Draft Guidance 211.110 (Process Validation & Control)
Like many in industry, I was somewhat surprised by the publication of the FDA draft guidance earlier this month, titled “Considerations for Complying With 21 CFR 211.110”. My first thoughts were publication due to the need to clarify the phrase “vigilant operations management oversight”, which is often cited in modern Warning Letters when sites lose focus on quality operations. As I read through the document, which is quite short, I found this may hold some truth, but really I found what appears to be a summary of already existing guidance (which are each listed at the conclusion of the document…). I had to read the document a second time to determine if there is any new guidance and/or expectations included. After a second reading, here are some of the key takeaways, in my opinion, although I could argue that these have been around for some time already:
In-process monitoring/sampling should not be considered solely a compliance activity based on traditional manufacturing strategies. The strategy for any in-process sampling/monitoring should be based on a risk assessment and process knowledge. This has been built into the regulation since forever via the use of the phrase “where appropriate”, which is included in both 110(a) and 110(b), we just haven’t been very good at demonstrating what is appropriate. Each process has its own unique characteristics, which should be identified and evaluated according to QRM principles, and not just based on the strategies used since the late 1900’s. Here we find some language largely drawn from the existing data integrity guideline: “Manufacturers must maintain the process in a state of control over the life of the process to ensure drug product quality, even as materials, equipment, production environment, personnel, and manufacturing procedures change”.
This is largely aligned with the components of a validated workflow outlined in the existing FDA DI guidance: “hardware, software, personnel, documentation”. Basically, if you are going to sample, monitor, or both, make sure your rationale for why you do what you do is based on risks that exist within the workflows, in addition to other factors such as chemistry/etc.
The guideline clarifies the definition of a “significant phase”, and follows up the discussion with an example of a process where only minor adjustments are permitted. If effective controls over changes to parameters are achieved via technical means (e.g. access controls), there may not be a need to implement extensive Quality Unit oversight. A simple review of a batch summary may suffice.
I very much like the inclusion of this example, as it backs up the existing guidance provided in the PIC/s guide for Data Governance, and provides a practical example of “review by exception” or a “risk-based approach” to QA oversight. Basically, don’t waste resources on extensive monitoring and oversight if you have invested in process understanding and digital solutions. This action would not be “significant”!
Use innovative means for process monitoring. Options include traditional offline testing (expensive and error-prone), in-process monitoring, or a combination of in-process monitoring and mathematical modeling. The latter is better, if possible!
Advanced Manufacturing is not quite ready to go live, unfortunately. In the final section of the guide, we find additional guidance largely in line with Q8, QRM and PAT existing guidance. Advanced manufacturing is no doubt the future, so what is the delay? It appears that proposals submitted thus far have lacked scientific rationale. For example, a lack of a QRM strategy for an “unplanned disturbance” that may occur during the process. Without a thorough QRM plan established where extensive hazards (planned and unplanned) are evaluated, it is unlikely that we as an industry can move forward in this space. It seems we need more work in this area.
In summary, I see FDA publishing a brief reminder that QRM is not optional, regardless of whether the dosage form has been around forever (e.g. rapid release tablets), and a statement on the current state of affairs regarding future technologies for process control (it’s not ready to go live). I see this publication largely in response to the record number of drug shortages being experienced in the past year… The root causes largely being attributed to “manufacturing and quality issues”. Basically, we need to get better at what we should have been doing since forever = QRM.
Pete
