Companies must make the investment to develop the good science, the proper product and process characterizations, the properly
derived quality system and product-control frameworks. "Companies are still not getting the essence of good product and process
characterization and how it drives into a risk-based control framework to make sure we are really controlling the things that
are critical to the product build," says Garvey.
An FDA inspection team will have these concepts in mind. "FDA likes to see risk management or risk assessment introduced in
the decision-making process regarding things like change control, product release, and product recall," advises Peter D. Smith,
vice-president of pharmaceutical compliance at Parexel Consulting (Lowell, MA). "Inspectors get an impression from a company
if they talk about a risk approach in decision-making. It's good for them to hear."
The risk-assessment plan involves getting everyone in the company on the same page. As a former FDA investigator, Carmen Medina
performed more than 200 inspections. Now a principal at Tunnell Consulting (King of Prussia, PA), she says it's easy to sense
disparities between various operating units, even before walking into an inspection site, based solely on a company's documents.
These disparities often are related to quality standards or prevalent risk within the company. In many cases, companies might
focus on making sure pivotal batch records and corresponding data are acceptable.
Investigators are trained to perform what's called a top-down assessment. "Twenty years ago, investigators walked in looking
at inadequacies in individual documents and manufacturing deviations and how those deficiencies impacted products in the field.
Today, we're looking at, 'What is the level of risk in a company that could potentially impact every single product within
the entire operation?'" says Medina.
This difference is important because it means each division in a company needs to be on the same page in terms of the level
of risk they are facing and how seriously it should be taken. For example, a quality unit may seem to be more stringent when
it comes to the release of a batch that underwent a manufacturing deviation than the head of manufacturing might be because
they place the deviation in a different perspective than quality assurance. Or a manufacturing unit may be more concerned
about limited resources than the company's executive management might be. These conflicting priorities must be recognized
and reconciled before an inspection begins.
It is too early to ascertain how FDA's most recent risk-based initiatives such as process analytical technology and quality
by design will affect inspection preparation. Two opposing approaches to quality, one solidified in ensuring sameness and
the other based on process understanding, are resulting in "a great deal of conceptual, scientific, and regulatory uncertainty,"
says Garvey. "If the agency is serious about moving these initiatives forward, they are going to have to be highly tolerant
of mistakes and missteps of companies along the way."
One of the major issues for the agency is one of follow-through, notes Garvey. "If the agency doesn't provide an extremely
consistent, aligned approach between how they actually conduct the inspections and their publicly stated intentions, any progress
made to date will be in jeopardy."
Do your research
"Failures don't just come from noncompliance with the regulations, but also out of industry expectations and industry standards,"
says Medina. Even though industry expectations are not yet codified into law, investigators may inspect against them and against
that particular trend.
For this reason, there is an entire body of documentation that any company preparing for an FDA inspection should study beforehand
in addition to CGMPs. "Review professional publications and go to conferences," advises Medina. "Obtain all the pertinent
CBER [Center for Biologics Evaluation and Research]and CDER [Center for Drug Evaluation and Research] guidances and compliance
programs. Get your hands on FDA's investigator inspection manual and read the preapproval inspection (PAI) sections. Obtain
any recent 483s issued in situations specific and similar to your industry. If you're a small or big manufacturer, read about
those that apply to you so you begin to know what the FDA investigator is scanning for when they walk in. They prepare before
heading to your site, so you should as well."