The goal
of a validation is to assure that the equipment and process produce acceptable
product (CGMP and ISO definitions, e.g., 21 CFR 820.3z (1, 2, and3)), repeatedly, and reproducibly. The
product is verified by adherence to validated process / equipment parameters
and/or QC inspections (100% automated (validated) or sampled) / verifications.
And to assure such, the PQ runs should incorporate all foreseable allowable
variations in inputs, especially allowable worst case variations, e.g., RM (raw material), personnel, work shifts, power variations,
tolerance ranges of all acceptable settings, et al. Failure to do any of this
results in the many production "surprises" that appear to be behind
most product recalls. So, getting back to the original question, one's production equipment / process validation should include several PQ runs with
varying lots of RM -- which can be a challenge with silo / rail car /
truck-trailer loads of the same lot of RM, different products expected to be
run on that line, the different work shifts, and week ends / holidays,
different acceptable power / compressed air loading, ..., if the line normally
runs then, and similar considerations.
With large incoming RM lots, e.g., APIs (Active Pharma Ingredients) or plastic resin lots (molded plastic parts), I might choose to run three PQs at least to validate the process and that first RM bulk lot. Then release lots having that RM bulk lot could be released to the field. Then as another bulk lot came in, I would run at least one more PQ using the new lot, to quality that FG lot using the new RM lot to be released. I would then do one more PQ on the next bulk RM lot, to qualify it. If there were no evidence of major variability in those three RM bulk lots, I would probably then consider the process with it's "worst case" allowable RM lots to now be fully validated, unless further QC / CAPA monitoring pointed to some additional problems.
Why a minimum of 3 lots? The FDA has backed away from 3 as a de facto minimum for PQ runs; and with good reason. One run proves nothing. Two runs does not prove a pattern. Three runs may if there's minimum variability between process inputs. But in many cases, more that 3 may be required, as in the example of bulk RM mentioned above. Other examples of allowable "worst case" inputs, were as alluded to in the first paragraph: If your production runs 24/7/365+, then you might want to do 3 runs on 1st shift weekdays, to prove the process design, and add a 3rd shift, and/or a Sunday, and/or a holiday, or all, for a total of 4, 5 or 6 PQs to cover potential problems caused by reduced supervision, casual attitudes of operators, impaired behavior of operators, or similar, due to odd shifts and/or holiday work. A further example of allowable worst case variables could be software / apps platforms, e.g., iPhones, Android phones, iPads, tablets, Macs laptops, Surface laptops, Android laptops, Mac desk computers, PCs, Unix, mainframes, servers, and so on, each with it's own PQ if required.
Another consideration alluded to above might be a company's electrical and/or compressed air variability in it's internal grid, e.g,. brownouts, especially when every one comes in to work at the same time and throws the power on to each of their workstations. If product is produced at that time, some may be compromised, not getting the full amount of electricity or air that the validated parameter settings imply, until the grid(s) stabilize. UPS and surge tanks may help, but these are some examples of considerations in validations I often see omitted.
Your company's unique situation and it's allowable varying worst case inputs would assist in making such a determination. A cause and effect diagram can help in determining worst case allowable process inputs. -- John E. Lincoln, J. E. Lincoln and Associates LLC; jelincoln.com
Another consideration alluded to above might be a company's electrical and/or compressed air variability in it's internal grid, e.g,. brownouts, especially when every one comes in to work at the same time and throws the power on to each of their workstations. If product is produced at that time, some may be compromised, not getting the full amount of electricity or air that the validated parameter settings imply, until the grid(s) stabilize. UPS and surge tanks may help, but these are some examples of considerations in validations I often see omitted.
Your company's unique situation and it's allowable varying worst case inputs would assist in making such a determination. A cause and effect diagram can help in determining worst case allowable process inputs. -- John E. Lincoln, J. E. Lincoln and Associates LLC; jelincoln.com
Updated: 06/20/2022
Recently I had to disagree with several postings on a popular validation forum on the minimizing of the importance of several (more than 3) PQ (Performance Qualification) runs in a validation.