The Value of High-Functionality Excipients in Continuous Manufacturing Tony Carpanzano, B.S., R. Ph. Director, R&D JRS Pharma, LP, Patterson, NY

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1 The Value of High-Functionality Excipients in Continuous Manufacturing Tony Carpanzano, B.S., R. Ph. Director, R&D JRS Pharma, LP, Patterson, NY

2 Agenda Studies in Progress Considerations Continuous Manufacturing (CM) vs Batch Production (BP) Critical Process Steps Outlook: Study Design Continuous Manufacturing

3 Background CURRENTLY The great majority of drug products are produced by the batch process Many other big industries operate mainly by continuous manufacturing (food, petrochemical, pulp and paper, mining, and etc.) Pharma industry wastes $50 billion each year because of lack of manufacturing efficiency 1 (down time, batch losses, investigations, recalls, etc.) BP equipment may stand idle for 12+ hours per day 1 - Jackson Nickerson, Olin School of Business at Washington University, St. Louis, & Jeffrey Macher, Georgetown University 3

4 Considerations BENEFITS OF CM / BURDENS OF BP In BP, lot size is dictated by equipment / facility size, whereas with CM lot size is dictated by processing time. Scale-up concerns are eliminated with CM Facility size is generally reduced with CM Reduced down-time, cleaning and waste Regulatory bodies encourage the CM in concert with QbD, DoE, PAT, Risk Management guidelines. FDAs Emerging Technology Program to promote the adoption of innovative approaches to pharmaceutical product design and manufacturing. POSSIBLE ISSUES WITH CM Can one assume that all BP products can be converted over to CM? May not be the best option for low volume products. Where dose one draw the line? Would production lines be dedicated to one product? Equipment still needs monitoring, maintenance and cleaning how long can it run? PAT feedback and feed-forward controls can be complex 4

5 Considerations BENEFITS OF CM / BURDENS OF BP Product quality can be monitored in real time in- and/or on-line -> Real-time release (through PAT) Can isolate material if process drifts - Higher end product quality total lot analysis Most of the time production runs in steadystate mode -> easy to control Production transfer is easier just move the line or copy it Reduced waste Reduced operator interaction POSSIBLE ISSUES WITH CM Specialized support of each product line CP may not be a good fit for all products still need some BP infrastructure Still needs maintenance Still needs cleaning how often? Release testing may be a mix of on-line vs post manufacture (i.e., dissolution) In-process testing and controls by protocol still have to be put through the system QA/QC Some of the current excipients and API grades are not optimal for continuous production, especially for continuous feeding. 5

6 Considerations BENEFITS OF CM / BURDENS OF BP Product quality can be monitored in real time in- and/or on-line -> Real-time release (through PAT) Can isolate material if process drifts - Higher end product quality total lot analysis Most of the time production runs in steadystate mode -> easy to control Production transfer is easier just move the line or Reduced waste Reduced operator interaction POSSIBLE ISSUES WITH CM Specialized support of each product line CP may not be a good fit for all products still need some BP infrastructure Still needs maintenance Still needs cleaning how often? Release testing may be a mix of on-line vs post manufacture (i.e., dissolution) In-process testing and controls by protocol still have to be put through the system QA/QC Some of the current excipients and API grades are not optimal for continuous production, especially for continuous feeding. 6

7 Continuous vs Batch Production

8 Continuous vs Batch Production OPERATION Weighing Blending Granulation Lubrication Compression Coating METHODS Automatic (gravimetric or volumetric) feeders vs. balances In-line (continuous) blending vs. bin blenders Similar to roller-compaction vs. conventional wet granulation Fixed blending time vs. Preselected blending time Compression Continuous coaters vs. Batch coaters CHALLENGES CM BP Content Uniformity Content Uniformity Overmixing Control Endpoint reproducibility Scale-up

9 Critical Process Steps The major challenges in continuous tablet manufacturing are related to powder feeding and blending. To ensure drug uniformity, powder feeding rates must be accurate and consistent, and blending must be thorough. To ensure tablet integrity and performance, lubricant blending must not be excessive.

10 Critical Process Steps: Feeding The major challenges in continuous tablet manufacturing are related to powder feeding and blending.

