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  1. Continuous Manufacturing & Process Analytical Chemistry - Environmental Contributions Rodolfo J. Romañach, Ph.D. Department of Chemistry Recinto Universitario de Mayagüez rromanac@yahoo.com rodolfoj.romanach@upr.edu Inter-American University, San Germán October 22, 2012

  2. “Drug Substances in their purified state usually exist as crystalline or amorphous powders or as viscous liquids. The majority of drug substances exist as white or light-colored crystalline powders. Although drugs were dispensed as such in powder papers as recently as several decades ago, this practice is virtually unknown in pharmacy practice today. With the possible exception of the anesthetic gases, all drugs in legitimate commerce are now presented to the patient as drug products.” Modern Pharmaceutics, Third Edition, Volume 72 Drugs and the Pharmaceutical Industry, Ed. G.S. Banker and C.T. Rhodes, Marcel Dekker, 1995, page 14.

  3. Formulation Examples • A CT Halcion tablet has about 0.125 mg of drug substance (API), but weighs about 100 mg. • An CT Ibuprofen tablet will have over 70% (w/w) drug substance content.

  4. Development of a New Drug Product Pharmaceutical scientists contribute to the evaluation of the safety and medical utility of drug candidates, and the industrialization (manufacturing) of approved drugs.

  5. A Drug Delivery System Modern Pharmaceutics, Third Edition, Volume 72 Drugs and the Pharmaceutical Industry, Ed. G.S. Banker and C.T. Rhodes, Marcel Dekker, 1995, page 15.


  6. Common Unit Operations in Pharmaceutical Manufacturing (Preparation of Drug Products) • Milling • Blending (Mixing) • Granulation • Lyophilization • Tablet compression • Sterilization These occur during box (lots are manufactured) in next diagram.

  7. 30 cubic feet V-blender Courtesy of Mova Pharmaceuticals.

  8. R.J. Romañach, “Pharmaceutical Analytical Chemistry: Bringing the Pharmaceutical Industry to the Classroom”, Journal of Process Analytical Technology, 2004, 1(2), 19 – 23. (http://www.patjournal.com)

  9. Batch Manufacturing Process Flow Intragranular materials dispensing and screening at Pharmacy area Extragranular addition, blending and lubrication Initial blend & lubrication Roller compaction Final blend Compression API addition to the IBC with intragranulars Tablet bins Coating

  10. Environmental & Economic Consequences of Batch Manufacturing Environmental • Need large manufacturing areas, different rooms for the equipment used. • May need areas for different sizes of the same equipment or need a storage area. • The equipment are shared between different processes – requiring cleaning. • May produce more product than needed. Economic • Energy costs. • Cleaning costs. • Cost of maintaining a sate in-doors environment. • Efforts to maintain pressure differences between areas. • Cost of storage of equipment. • Cost of products stored.

  11. Continuous Manufacturing You will have orange juice as long as you continuously feed oranges. You decide how much orange juice you need. Photo used for educational purposes

  12. Batch Manufacturing • Always work with 100,000 oranges. • The juice is accumulated at evaporator, which is large and does not work well with less than 100,000 oranges. • Blender , freezers, and all other parts also require a minimum of 100,000 oranges. • Total amount of juice passed from one part to the other. http://foodmapper.wordpress.com/2008/04/16/when-local-doesnt-work-orange-juice/ Used for educational purposes

  13. Continuous Mixing Process Continuous – there is no accumulation of mass within system. The material is mixed and volume in the mixer is maintained by equal amounts of materials that are introduced by feeders. P.M. Portillo , M. Ierapetritou, F.J. Muzzio, Powder Technology 182 (2008) 368–378.

  14. Definition of lot • Lot specific quantity produced expected to have uniform properties. cGMPs 210.3 definition #10. • (10)Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. • (11)Lot number, control number, or batch number means any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of drug product or other material can be determined.

  15. Beginning of blending process, blades can be seen (not at steady state).

  16. Monitoring of Continuous Mfg. Process Each NIR scan interacting with about 260 mg sample. RMSEP ≈ 0.34 % (w/w). Each measurement every 0.5 secs. Chemical Engineering Science, 2010, 65(21), 5728 – 5733.

  17. Design, Analysis & Control of Mfg with measurements obtained during processing for critical quality and In-line performance attributes of raw and in process materials to ensure final product quality On-line Off-line At-line

  18. Analytical Methods • Majority will be in-line or on-line methods, that do not require sample preparation. • In-line methods monitor the process as it is occurring, and the sample is not removed from the process stream. • On-line methods – a sample is diverted from the manufacturing process but may returned. • Near line – sample is taken to an analytical instrument located near process line. • Off-line – remote lab, current system.

