“One Wing and a Prayer”

Today I am having a little fun with the title of this blog entry…  We have seen multiple recent FDA Warning Letters for OTC or other non-application products as the regulators around the world respond to catastrophic ongoing public health emergencies.  These Warning Letters are for serious and basic failures, such as the lack of incoming raw material evaluation and/or lack of a process validation program (e.g., products containing glycerin). 

Note: I did not use “lack of process validation”, as that would suggest that process validation is a one-time activity involving three batches and a report no one really ever uses. 

You might initially dismiss these Warning Letters as not relevant learning opportunities for application-based GMP facilities, as I once did (to be completely honest).  However, there is a wealth of knowledge regarding CurrentGMP expectations (diamonds) hidden in the rough (egregious basic GMP deficiencies).  The most recent Warning Letter as of the writing of this entry is dated 31JAN2024 (WL# 320-24-18).  Check out this guidance, and let’s break it down:

“You have not validated your manufacturing process used to produce homeopathic drug products, including those intended for infants and children. During the inspection, you indicated that you were not aware of the requirement.”

– Yikes!  No comment here.

And now the learning part:

“…you must assure that your production process is capable of assuring all of your drugs are of acceptable quality, identity, strength, and purity. During process validation, the process design should be evaluated to determine if it is capable of reproducible commercial manufacturing.”

– Here we see FDA point directly to Design as the key ingredient to Quality assurance.  The quality of commercial product is uncertain without a demonstration of good design principles.  Passing the PPQ protocol requirements does not itself demonstrate good design.  Rationale: PPQ batches are typically done under heavy scrutiny, as the are required for entry into the market, and are not representative of commercial manufacturing (e.g., volume/resources/etc.).  A mature organization already knows this, so supplements these limitations with a plan for the future = “vigilant monitoring” (data & process mapping + qualitative risk assessment)

“A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.”

“This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.”

– Here we see a focus on the “validation program” for PPQ batches and commercial manufacturing, as discussed earlier. 

Q: How can we demonstrate adequacy of the “validation program”? 

A: Via knowledge of the variability inherent to each process step (remember the DI guidance? variability arises from the four scoundrels: Hardware, Software, Personnel, Documentation). 

What you plan to vigilantly monitor depends on the outcome of your variability assessment (aka risk assessment)!  Again, this is necessary because of the non-representative nature of PPQ batches.

– Let’s be honest, there is no way to determine the capability and reliability of each manufacturing process step and its controls via a traditional PPQ protocol/report.  If we rely on this report alone, we might refer to that as a “wing and a prayer”. 

FYI (a bit of history here): “a wing and a prayer” probably originated from the film Flying Tigers (1942), where planes were barely able to return to base after flying over the “hump” or Himalaya range as they brought in supplies to China during WW2, hence: “coming in on one wing and a prayer”. We cannot enter commercial manufacturing on “one wing and a prayer” - we can do better than that!

Conclusion: Process Validation is how we demonstrate quality, despite all the unknowns that come with batch manufacturing (meaning we cannot test each individual unit).  It is a combination of development and design experimentation, risk management, traditional GMP controls, psychology and culture.  What it is definitely not: a compliance report that simply consumes energy on some server in an attempt to be “inspection ready”…  Honestly, I think we need to start moving away from that term “inspection ready” – it causes unnecessary fear and panic among staff, which never adds value.  Just be confident in your processes and inspections will become an afterthought.

Pete