European regulators have announced that they, along with the US Food and Drug Administration (FDA), have released a second question-and-answer document intended to provide guidance to industry on the concept of "quality by design," or QbD.

Background

The QbD concept is well-known within most regulatory circles. Simply stated, it is the belief that quality should be designed-not tested-into the final product, including its manufacturing processes. In theory (and regulators say in practice as well), this results in fewer compliance problems because a manufacturer addresses problems before they exist, and more systematically when they occur.

In the pharmaceutical sector, QbD concepts are broadly incorporated into the regulatory systems of any region that uses the International Conference on Harmonisation (ICH) and its Q8, Q9, Q10 and Q11 documents.

Both FDA and the European Medicines Agency (EMA) have been pushing QbD concepts heavily in recent years.

"CDER is focusing on ways of improving its assessment of quality," said Howard Sklamberg, director of the Center for Drug Evaluation and Research's (CDER) Office of Compliance, at the 2013 RAPS conference in Boston. "We're in the process of forming an Office of Pharmaceutical Quality (OPQ)," which would combine many review functions-good manufacturing practices and chemistry, manufacturing and controls, for example-that are currently spread throughout various CDER offices into one office."

The goal, Skalmberg said, is to adopt a "lifecycle approach to reviewing products," much in the same way that regulators within industry often work.

Richard Friedman, associate director of the Office of Manufacturing and Product Quality, also within the Office of Compliance, elaborated on the importance of quality at the same conference. Asked Friedman, "We must ask ourselves, in an area where the stakes are so high, why are high degrees of quality not being achieved?"

The Pilot Program

In March 2011, EMA and FDA announced the launch of a pilot program they said was intended to allow them to better communicate review findings with respect to QbD elements of applications chosen for review. Regulators said the pilot program is meant to allow simultaneous review by both regulators of certain aspects of the application-in this case, QbD elements-allowing for an expedited and more thorough review process.

Under the program, applications "are submitted to either both agencies at the same time resulting in a parallel evaluation, or either to EMA or FDA in which case the agency doing the evaluation obtains consultative advice from the other agency," EMA wrote in its Q&A document.

"This parallel assessment aids sharing of regulatory decisions and facilitates the availability of consistent quality pharmaceutical products throughout the US and EU," FDA wrote in a statement.

Q&A Guidance

In August, EMA and FDA released a question-and answer document with advice on several aspects of the QbD process based on what they had learned through their participation in the pilot to date.

Some of the initial advice regarded:

• submissions of Quality Target Product Profiles (QTPPs) and Critical Quality Attributes (CQAs) (both should be provided)
• the use of Key Process Parameters (not supported by ICH or FDA/EMA)
• expectations for manufacturing process descriptions (same comprehensive level of detail should be provided to regulators regardless of the approach used)
• the use of analytical target profiles (ATPs) for analytical methods (acceptable, though with certain qualifications)

At the time, both regulators said additional Q&A documents would be forthcoming, and now a second Q&A document has been released. The slightly longer three-page document contains nine questions and answers, including:

• Why would a design space be verified during the product lifecycle? (There are risks inherent in scaling-up or making new model assumptions, and it is necessary to understand these risks.)
• What is the purpose of design space verification at commercial scale? (to demonstrate control over the product and its quality)
• How is a design space initially developed and verified at commercial scale? (based on experiments conducted at laboratory or pilot scale, which requires subsequent validation at larger scales)
• How can a design space be verified at commercial scale? (It is not necessary to repeat at commercial scale the experiments initially conducted to define a design space at lab or pilot scale, but should be guided by the results of risk assessments.)
• How should design space verification protocol be addressed in the submission? (General and specific requirements for both EMA and FDA are explained.)
• What if unexpected results/events are obtained during the design space verification studies? (The results should be studied and, if necessary, reported to regulatory authorities.)
• How can a design space be verified at commercial scale for biological products?  (The principles are the same for both chemical and biological products.)
• What is the difference between process validation and design space verification? (Process validation demonstrates consistency of the process at normal operating ranges, design space verification demonstrates that scale effect and or model assumptions are under control in the new area of design space and do not affect product quality.)
• How should design space verification approach be addressed in the pharmaceutical quality system? (Firms should have a written plan for when and how to evaluate the need for design space verification.)

As with the August 2013 document, EMA and FDA said further Q&A documents will be released in the future.

FDA/EMA Q&A Report

EMA Press Statement