register notice, the OBP pilot will provide more information to FDA for use in facilitating QbD and risk-based approaches for complex molecules.

"OBP will work with each participant on an individual basis. Pilot submissions will be either original applications or manufacturing supplements.

"Based on experience gained during the pilot program and prior knowledge, FDA will develop procedures to facilitate implementing a QbD risk-based approach for complex products" and guidance to industry as a result.

The pilot is limited to 10 supplements to be submitted by March 31, 2010, and five original applications, either BLA or NDA. Explaining QbD at the annual Drug Information Assn. annual meeting in Boston last month, Arzu Selen, associate director of biopharmaceuticals at the Office of Pharmaceutical Science, said:

"Quality by design is continuous improvement based on product knowledge and process understanding. It is both product and process, with continuous improvement as the goal, and resulting in patient benefit. If quality is defined as patient benefit, there are three critical considerations: product, manufacturing process, and understanding the sources of variability."

Selen sees a strong connection between quality by design and biopharmaceutics. "In biopharmaceutics, applying quality by design principles helps determine key product characteristics, develop and verify in vitro methods and characteristics against target product profile, identify relationships between product attributes and in vivo performance, determine sources of variability, and build on knowledge through an iterative process," she explained during the conference.

Selen outlined three considerations critical for quality "if quality is defined as patient benefit" -the product is designed to meet its intended use and consistently delivers the desired or intended dose; the manufacturing process is designed to consistently meet the product critical-quality attributes and is suitable for continuous monitoring and updates and allows for consistent quality over its lifecycle; and understanding the main sources of variability due to starting materials and process, methodology and assumptions, and product-patient interface.

The key concern, according to Selen, is that "there is a continuous link from the product to the process to the patient, and back again." Both in vitro and in vivo considerations need to be taken into account.

"The question to ask is, what in vitro characteristics will achieve the in vivo target?" said Selen. "Is it rapid dissolution and release consistent with early onset? Or rather extended release for optimizing patient compliance? What is a significant change in in vitro dissolution-release? What is the clinical relevance of in vitro methods? How can in vitro dissolution-release be altered to achieve the in vivo target?"

In vivo studies elicit similar questions, such as which prototypes should be tested in vivo, and whether the in vivo study is designed to address a specific question such as prototype selection or general PK assessment.

Finally, the question concerning process and product knowledge and experience must be posed: is there adequate data demonstrating understanding and knowledge of the process and product?

So what would be a possible quality by design approach? "First, determine the target indication, route of administration, and target patient population," said Selen. "Then identify the desired in vivo drug performance. Next, investigate and identify quality attributes--like particle size, tablet hardness, excipient ratio, or moisture content--that best link the drug release to the manufacturing process. Then you can develop in vitro drug release methods that are linked to quality attributes so that the method is suitable to track changes during development and for quality assurance throughout the product lifecycle."

She went on, "In parallel to these activities, estimate the therapeutic range and the maximum acceptable variability, and continue to refine the in vitro method during clinical development as a part of the quality by design efforts. This should be going on before the NDA submission! Finally, if it is necessary, simplify the predictive in vitro dissolution-release method and link the release test to a clinically meaningful or predictive test that can be used to quantify changes."

"Advancing available tools and exploring novel in vitro testing approaches," concluded Selen, "can harness the potential in in vitro methods. Application of quality by design principles can facilitate development of quality products and lifecycle assessment, and ultimately result in greater patient benefit."

Tahseen Mirza, director of technical R&D at Novartis, sees quality by design as a "continuous improvement vision." Quality by design "starts with defining the target product profile, then identifying the knowledge baseline, then developing a control strategy, then doing quality monitoring, and finally arriving at the summit of this peak, which is quality by design that includes continuous improvement."

The pharmaceutical industry has not advanced in every area over time, Mirza asserted. "The norm is still batch processing," he said.

"There's a static manufacturing process: specifications are based on discrete or zerotolerance criteria, and release testing is done post-manufacturing."

But he conceded that change is coming, and it's coming from FDA. "The regulatory environment is changing and investment in new tools and technologies will result in innovative systems in manufacturing, while product and process understanding will give regulatory flexibility. Most importantly, quality will be designed in the product ... as opposed to testing in the product."

Correspondent Jeannette Cezanne contributed to this report

Validation Times Staff