INDUSTRY-WIDE APPROACHES, OR CASE-BY-CASE NEGOTIATIONS?
Participants also questioned what regulatory guidance documents should say regarding what information companies must provide
regulators about noncritical parameters, and more broadly about their overall manufacturing control strategies, including
movement within and at the edges of a design space.
"We need to be able to translate this discussion into something we can share with people outside this room," said Brian Withers,
director of CMC regulatory affairs at Abbott and an industry rapporteur for the ICH Q11 guideline on drug substance development
"A lot of these issues about critical and noncritical process parameters are fundamentally review issues and will be handled
in negotiations with the review team," noted Patrick Swann, deputy director of the Division of Monoclonal Antibodies in the
FDA's Office of Biotechnology Products. "Yet I share Brian's concern. Can't the guidance provide a little bit more than saying
'the fundamental issues are review issues'?" Failing to provide guidance, he said, would lead to heterogeneity, with important
matters being handled differently from reviewer to reviewer.
"Perhaps we can suggest a risk classification system linked to the control strategy," suggested Kowid Ho, a quality assessor
for biological products at AFSSAPS, the French regulatory agency. Depending on the level of risk associated with a given process
parameter, he said, different actions would be taken.
"For example, if a range were exceeded for a given parameter, in some cases that might require an extensive internal investigation
that may lead to a regulatory submission, whereas for other parameters it might require intermediate levels of testing," he
said. "Others might not require much action at all."
"That's a very good idea," said Kozlowski. "Companies would manage their noncritical process parameters in their quality systems,
but would share information in advance about how they would do that."
Other participants fleshed out this idea, suggesting that companies could present the information in a tabular format, describing
the types of changes they could foresee making, either within the design space or outside it, including the additional testing
they would do and how they would report it.
Stefanie Pluschkell, an associate research fellow in global CMC at Pfizer, countered that no matter what was included in guidance
documents, case-by-case negotiations would always be necessary.
"We may propose something and the regulators may disagree, in which case we may need to add more parameters to a design space,
shrink the design space, or add more to our control strategy," she said. "These are not things you can put in a guidance;
they will need to be negotiated."
Also, Pluschkell cautioned, excessive standardization of the rules might hinder companies' ability to make postapproval manufacturing
improvements without regulatory oversight.
"Quality by Design is about continuous improvement," she said. "If we don't have that, industry won't see the gain in doing
Quality by Design."
DO WE TRUST RISK ASSESSMENTS?
Jon Coffman, a principal engineer in biotherapeutic pharmaceutical science at Pfizer, commented that it was ironic that the
group was focusing so much energy on noncritical parameters. The purpose of risk assessments, of course, is to do just the
opposite—to concentrate on the areas of greatest concern.
He presented this as a challenge to everyone in the room. "So what it comes down to is this: Do you believe in quality risk
Kozlowski responded that the process of letting go is tricky, and requires a certain level of trust. "It's a bit like when
your child goes off to college," he said. "At first, you want to have a lot of phone calls. Eventually, over time, you may
become comfortable that he or she is acting responsibly and needs less attention."
Laura Bush is the editor in chiefof BioPharm International, email@example.com