Progress Towards Advanced Pharmaceutical Manufacturing

• Rutgers – The State University of New Jersey

• University of Puerto Rico – Mayagüez Campus

The recent 14th Annual IFPAC and INDUNIV Summer Summit held in San Juan, Puerto Rico included a number of presentations on continuous manufacturing, process analytical technology (PAT), and the application of near infrared and Raman spectroscopy in both small molecule and biopharmaceutical manufacturing scenarios. The highlight of the conference was the significant progress of PAT, Quality by Design and continuous manufacturing. Pharmaceutical manufacturing is now progressing with the implementation of continuous manufacturing, and the concepts discussed in the PAT Guidance,¹ and the GMPS for 21st Century.² In this, or other conferences, involving pharmaceutical scientists and engineers, talks focused solely on the potential or advantages of continuous manufacturing, PAT, or NIR and Raman spectroscopy would be completely obsolete. Industry has moved beyond the discussion of the advantages of these initiatives and pharmaceutical manufacturing is now fully engaged and progressing in a new world of PAT, Quality by Design (QbD) and continuous manufacturing.

PAT is now increasingly visualized as an element of Quality by Design, and not an isolated field of study. The discussions on PAT also involve other important elements for real time release testing (RTRT). PAT is now discussed in light of the prior process knowledge often obtained through design of experiments and thorough evaluations of the properties of process materials. PAT is also increasingly discussed at the same time as risk management. PAT is seen as a way to reduce risk, and an enabler of RTRT. PAT is advancing in industry, but requires a transformation in pharmaceutical manufacturing.³ Investment in PAT follows a need for a control strategy and requires a value proposition, organization capability and commitment, and inclusion within the quality system. If one of these practical dimensions is lost, then success in PAT is unlikely.³ The development of new PAT sensors⁴ and the understanding of the data obtained from real time process measurements is still of interest.⁵ However, the efforts to improve pharmaceutical manufacturing are much wider than monitoring a process. For example, data from process hardware may be used to optimize equipment maintenance and the entire business operation.⁶ The discussion has turned towards PAT being one of the important elements of Quality by Design and advanced pharmaceutical manufacturing.

Progress in Continuous Manufacturing

The integration of Quality by Design and continuous manufacturing in an industrial process is clearly evident in a recent publication.⁷ This study was focused on characterizing the effect of processing parameters on the drug content, dissolution, average weight, thickness and breaking force of tablets produced by continuous manufacturing. The orientation of the mixer paddle, total mass flow rate, and mixer speed were studied in a nine run design of experiment (DOE). The drug used in the study had poor flow properties, and required the development of a preblend. Thus, this study is an example of formulation development for a continuous manufacturing process. The study also marks an important transition from the blend uniformity issues that has often dominated industrial discussions.⁸ The study acknowledges that de-mixing may occur, and the focus is on the tablet – the product received by the patient.

Progress in continuous manufacturing was also evident in two recent presentations that described the knowledge gained in the first year of commercial production at Janssen’s Ortho, LLC Gurabo, Puerto Rico manufacturing site.^9,10 This knowledge is now being used to improve process robustness. The understanding of the properties of the raw materials is essential for process robustness. The material properties must be understood to obtain the desired blending efficiency, compression performance and the desired final product. Variation in material properties will also be detected in the near infrared spectra obtained in the real time monitoring of the mixing process. The company is also addressing the skills needed by the workforce dedicated to continuous manufacturing and is now developing inhouse expertise in chemometrics, residence time distribution (RTD) measurements, and working with the continuous manufacturing process equipment.¹⁰

The implementation of near infrared (NIR) spectroscopy in an industrial environment requires the evaluation of all sources of error associated with the analytical method.^11,12 NIR plays a key role in a continuous process. The NIR spectrometer is used to monitor a process which could take several hours to complete, and could easily obtain over 1000 spectra while monitoring the process.¹³ The goal is not to indicate the end-point of blending as in a batch process and then stop, but to continue monitoring the process after steady state is obtained.¹⁴ Thus, the robustness of an NIR spectroscopic method is especially important in a continuous process. The NIR spectrometer obtains a spectrum of the blend that exits the mixer every 5 seconds, and this system is an ideal example of what has been termed a 1-D lot in the Theory of Sampling.^8,15,16 Thus, continuous processes facilitate the evaluation of the sources of error associated with NIR spectroscopy, including sampling errors.^8,11

