If the effective version generated during protocol generation is the same as what is being used on the production floor, then
it is safe to initiate the process validation production runs. If not, there is a high probability that the protocol may be
inaccurate (possibly resulting in numerous "failures") or that the process itself is not ready for process validation or even
worse, commercial production.
For example, during a recent process validation activity at a liquid dosage pharmaceutical plant, modifications were made
to the MBR less than a day before the already approved protocol was to be executed. Certain processes were modified without
the knowledge and consent of the validation team. As a result, there were numerous deviations (i.e., investigations) that
needed to be documented and addressed during the execution of the process validation production runs. This was due to the
approved protocol not stating the correct directions to follow, which resulted in a big waste of time and money-let alone
questioning compliance (i.e., the ability of the quality system to catch issues prior to and during production). If the MBR
status was verified as a prerequisite, this issue would have been caught prior to executing the runs.
Operator and test personnel training verification. In manufacturing as well as in the analytical laboratory, many standard operating procedures (SOPs) and analytical test procedures
are used. As the purpose of process validation is to provide assurance of the repeatability of a process, operators and analysts
must be trained on all procedures that may affect the manufacturing and testing of the process. This prerequisite checks the
training records of the operators and laboratory testing analysts to ensure that they have documented training on the procedures
that they will be performing during the process validation activity. Again, not only is this a compliance risk, but it is
also good business practice as failures due purely to untrained operator or analyst errors result in additional consecutive
process validation production runs (i.e., avoidable wastes of time and money).
For example, during a recent pre-approval inspection of a pharmaceutical manufacturer, an investigator was reviewing the executed
process validation protocol for the product being assessed. The investigator asked to see the training records for two of
the analysts who performed the release testing on the finished lot of product. When given those records, the company realized
that the two analysts had not been trained on the test procedures. This situation called into question the validity of the
test results and ended in the company repeating the costly and time consuming testing. This situation would have been easily
avoided by verifying training prior to execution.
Equipment and utility system qualification verification.
Just as an individual marathon runner chooses a very specific pair of running shoes to compete in versus a pair of everyday
flip flops, equipment and utility systems are two of the most critical areas affecting the outcome of a manufacturing process.
It is important to verify that the commercial equipment and support utility systems have first been qualified and second have
been qualified within the specified process ranges prior to executing the process validation manufacturing runs.
Not only is the lack of equipment or utility system qualification a common gap discovered during inspections, and for which
entire process validation efforts been disregarded, but many unforeseen commercial production issues may arise when these
activities have not been completed prior to process validation production runs. This situation was clearly demonstrated when
a coating process for a solid oral dosage pharmaceutical was developed and optimized at a specific spray rate using a process
development pan coater. The pan coater used during the process validation runs, although similar in function to the process
development pan coater, was not challenged during equipment qualification at a spray rate that bracketed the intended use.
When the process went into validation, the difference in the spray nozzles caused the commercial pan coater to be unable to
consistently obtain the specified MBR specifications for spray rate.
In this case, the entire batch was lost because the problem was discovered after the coating process was already in progress.
A prerequisite verification of equipment qualification would have avoided the loss of a potentially saleable batch as well
as the requirement to run a new set of consecutive process validation batches.