1. Polymorph screening - Why, when and how? IFF 2013 Karin Liltorp Particle Analytical ApS www.particle.dk

2. Outline What? Scientific background Why? Cases & guidelines When? Risk Assessment - Quality by Design How? Examples of polymorph screenings

3. What - Glossary Crystal Crystal: Solid having, in all three dimensions of space, a regular repeating internal unit of structure. Most solid API’s are dosed as crystals. Polymorphs Polymorphs: Different ways of arranging same type of molecules in a crystal lattice Amorphous Amorphous: Lack of long range pattern Polymorph screening: Experiments in order to make new crystal forms/polymorphic forms Physical properties: Solubility, stability, dissolution rate etc. All polymorphs have different physical properties which might affect patient safety.

4. What are polymorphic forms?

5. Examples of polymorphism Conclusion: All crystalline API’s have more than one crystal form

6. What are the difference between polymorphis forms? Polymorphic forms differ with regard to: Stability (degradation, reactivity, compatibility)Stability (degradation, reactivity, compatibility) I.e. impact on storage etc.(impurities)I.e. impact on storage etc.(impurities) Solubility and dissolution rateSolubility and dissolution rate Impact on bioavailabilityImpact on bioavailability Manufacturing propertiesManufacturing properties I.e. impact on flowability, blending etc.(content homogenity) Lack of control = reduced patient safety

7. What are the difference between polymorphis forms? Physical: Solubility/stability Melting temperature Density Morphology Hygroscopicity Kinetic: Dissolution rate Reaction rate Rate of crystallisation Mechanical: Flowability Tableting properties Compactability Hardness At some time point a spontanous transition from a metastable to a stable polymorph WILL occur – but when? More stable form: Lower solubility

8. Transformation of polymorphic forms Some ”rules” A metastable form might be sufficiently stable to use as active ingredient Spontanous transition from a metastable to a stable polymorph is always a risk The relative stability of forms might change with temperature or pressure Using the stable polymorph = reducing risk of transformation

9. Safety can be affected if….. The product does not contain the right amount of the API The product contains impurities The product has a new dissolution profile Main focus of the FDA guideline Guidelines based on patient safety!

10. Crystal control during manufacturing Content of API in product Inhomogeneous distribution?  New polymorphic form has different particle properties and behaves different during manufacturing Impurities Stability? Interactions with excipients?  New polymorphic form has different stability and might interact differently with the excipients ’

11. Particle control in vivo New dissolution profile? Change in crystal form gives higher/lower dissolution rate.

12. WHY….. The importance of controlling polymorphy The ”Ritonavir-case” Discovery off a new, more stable polymorph of ritonavir, Form II, with much a lower solubility. Abbott had to reintroduce the product formulated with Form II, but encountered serious challenges in maintaining the drug supply of this life saving treatment for AIDS.

13. + many examples from development…. Vermox New polymorphic form with reduced efficiency Neupro - recall Crystallisation of new form Coumadin - recall Lack of control of crystal form Norvir - withdrawal New polymorphic form Tegretol – clinical failure due to crystal transformation Avalid - recall Lack of control of crystal form

14. New example: Lack of control of crystal forms FOR IMMEDIATE RELEASE - May 10, 2013 - Weston, Florida: Apotex Corp. announced today that it is conducting, on behalf of the manufacturer Hospira, Inc., a voluntary nationwide recall of 21 lots of Piperacillin and Tazobactam for Injection, USP 40.5 grams, NDC number 60505-0773-00 to the hospital / healthcare provider /user level. The impacted lots of Piperacillin and Tazobactam for Injection, USP 40.5 grams may show precipitation / crystallization in IV bag or IV line after reconstitution.

15. What do the guidelines say?

16. ICH guideline

17. ICH Q6A: Decision Tree Keep searching?

18. All polymorphic forms have different properties…..but how different? ICH Q6A: Decision Tree Risk Assessment!

19. ICH Q6A: Decision Tree Does your drug product performance testing (e.g., dissolution testing) provide adequate controls if the polymorph ratio changes? Risk Assessment!