NIR spectroscopy is now being used within the commercial pharmaceutical environment. The days of “Near Infrared Spectroscopy will never be approved by FDA” are gone.¹⁷ The adoption in the industrial environment requires further understanding of NIR spectroscopy, in ways that were not foreseeable in academic research. For example, an NIR transmission method is now being used to determine an active pharmaceutical ingredient (API) that interchanges solvent molecules with water molecules from the environment.¹⁸ This solvent exchange does not affect product quality, but it affects NIR spectra, which are highly sensitive to changes in hydrogen bonding and water concentration. The calibration model was optimized by excluding O-H bands from the spectral range used to determine the drug concentration. The calibration model was then challenged by the acquisition of spectra of tablets for up to 113 hours after compaction, and shown to be robust to the solvent exchange. In spite of the many contributions from academic research laboratories to advancement of NIR spectroscopy, this type of application was not foreseable.¹⁹

Continuous Manufacturing is Now a Global Initiative

While much of the advanced pharmaceutical manufacturing endeavors taking hold today, PAT, QbD, and continuous manufacturing, were spearheaded by the FDA and U.S. based research efforts; the pharmaceutical industry along with most of the organizations at the technological forefront are global. As a result, global alignment is needed on many of the aspects that come together when continuous manufacturing is to be implemented. Aspects already mentioned, such as sampling and model maintenance will most likely differ for a continuous process as compared to a batch process. Challenges arise and the rate of implementation slows when adopters are unsure how these new approaches will be accepted in different markets, and even though the days of “Near Infrared Spectroscopy will never be approved by FDA” are gone;¹⁷ how quickly and easily the same approval can be replicated from market to market has become the topic of discussion. As a result, several recent international forums were held on this subject.

On May 9th, 2017 a unique gathering occurred on the small Island of Malta with key industrial adopters and academics from across the globe and several European Union health ministries. The summit was held under the banner of the International Institute for Advanced Pharmaceutical Manufacturing (I2APM), which is a coalition of academic research centers from across the globe. This summit was focused on oral solid dosage pharmaceuticals, and chaired by The Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based at Rutgers University in New Jersey, USA, which focuses on solid dose continuous manufacturing. With regard to items that related to PAT and continuous processes versus batch, regulators provided their perspective around in-process testing and aspects related to malfunction/redundancy or calibration.²⁰ In turn, adopters presented on sampling and control strategies for continuous direct compression built on the key aspects of increased information and related process understanding emanating from continuous manufacturing processes. This demonstrated that a well-developed process model working with parametric feeder control can be more robust and significantly less variable than an in-line analytical method and advocated choice for control feedback with analytical methods used separately for “sampling”.²¹

On the other side of the globe, in Mumbai, India on May 16th 2017, The United States Pharmacopeia held the “USP Pharmaceutical Continuous Manufacturing (PCM) Technology Development and Implementation Workshop”. This workshop was aimed at demonstrating the pathway for adoption of the technology to the generic industry. The USP is working towards providing standards and compendia to aid in continuous manufacturing implementation both in the U.S. and in markets across the globe.

The efforts of groups such as C-SOPS and USP are part of the larger ongoing effort to provide guidance elements to continuous manufacturing of pharmaceutical products. While there has been much discussion on continuous in recent years, other than ASTM E2968-14, there is nothing out there in draft form or otherwise to help provide clarity on methodologies and approaches. It had seemed as if ICH would address continuous manufacturing when it convened in in Montreal during May/June 2017. Unfortunately, continuous manufacturing was not selected as an ICH topic for 2018 at the 2017 meeting and the start or work on a ICH guidance will need to wait at least one more year. Recently though, the FDA has opened a public docket, Submission of Proposed Recommendations for Industry on Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing (https://www.regulations. gov/document?D=FDA-2017-N-2697-0001). Comments are due in September, so it is likely there will be additional guidance resources for adopters of continuous manufacturing in 2018.

Advanced manufacturing, PAT, QbD, and continuous manufacturing are now a reality in innovative pharmaceutical companies. These advances are now the current state of the art manufacturing within Pharma. Today it is still primarily occurring in the leading pharmaceutical companies, but these technologies may become the norm as guidance and regulation catch up with how these aspects of advanced manufacturing come together and are implemented.

