Greetings, loyal readers, I have a treat for you this month. After attending IFPAC ‘23 (San Juan, Puerto Rico) and presenting a paper last summer, I got to spend a day at the University of PR, Mayagüez, with the group led by Dr. Rodolfo J Romañach and Dr. Rafael Méndez. Their bright and courteous grad students are doing some cutting-edge work with PAT and continuous manufacturing, and I would like to share one of their super inventions with you all.

Since I only have a cursory idea about the unit described herein, I asked Prof. Romañach to give me write-up about the history and operation of the stream-sampler they invented. This is merely one of the many projects his group of talented students is performing. I regret that I cannot attend the IFPAC conference this year, but I strongly advise anyone looking for a second source (versus IFPAC in MD) for PAT/QbD presentations to check out this well-run conference in San Jaun, this year or next.

If you have any questions about this device or any other projects at Mayagüez, Rodolfo’s email is rodolfoj.romanach@upr.edu. Enjoy!     -Emil Ciurczak

Introduction

This paper describes a stream sampler for real-time monitoring of powder blends that is currently under development.^1-5 This sampler has been described in several publications and the authors are now looking for commercialization partners to make it widely available.

Regulatory impact

The monitoring and evaluation of blend uniformity are required by the current Good Manufacturing Practices (cGMP, Title 21, part 211, subpart F, section 211.110).^6,7 This section describes the general requirements for sampling and testing of in-process materials and drug products. Section 211.110a requires written procedures of in-process controls and tests to monitor critical parameters such as “adequacy of mixing to assure uniformity and homogeneity.” Section 211.110b requires that “valid in-process specifications for such characteristics shall be consistent with drug product final specifications,” while section 211.110c requires that in-process materials should be tested and approved or rejected by the quality control unit. Finally, section 211.110d requires that a rejected material should be identified and physically isolated to avoid cross contamination.

Sampler design

This paper describes a new stream sampler that may be used for monitoring blending of pharmaceutical powder mixtures for both batch and continuous manufacturing of solid oral dosage forms.³ Note that sampling, in this respect, does not refer to the physical extraction of powder from the blender. Sampling herein refers to providing a confined powder flow for analysis of flowing powder mixtures by Near Infrared (NIR) or Raman spectroscopy. This sampler is designed for Process Analytical Technology (PAT) applications, where sensors analyze a small fraction of the total mass with the expectation that it be representative of the entire lot.⁸

The stream-sampler provides a confined powder flow, avoiding further mixing or segregation of the powder blend. The confined powder flow also makes it possible to reduce variation on the surface of flowing powder blends and the obtainment of NIR spectra while avoiding baseline changes. The baseline changes are minimal once mass steady state is achieved.

Our stream sampler is grounded in the principles of the Theory of Sampling which stipulates that all parts of the lot should have the same opportunity of being selected as a sample.⁸ The stream sampler may be installed over a compressing machine.⁹ The blend uniformity is then be monitored by NIR or Raman spectroscopy, whether the blending is performed by a batch or continuous mixing process. Previous studies have shown that the sampler does not affect the flow properties of the blend.^1-4

The powder enters the stream sampler where a set of paddles moves the confined powder to the opposite side where the NIR or Raman spectrum is obtained at 180° from the entry point (see Figure 1). The powder exits at 270° from the entry point to avoid recirculation. The powder may exit towards a compressing machine or to a hopper. As powder exits, new powder comes into the stream sampler obtaining mass steady-state flow.

Figure 1. Powder flows into the stream sampler and obtainment of NIR or Raman specturm at 180 degrees from entry point, before exiting at 270 degrees from entry point. The insert shows the paddle’s that move the powder through the sampler.

The advantage of using the stream sampler instead of monitoring at the feed frame lies in having a uniform powder flow that simplifies obtaining the NIR and Raman spectra. A number of PAT researchers have monitored powder at the feed frame of a tablet press,^10-12 however, the dynamics of the powder flow depends on the design of the particular feed frame being used. This stream-sampler seeks to provide a uniform confined powder flow regardless of the tablet press used. 

Acknowledgement: The authors thank the Puerto Rico Science Technology and Research Trust for funding through grant (2024-00182).

References
1. Alvarado-Hernández BB, Sierra-Vega NO, Martínez-Cartagena P, Hormaza M, Méndez R, Romañach RJ. A sampling system for flowing powders based on the theory of sampling. Int J Pharm. 2020;574:118874.
2. Sierra-Vega NO, Martínez-Cartagena PA, Alvarado-Hernández BB, Romañach RJ, Méndez R. In-line monitoring of low drug concentration of flowing powders in a new sampler device. Int J Pharm. 2020;583:119358.
3. Sierra-Vega NO, Romañach RJ, Méndez R. Real-time quantification of low-dose cohesive formulations within a sampling interface for flowing powders. Int J Pharm. 2020;588:119726.
4. Rangel-Gil RS, Sierra-Vega NO, Romañach RJ, Méndez R. Assessment of blend uniformity in a stream sampler device using Raman spectroscopy. Int J Pharm. 2023;639:122934.
5. Romañach RJ, Mendez R, inventors; University of Puerto Rico, assignee. Stream sampler—mass reduction system for flowing powders. United States 2019 December 31, 2019.
6. Food and Drug Administration, Department of Health and Human Services. CFR – Code of Federal Regulations Title 21, Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals, Food and Drug Administration 2023.
7. U.S. Department of Health and Human Services FDA. Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance – Production and Process Controls 2015 [updated June 11, 2015. Available from: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm#15.
8. Esbensen KH, Romañach RJ. A Framework for Representative Sampling for NIR Analysis–Theory of Sampling (TOS). In: ciurczak EW, Igne, B., Workman, J., Burns, D.A. ,, editor. Handbook of near-infrared analysis2021. p. 415.
9. Fontalvo-Lascano MA, Alvarado-Hernández BB, Conde C, Sánchez EJ, Méndez-Piñero MI, Romañach RJ. Development and Application of a Business Case Model for a Stream Sampler in the Pharmaceutical Industry. J Pharm Innov. 2023;18(1):182-94.
10. Sierra-Vega NO, Romañach RJ, Méndez R. Feed frame: The last processing step before the tablet compaction in pharmaceutical manufacturing. Int J Pharm. 2019;572:118728.
11. Hetrick EM, Shi Z, Barnes LE, Garrett AW, Rupard RG, Kramer TT, et al. Development of Near Infrared Spectroscopy-based Process Monitoring Methodology for Pharmaceutical Continuous Manufacturing Using an Offline Calibration Approach. Anal Chem. 2017;89(17):9175-83.
12. Román-Ospino AD, Baranwal Y, Li J, Vargas J, Igne B, Bate S, et al. Sampling optimization for blend monitoring of a low dose formulation in a tablet press feed frame using spatially resolved near-infrared spectroscopy. Int J Pharm. 2021;602:120594.

Emil W. Ciurczak, also known as the NIR Professor, has roughly 50 years of cGMP pharmaceutical experience and more than 35 years of Near-Infrared Spectroscopy (NIRS) experience with industries, universities, and instrument manufacturers. Emil teaches courses in NIRS, NIR/Raman, Design of Experiment, and PAT/QbD; has designed and patented hardware and software (including hardware and software related to anti-counterfeiting; written numerous technical texts and chapters; published extensively in journals; and presented hundreds of technical papers at many conferences, worldwide. He has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. For more info: emil@ciurczak.com.