Consider the example of a drug manufacturer of a liquid suspension. The manufacturer retrofitted the processing equipment
of a decommissioned true-solution production line, which seemed like a cost-effective alternative. Mixers were added to all
the tanks to ensure even distribution of the suspension in all mixing and holding vessels. The process was readily validated
as the firm applied its long-standing process knowledge of liquid manufacturing.
Just days before the new product launch, a uniformity problem emerged. Batch records confirmed continuous tank mixing, and
laboratory records confirmed that all testing was in control. Yet, across-the-lot sampling revealed portions that were subpotent
and portions that were superpotent.
The manufacturer failed to recognize that tanks were not the only place where even distribution of the suspension was necessary.
Upon further investigation, it was discovered that there were periods when filling was stopped to deal with downstream filling
issues. Although mixers kept the suspension adequately mixed in the tanks, there was no in-line mixing for the long process
lines connecting the equipment train. Although process lines were thought to account for a relatively small proportion of
the total volume, the settling of the suspension in the lines during lengthy down times effectively redistributed the active
ingredient across the filled containers.
The manufacturer complied with its policy to validate its manufacturing processes. However, mindful compliance is based on
identifying and controlling risks. Critical control points of the process are identified and validated, and data from these
points are monitored in routine production to ensure continuous control. In this example, loss to the company and the potential
for a patient adverse event could have been avoided by a disciplined approach to identifying and controlling risk based on
Quality System Knowledge
Quality systems knowledge is the collective awareness and experience of designing, integrating, and implementing written business
process instructions that drive consistent behaviors to meet requirements effectively and efficiently. A quality system stabilizes
operations by ensuring that required practices are performed consistently and predictably yield the intended result.
FDA cited a biologics manufacturer for an excessive number of open investigations of process deviations and customer complaints.
There were hundreds of open investigations, many of which had been open for over 90 days and several over six months. The
company promised in its response to FDA to triage the backlog to close out the most important investigations in 30 days and
the balance in 60 days. The procedure for conducting investigations was revised to require future investigations to be completed
within 30 days. The revised procedure was part of the company's response to FDA. To management's surprise, FDA reported that
a subsequent inspection following a customer complaint revealed that the situation remained essentially the same. The open
investigations may have been different ones, but the numbers were just as high.
The manufacturer failed to recognize that a revised procedure alone does not change behavior. Concerned about FDA enforcement
action for the repeated citation, management conducted its own investigation into the failure to adhere to the new 30-day
closure requirement. Many issues were discovered that required management's attention. Foremost was preponderance of the same
deviations and complaints, pointing to a lack of thoroughness in investigations of the root cause of the problems. It was
also noted that current protocols demanded the same degree of rigor for investigating a minor documentation error as a serious
adverse event. Everything was given the same priority, and the system became clogged. Combined with administrative duplication
and lack of accountability, it became apparent that the situation required far more attention than just a wording change in
The manufacturer had policies and procedures constituting a quality system. However, mindful compliance recognizes that policies
and procedures of the quality system live in relationship to each other and within an overall management context. In this
example, the potential risk to the consumer and the enforcement risk to the manufacturer could have been avoided by looking
beyond a single procedure. The process of conducting an investigation needed streamlining, and the rigor of the investigation
needed to be based on risk. There were also training and accountability issues. Management realized it needed a means other
than FDA inspections to learn that the quality system was not functioning well.