References

1. U.S. Department of Health and Human Services FDA. Guidance for Industry - PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. 2004:1-19.
2. U.S. Department of Health and Human Services FDA. Pharmaceutical CGMPS for the 21st Century— A Risk-Based Approach Final Report 2004.
3. Guenard R. PAT for Bio Lifecycle Management. 14th Annual IFPAC and INDUNIV PAT and QbD Summer Summit 2017; San Juan, Puerto Rico.
4. Gupta A, Austin J, Davis S, Harris M, Reklaitis G. A Novel Microwave Sensor for Real-Time Online Monitoring of Roll Compacts of Pharmaceutical Powders Online-A Comparative Case Study with NIR. J Pharm Sci. 2015;104(5):1787-1794.
5. Irizarry R, Chen A, Crawford R, Codan L, Schoell J. Data-driven model and model paradigm to predict 1D and 2D particle size distribution from measured chord-length distribution. Chemical Engineering Science. 2017;164:202-218.
6. Romero-Torres S, Moyne J, Kidambi M. Towards Pharma 4.0; Levaraging Lessons and Innovation from Silicon Valley. American Pharmaceutical Review. 2017;20(1):34-41.
7. Roth WJ, Almaya A, Kramer TT, Hofer JD. A Demonstration of Mixing Robustness in a Direct Compression Continuous Manufacturing Process. J Pharm Sci. 2017;106(5):1339-1346.
8. Esbensen KH, Román-Ospino AD, Sanchez A, Romañach RJ. Adequacy and verifiability of pharmaceutical mixtures and dose units by variographic analysis (Theory of Sampling) – A call for a regulatory paradigm shift. Int J Pharm. 2016;499(1–2):156-174.
9. Sanchez Rolon E. Building Robustness in Direct Compressible Continuous Manufacturing Processes Through Material Properties Process Understanding 14th Annual IFPAC and INDUNIV PAT and QbD Summer Summit 2017; San Juan, Puerto Rico.
10. Rodriguez N. Manufacturing of the Future… Today! Continuous Manufacturing at Janssen. 14th Annual IFPAC and INDUNIV PAT and QbD Summer Summit 2017; San Juan, Puerto Rico.
11. Vargas JM, Roman-Ospino AD, Sanchez E, Romañach RJ. Evaluation of Analytical and Sampling Errors in the Prediction of the Active Pharmaceutical Ingredient Concentration in Blends From a Continuous Manufacturing Process. J Pharm Innov. 2017;12(2):155–167.
12. Corredor C, Lozano R, Bu X, et al. Analytical Method Quality by Design for an On-Line Near-Infrared Method to Monitor Blend Potency and Uniformity. J Pharm Innov. 2015;10(1):47-55.
13. Barajas MJ, Cassiani AR, Vargas W, et al. Near-Infrared Spectroscopic Method for Real-Time Monitoring of Pharmaceutical Powders During Voiding. Appl Spectrosc. 2007;61(5):490- 496.
14. Alcala M, Martinez L, Esquerdo R, Hausner D, Romañach RJ. Continuous Manufacturing, Near Infrared Spectroscopy and Process Knowledge. American Pharmaceutical Review. 2015;18(5):59-63.
15. Esbensen KH, Paasch-Mortensen P. Process Sampling: Theory of Sampling – the Missing Link in Process Analytical Technologies (PAT). Process Analytical Technology: John Wiley & Sons, Ltd; 2010:37-80.
16. Romañach RJ. Theory of Sampling - From Missing Link to Key Enabler for Process Analytical Technology (PAT). Paper presented at: 8th World Conference on Sampling and Blending; May 9- 11, 2017, 2017; Perth, Australia.
17. Romañach R. Near infrared spectroscopy: from feasibility to implementation in the pharmaceutical industry. NIR news. 2016;27(1):33-38.
18. Colón YM, Vargas J, Sánchez E, Navarro G, Romañach RJ. Assessment of Robustness for a Near-Infrared Concentration Model for Real-Time Release Testing in a Continuous Manufacturing Process. J Pharm Innov. 2017;12(1):14-25.
19. Romañach R, Román-Ospino A, Alcalà M. A Procedure for Developing Quantitative Near Infrared (NIR) Methods for Pharmaceutical Products. In: Ierapetritou MG, Ramachandran R, eds. Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture: Springer New York; 2016:133-158.
20. Norton E. MHRA Experience on ‘Early Adopter’ Continuous Manufacturing Inspections. I2APM Emerging Pharmaceutical Manufacturing in the Current Regulatory Landscape; 2017; Malta.
21. Meyer RF. Sampling and Control: Appropriate Control Strategies for Continuous Direct Compression. I2APM Emerging Pharmaceutical Manufacturing in the Current Regulatory Landscape; 2017; Malta.

Author Biographies

Rodolfo J. Romañach, PhD is Professor of Chemistry and Site Leader for the Engineering Research Center for Structured Organic Particulate Systems at Mayagüez. His research is focused in understanding the sources of error in near infrared spectroscopic methods.

Douglas B. Hausner, PhD is the Associate Director for the Engineering Research Center for Structured Organic Particulate Systems at Rutgers University. He overseas numerous activities and forums related to continuous pharmaceutical manufacturing technology from fundamental research through commercial implementation.