  19. Process Analytical Chemistry (PAC) PAC is a branch of Analytical Chemistry dedicated to obtaining real time quantitative and qualitative information about a chemical process. • to monitor and control a process • efficient use of energy, time and raw material Callis, Illman, Kowalsky. Process Analytical Chemistry. Analytical Chemistry. Vol 59(9). 1987

  20. PAT & QbD in the Manufacturing Process Variation in Raw Materials is expected and understood. Process Provides a Design Space or Boundaries for Raw Materials.

  21. Force fine powders into two counter rotating rolls. As the volume decreases through the region of maximum pressure, the material is formed into a solid compact or sheet. Roller Compaction To visualize see: http://www.fitzmill.pharmaceutical/dry_granulation/dry_granulation_pharma.html

  22. Roller Compaction Material for Milling Adapted from Alexanderwerk Roller Compaction Presentation,

  23. Advantages of Roller Compaction • Powder densification without need for drying vs. wet granulation. • Eliminates aqueous degradation (some compounds not stable in water). • Facilitates powder flow • Facilitates a continuous powder manufacturing process. Based on presentation by Garnet Peck, Near Infrared Monitoring of Roller Compaction, Garnet Peck Symposium, Purdue University, 2006.

  24. Densification in Roller Compaction The volume of material in Vα must be reduced to Vθ, requiring that the bulk densities (γα and γθ) and volumes be related. R.W. Miller and P.J. Sheskey, Roller Compaction Technology for the Pharmaceutical Industry, Handbook of Pharmaceutical Technology.

  25. D. Acevedo, A. Muliadi, A. Giridhar, J.D. Litster, R. J. Romañach, AAPSPharmscitech, DOI: 10.1208/s12249-012-9825-0.

  26. NSF Engineering Research Center for Structured Organic Particulate System (http://ercforsops.rutgers.edu/)

  27. Engineering of Pharmaceutical Materials & Processes Given active organic substances & administration/delivery requirements, have integrated framework with predictive models to systematically design: Particles (Material) Composite Product (Manufacturing Science) With a minimum number of supportive experiments !!

  28. UPRM-Resources for Pharmaceutical Industry • Dr. Carlos Velazquez (Chemical Engineering) carlos.velazquez9@upr.edu – heat transfer, mass transfer, control strategies, pharmaceutical blending, control of wet granulation. • Dr. Rafael Mendez (Chemical Engineering) – powder technology. • Dr. Aldo Acevedo (Chemical Engineering) - Electrorheological fluids; complex fluids; rheology. • Dr. Madeline Torres (Chemical Engineering) - Biomedical Engineering, Materials, and Polymers. Teaching Interests: Polymers, Thermodynamics.

  29. Test Bed 2: Manufacture of Strip Film Unit dosage Goal: Develop the scalable methods, experimental setups and material knowledge base for forming films loaded with engineered particles of sub-micron and low micron size to achieve desired delivery properties Benefits/Impact • Processing of sub-micron and micron particles within suspensions avoids contamination/safety and handling issues of dry powder processing – the output can be a final dosage or an intermediate one • Engineered particle dispersion into gel/polymer matrix allows consistent loading of low dosage and/or low solubility actives • Manufacturing is inherently continuous • Full (100%) automated inspection possible • Drug dissolution may be controlled by particle size & coating Leader: Raj Dave, NJIT

  30. Thin Films ZUPLENZ (ondasentron) first quick-dissolving film prescription product that is approved. Approved for nausea and vomitting. http://www.zuplenz.com/ Benzocaine films by Zengen. Triaminic and Theraflu by Novartis. J. I. Jérez Rozo, A. Zarow,B. Zhou, R. Pinal, Z. Iqbal, R.J. Romañach, “Complementary Near-Infrared and Raman Chemical Imaging of Pharmaceutical Gel Strip Films”, Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22653

  31. Sievens-Figueroa, A. Bhakay; J.I Jerez-Rozo; N. Pandya; R. Romañach; B. Michniak-Kohn ; Z. Iqbal; E. Bilgili; R.N Dave, Int J Pharmaceutics (2012), 423, 496 – 508.

  32. Ink-jet printing Micro-arraying Test Bed 3: Multi-layered Architectures Using Drop-on-Demand Technology Goal: Integrated application of drop-on-demand technology for predictable & controllable deposition of active substances on edible substrate to form3-D dosage structures with engineered release profile Impact • Compact small scale manufacture for clinical trial quantities, hospital dispensaries • Linearly scalable • High precision dose control • Customized, patient specific dosage formulations • Delivery of multiple active components

  33. Scientific Challenges: • Understand & predict formation of drops of uniform size from complex fluids • Understand impact & spread of drops of complex fluids on solid substrates • Understand and predict active-carrier interactions • Understand and predict drop-substrate interactions • Understand and control morphology of drug during solidification Mike Harris, Osman Basaran (ChE)