Streamlining Freeze Drying Development with BTL
- 3. Contents • History • BTL’s mission • Products handled • Principles of freeze-drying • Typical issues & consequences • Product critical temperatures • Instruments: Lyostat and its operation • Instruments: Lyotherm for frozen state analysis • Product Characterisation • Development Services • Formulation Development • Cycle Development • Optimisation and scale up • Post-process Analysis • Troubleshooting • Typical timelines • BTL’s Research • Training • Meet the Team • Our facilities • Main Laboratory • Potent compounds’ Suite • Freeze-Drying capacity • Partnering with BTL • Case Studies
- 4. History • Started in 1997 with laboratory services • Historically supported BPS sales of equipment as supplier in UK & Ireland • Since 2011, with the set-up of a commercial arm, has expanded internationally with representation in 8 territories • In 2012, opened a negative pressure facility for handling potent compounds
- 5. BTL’s Mission • Quantitative approach to process development • Product characterisation: empirical foundation for development • Holistic view: Product, process, scale and equipment • Post-process analysis • Championing the establishment of a QbD approach • Expert support the freeze drying industries • Ongoing collaborative research in science of freeze drying
- 6. Products Handled Small Molecules 25% -Traditional Drugs -Small Peptides Large Molecules 50% -Large peptides / polypeptides -Enzymes and other proteins -Mono / polyclonal antibodies -DNA-based reagents -Antibody based diagnostics Structured Materials 15% -Collagen matrices -Nanoparticulates, hydrogels, microspheres -Foods and artefacts Cellullar & Organisms 10% -Bacteria -Tissue samples -Purified body fluids for personalised medicines -Red blood cells
- 7. Principles of Freeze Drying Freeze drying ideal to produce: • Stable product • High levels of activity • Homogeneous powder or cake • Rapid reconstitution • Controllable batch production • Batch consistency
- 8. Typical issues & Consequences Clients can experience issues with: • Poor characterisation • Batch reproducibility • Poor stability, activity or reconstitution • Inconsistent dryness across samples • Cycle control • Breakage of vials and containers • Product quality failure • Long, expensive cycles
- 9. Typical issues & Consequences (Continued) Consequences: • Financial inefficiencies • Quality and regulatory drawbacks • Operational setbacks
- 10. Product Critical Temperatures • Freeze-drying success depends on knowledge of critical temperatures • Provide empirical basis for R&D and scale-up • Collapse (Tc) most important. • Also, glass transition (Tg’) or eutectic point (Te) and other frozen-state events affect processing
- 11. Product Critical Temperatures (continued) • Freeze drying without empirical data leads to: – Poorly defined and justified process’ parameters – Loss of product or batch recall – Mismatch between process and equipment – Lack of quantified, well characterised product and cycle, detrimental to any regulatory submissions
- 12. Instruments • BTL helped develop 2 instruments for freeze- drying specific analyses: – Lyostat freeze drying microscope (FDM): real-time analysis of freezing and drying events – Lyotherm frozen-state analysis: combines DTA and impedance analysis
- 13. Lyostat Freeze Drying Microscope (FDM)
- 14. Lyostat • Acts as a micro-freeze dryer • Observation of freezing and drying under microscope • FDM is the only technique that identifies collapse temperature (Tc) • Also used to investigate the effects of annealing • Available for purchase at BTL
- 15. Lyostat Operation • Requires just 2µl sample • Set freezing temperature and hold to ensure complete freezing • Turn on vacuum pump to initiate drying • Sublimation front will move from one side of the sample to the other. Raising the temperature will cause the sample to eventually collapse.
- 16. Lyostat Screenshots of Lyostat analysis, showing frozen product (1), dried with good structure (2) and collapse (3) 1 2 3
- 18. Lyotherm Frozen State Analysis • Developed in collaboration with Dr Louis Rey • Exclusive to BTL • Combines Differential Thermal Analysis and Impedance Analysis • Identifies glass transition (Tg’), eutectic, melting, and any other endo- or exothermic events.
- 19. Lyotherm Frozen State Analysis • On-site installation and training by an experienced scientist • Supplied validated against reference solutions • Measurable temperature range -190°C to +60°C • Accuracy 0.05°C, resolution ±0.05°C • Easy export of data directly into Microsoft Excel
- 20. Product Characterisation • To develop process, product characterisation is essential • Lyostat and Lyotherm analysis enable identification of critical temperatures • BTL provides full report • The report can be incorporated into any customer’s documentation and regulatory submissions
- 21. Development Services • Many products and processes developed by trial- and-error • As a result, cycles can be inefficient, expensive, process poorly • Collapse can occur invisibly • Developing formulations to avoid critical temperatures being too low • If critical temperatures are too low, cycles are too long, energy intensive and expensive • All cycles need validation for batch uniformity
- 22. Development Services • Favourable thermal characteristics by optimal excipients selection • Different excipients provide different lyo- and cryo-protective attributes • Product & process development with freeze drying in mind from the start • Yet, pre-existing formulations and cycles can be optimised
- 23. Formulation Development • BTL has worked with over 1000 products • Significant experience with a multitude of excipients, their various qualities and suitability • Empirical characterisation of products and its optimisation to yield ideal product for processing and subsequent use
- 24. Cycle Development • Cycles best developed for each product formulation • Cycles tailored for the specific equipment, batch size, container • Using data cycle development can be streamlined • BTL completes a cycle development with 3 trial runs, and a confirmatory run
- 25. Cycle Development Example of a typical freeze drying cycle
- 26. Cycle Optimisation & Scale-Up • Equipment dimensions, chamber dimensions, container type, fill depth, and batch size affect: Heat transfer, moisture capture rate, vapour flow • These can all affect the rate of drying • Cycles need to be reassessed when scaling up and/or changing equipment • Process validation provides documented evidence for parameters specified