11 Critical Process Steps: Feeding Powder Tablet Tabletting Filler Binder Glidant Disintegrant Lubricant Flowability X X (X) Compactability X X! Homogeneity X Mass / Volume X Toughness X X! Uniformity X X (X) Dissolution X! Reduce Wall Friction X Reduce Punch Adhesion X

12 Critical Process Steps: Feeding Product Manufacturer Functionality Filler/Binder Glidant Disintegrant Lubricant PROSOLV EASYtab SP JRS PHARMA MCC Colloidal Silica SSG SSF PROSOLV ODT JRS PHARMA MCC Mannitol Fructose Colloidal Silica cpvp - PROSOLV SMCC JRS PHARMA MCC Colloidal Silica - - Multifunctional excipients help to reduce the number of necessary feeder units.

13 Critical Process Steps: Blending Achieving good blend uniformity is crucial for any tableting process. It is particularly challenging, however, in the case of continuous (in-line) blending. PROSOLV products have often been shown to promote good blend uniformity.

14 Critical Process Steps: Blending Formula Process %RSD Original product MCC/lactose wet granulation 5-8.0% MCC blend Direct compression blend with PH % PROSOLV blend Direct compression blend with SMCC % PROSOLV pre-blend PROSOLV mixed grade pre-blend Pre-blend with 15% of SMCC 90 requirement Pre-blend with 15% of SMCC 90 requirement; titrated with 50/50 SMCC 90 and SMCC % % Improvement of levothyroxine content uniformity

15 Critical Process Steps: Blending Formula Process %RSD Original product MCC/lactose wet granulation 5-8.0% MCC blend Direct compression blend with PH % PROSOLV blend Direct compression blend with SMCC % PROSOLV pre-blend PROSOLV mixed grade pre-blend Pre-blend with 15% of SMCC 90 requirement Pre-blend with 15% of SMCC 90 requirement; titrated with 50/50 SMCC 90 and SMCC % % Improvement of levothyroxine content uniformity

16 Critical Process Steps: Blending Formula Process %RSD Original product MCC/lactose wet granulation 5-8.0% MCC blend Direct compression blend with PH % PROSOLV blend Direct compression blend with SMCC % PROSOLV pre-blend PROSOLV mixed grade pre-blend Pre-blend with 15% of SMCC 90 requirement Pre-blend with 15% of SMCC 90 requirement; titrated with 50/50 SMCC 90 and SMCC % % Improvement of levothyroxine content uniformity

17 Critical Process Steps: Blending Formula Process %RSD Original product MCC/lactose wet granulation 5-8.0% MCC blend Direct compression blend with PH % PROSOLV blend Direct compression blend with SMCC % PROSOLV pre-blend PROSOLV mixed grade pre-blend Pre-blend with 15% of SMCC 90 requirement Pre-blend with 15% of SMCC 90 requirement; titrated with 50/50 SMCC 90 and SMCC % % Improvement of levothyroxine content uniformity

18 Critical Process Steps: Blending Formula Process %RSD Original product MCC/lactose wet granulation 5-8.0% MCC blend Direct compression blend with PH % PROSOLV blend Direct compression blend with SMCC % PROSOLV pre-blend PROSOLV mixed grade pre-blend Pre-blend with 15% of SMCC 90 requirement Pre-blend with 15% of SMCC 90 requirement; titrated with 50/50 SMCC 90 and SMCC % % Improvement of levothyroxine content uniformity

19 Critical Process Steps: Blending

20 Critical Process Steps: Blending

21 Critical Process Steps: Blending

22 Critical Process Steps: Blending

23 Outlook: Study Design PROSOLV EASYtab SP appears to be particularly well-suited for continuous manufacturing. In order to verify this assumption, studies will be carried out at the University of Eastern Finland in Kuopio.

24 Outlook: Study Design The following parameters will be tested: 1. Feeding performance (accuracy and time to steadystate feed rate) for EASYtab in comparison with its individual components. 2. Effect of blending on particle size distribution. 3. Blend homogeneity with model API. EASYtab vs physical mixture.

25 Outlook: Study Design Looking forward to sharing the results with you next year. Stay tuned!

26 Thank you for your attention! Tony Carpanzano, B.S., R. Ph. Director, R&D JRS Pharma, LP Patterson, New York