Since the issue of Process Analytical Technology (PAT) guidelines by FDA in 2004, a variety of in-line non-invasive sensors have been introduced and implemented on pharmaceutical manufacturing processes to provide real-time process monitoring and control. Most process analytical technologies have been developed for the manufacture of formulations with high drug loads. However, there is a lack of sensitive and robust analytical tools to provide real-time monitoring for low-dose drug formulations (<1%, w/w). Pharmaceutical scientists have used techniques such as light-induced fluorescence (LIF), x-ray fluorescence (XRF) and laser-induced breakdown spectroscopy (LIBS) for real-time monitoring of low-dose formulations with limited success in both development and manufacturing. Given the popularity of continuous manufacturing for drug substance and drug product, and the criticality for real-time analytics for control of these processes, there is a need for a process analytics tool providing an ability to monitor sub-percent drug levels in pharmaceutical liquid and solid formulations..
RFI ISSUED NOVEMBER 4, 2019
QUESTIONS DUE DECEMBER 31, 2019
RESPONSES DUE JANUARY 31, 2020
Instrument performance (reliability, robustness) across long term usage: Could you expand on this requirement, please? Our instrument would have a periodic internal calibration routine (which would be fast to run and not interfere with the measurement) that would activate during the run to maintain calibration. Are there any restrictions on calibration during the run?
Calibration during the run should not be an issue. Historically, LED-based LIF instruments suffer from temperature variability during long term use. This would be a reliability and robustness issue.
Dynamic API concentration range sensitive by the instrument: I don’t quite understand this requirement. Is this effectively the limit of quantification (LOQ)?
This is the range of concentration we would like the instrument to be sensitive to. Since the proposal is targeted for low-dosed formulation, the target concentration is below 1% (w/w).
Sample size: Is this the sample size of the product – i.e., the statistical samples per batch? It seems to be sampling volume of the dosage unit, i.e., whether you are sampling all of the tablet or only a part. Can you please clarify?
This understanding is correct. The sample size means the volume of sample interrogated by the intended analytical technique. For instance, the sample volume by a spectroscopic tool on a single tablet is reported not to be the full tablet, instead a portion of that.
Accuracy/sensitivity in a matrix environment: Does the matrix environment refer to a blend with API in, i.e., tablet or powder?
Yes. Either tablet or powder is composed of a mixture of API and other excipients. Matrix environment means the interference from other excipients, such as lactose and microcrystalline cellulose, etc.
I see that the RFI desires a robust analytical tool for real-time “Monitoring” for low-dose drug formulations in sub-percent drug levels in liquid and solid formulations. I also see that existing techniques are LIF, XRF and LIBS. We do have the ability of detecting, analyzing (measuring with 30 size and shape parameters), concentration measurement, and saving photos of each measured particle using dynamic image analysis. This technique is also a number-based measurement tool which allows for low concentration levels; however, I am not sure what the Project Sponsors are looking for when they state they want to “Monitor” for these particles. Are they interested in looking for some in-line version of LIF, XRF, or LIBS, which seem to be more qualitative in nature? Or are they looking for any technique that can detect, identify and quantify each particle in-line / on-line?
Preferably, we would like to have quantitative measurement down to sub-1 percent concentration range of API in either final blend or oral solid dosage form and the measurement needs to be amenable for a process application (preferably inline). LIF, XRF and LIBS have been tried by pharmaceutical researchers with very limited success. If the advance of in-line version of these aforementioned techniques can deliver either the minimum or preferred requirements, the project sponsors will be interested to take a look at the proposal. It is not a requirement for the intended technique to identify and quantify each particle in-line or online.
Accuracy objective “in a matrix environment” …… Preferred requirements “Equivalent to reference methods (HPLC)”. Can the Project Sponsors clarify this please?
Either tablet or powder is composed of a mixture of API and other excipients. Matrix environment means that the demonstration of sensitivity and accuracy need to be within a representative composition including common excipients, such as lactose and microcrystalline cellulose, etc.
I noticed that the RFI states that the goal is to create a prototype, I imagine if a product already exists on the market then this would be acceptable and probably favourable to the project sponsors – could you confirm? Pending some sort of evaluation of course.
The team is willing to receive a proposal for a product currently on the market. Existing capabilities should be indicated in Section 5.2 for each requirement.