- 27. Post-Process Analysis • Post-process characterisation of great value for batch quality assurance and covers at least: • Moisture determination by Karl Fischer Titration • BTL, in collaboration with Imperial College, can perform Mechanical tests of cake
- 28. Post-Process Analysis • mDSC provides glass transition in dry state (Tg) which is necessary to specify appropriate storage conditions • Non-destructive complete batch analysis or long-term studies can be conducted using FMS • Other product-specific analyses can be provided for physical, chemical and biological parameters, e.g. SEM, DVS, XRD Moisture mapping of an entire freeze dryer shelf, using FMS
- 29. Troubleshooting • Issues can occur unexpectedly at any stage: development or manufacture • BTL expert at addressing multitude of products, different stages of development and makes and models of equipment • Experience and science-led investigation makes us ideally placed to timely problem resolution • Empirical data provides foundations of QbD and explanation of rectifications
- 30. Typical Timelines Characterisation: typically 1-2 weeks, but same-day analysis can arranged for urgent requirements Formulation Development: 1-4 weeks, depending on number of formulations and testing required Cycle Development: Typically 4-8 weeks Process Scale-Up / Optimisation: Typically 2-10 weeks Troubleshooting: Up to 6 weeks
- 31. BTL’s Research Projects • We engage in collaborative research to further the field of freeze drying • We remain at the cutting edge • Examples: red blood cells, collagen implants, probiotic bacteria, fusion proteins, headspace moisture analysis, polymorphism in herbicides
- 32. Training • Part of our mission is to educate on freeze drying • Since 1997 we have run more than 120 courses and trained more than 2500 people • Courses held regularly in UK, mainland Europe and USA • Courses are regularly updated with new technologies and concepts
- 33. Training • Latest courses include practical workshop in BTL’s laboratory allowing hands- on experience of equipment • Courses can also be offered at customer site and include consultancy on customer’s product and equipment
- 34. Meet the Team • Management: Dr Kevin Ward PhD FRSC • Director of R&D – Joined in 2000 Dr Laura Ciccolini PhD, MEng Hons, Dean Listed • Commercial Director – Joined in 2011
- 35. Meet the Team • Science Team: – Isobel Cook MSC Principal Research Scientist & QA Manager – Nicholas White MChem Senior Scientists and Workflow Manager – David Banks Senior Scientist – Mervyn Middleton BSc Research Scientist – Magdalena Witek MSc Research Scientist – Thomas Codd MChem Research Assistant
- 36. Meet the Team • Sales Team: – Nektaria Servi MBA Business Development Executive & Instruments Product Manager – Elysabeth Sheppard Business Development Executive & Training Courses Manager
- 37. Our Facilities • We operate two laboratories, one standard freeze drying laboratory and one standalone laboratory for potent materials.
- 38. Main Laboratory • 3 research-scale freeze dryers with 4-10 shelves each, stoppering and process monitoring • Lyostat freeze drying microscope • Lyotherm frozen-state analyser • mDSC, Karl Fischer • Filling, labelling & capping services
- 39. Toxic Compounds’ Suite • Product analysis, cycle and formulation development • Small-scale production • Dedicated, negative pressure suite: no cross-contamination with other products
- 40. FREEZE-DRYING CAPACITY • Pilot Scale Genesis: offers 4 shelves, with processing capacity range from • 1mL product (in 2mL vial) over 4 shelves = 1824 vials (1.824 L ) • to 20ml (in 50mL vial) over 4 shelves = 165 vials (3.3 L) • Small production scale runs • Ultra: offers 10 shelves, with processing capacity range from • 1mL product in 2mL vials, over 10 shelves = 4560 vials (4.56 L) • 20mL product in 50mL vials, over 10 shelves = 412 vials (8.25 L) • Or, bulk trays can offer 3L per shelf, yielding: • Genesis: 12L (4 trays) • Ultra: 30L (10 trays)
- 41. Partnering with BTL • Gain access to our process expertise • Experience with a wide range of product types and process challenges • Science-led practice for streamlined development and data-backed recommendations • At the cutting edge of QbD in the field • ISO 9001 with comprehensive QA documentation and procedures
- 43. CASE STUDIES
- 44. Formulation Development Case Study • Customer needed to develop a freeze drying cycle but the product had a low collapse temperature of -42°C. Low collapse temperatures require slow,lengthy and energy intensive cycles. • BTL reformulated the product, as this was allowed, to replace some of the sucrose with dextran. Dextran can affect biological products but the small amount used ensured there were no detrimental effects to the active ingredient. • The final formulation had an overall collapse temperature of -23°C, a significant improvement over the original.
- 45. Cycle Development : A Case Study • A company had been progressing their product through clinical trials, but the EMEA highlighted the absence of lyophilisation parameters from their DMF. • BTL analysed the product with Lyostat, Lyotherm and mDSC. It was found that the existing cycle was far more conservative than it needed to be, adding unnecessary energy costs (to produce colder temperatures) and time. • The analysis results were used to propose a new cycle which was then tested. The product dried well, but was visually inconsistent due to contents settling out. • A revised cycle included a faster freezing step to prevent settling out and new handling procedures specified greater care during loading. The new cycle was significantly shorter than the original. • A more thorough DMF was submitted and the product received EMEA approval.
- 46. Cycle Optimisation: A Case Study A client wanted to reduce their cycle time of 61 hours. Lyostat analysis identified a collapse range of -8.6°C to - 17.4°C. Lyotherm analysis indicated a softening event at -25°C. A cycle was designed to keep the product below -30°C, allowing a 5°C safety margin below the lowest critical temperature. The new cycle, once tested, refined and validated, was 45 hours long representing a significant saving in time and process costs.