20. Read more: Non-binding recommendations from FDA http://www.fda.gov/downloads/Dru gs/GuidanceComplianceRegulatoryInf ormation/Guidances/ucm072866.pdf “Although the conceptual framework adopted by these decision trees is based primarily on the potential for polymorphic forms to affect drug product BA/BE, we recommend that you still consider the influence polymorphic forms may have on the ability to manufacture the drug product and on the stability of the drug product.”

21. Summary: Why perform polymorph screening? 1.To fulfill guidelines 2.To secure that you have the stable API – i.e. no risk of transformation 3.To find a metastable polymorph that have the needed properties – and define the ”stability limits” 4.(To protect IPR)

22. Polymorph screening – When?

23. When do I start polymorph screening The earlier the better….. Potential risk: Repetition of full development program Interpretation of results….. What if lack of efficiency is due to crystallisation? Consider perfoming a reduced polymorph screening in very early development

24. Polymorphy, Quality by Design and Risk Accessment ”The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient....” ICH Q8/Q9

25. Risk Assessment RISK Polymorph transition Probability that it will happen Depends on relative stability of polymorphic form Consequence if it goes wrong Depends on therapeutic window, solubility, etc. Consequence if it goes wrong Depends on therapeutic window, solubility, etc. http://www.leonaking.org/risk-management

26. Impact? Maybe not – but you will have to show Will a polymorphic transformation have significant impact on product properties? At some time point a spontanous transition from a metastable to a stable polymorph WILL occur….but when?

27. Evaluating risk Time (hours) Systemic concentration Therapeutic window Time (hours) Systemic concentration Therapeutic window Broad therapeutic window and high solubility: Simple screening Narrow therapeutic window and low solubility: Extensive screening and testing

28. Evaluating risk - guidelines An integrated set of guidelines:  Q8 Pharmaceutical Development  Q9 Quality Risk Management  Q10 Pharmaceutical Quality Systems

29. Risk assessment with regard to bioavailability 1.What is the risk that a much more stable polymorph form will be discovered? 2.Solubility and dissolution: Is bioavalability dependent on dissolution (at all physiological pH values)? What if dose increases? 3.What would be ”worst case” if polymorphic transformation occured? (± 2% or ± 100%) 4.Would it be discovered if a polymorphic change took place with the current analytical methods? (dissolution, DVS, XRD?)

30. Example Form A: Solubility 1.2 mg/ml Form B: Solubility 1.4 mg/ml (pH independant) Dose: 10 mg Form A is the stable form (but almost equal stability) Highly soluble at given dose ”High” risk with regard to transformation – but no risk in relation to bioavailability

31. Example Form A: Solubility 1.2 mg/ml Form B: Solubility 1.4 mg/ml (pH independant) Dose: 500-1000 mg Form A is the stable form (but almost equal stability) Limited solubility ”High” risk with regard to transformation – ”some” effect in relation to bioavailability

32. Example Form A: Solubility 1.2 mg/ml Form B: Solubility 10 mg/ml (pH independant) Dose: 500-1000 mg Form A is the stable form (and very different stability) Limited risk with regard to transformation – but if it occurs it will have a high influence on BA.

33. RISK OF TRANSFORMATION Identified risk: Change in polymorphic form/ desalting and thereby a change in dissolution rate/solubility highhigh low Reduce risk: Perform polymorph screening with ”all possible” known risks potentially leading to transformation API arrive from chemist Initial characterisation of compound (crystal form, MP, etc) Pressure Solvents Concentration heating/cooling ”Full” polymorph screening Time line Polymorph screening – when?

34. In early development: In order to minimise the risk of transformation into more stable form (searching for the stable form) “ASSURANCE” In late development: To protect your compound with regard to IPR (including search for “all” metastable forms) Feared scenario: The appearance of a new more stable crystal form in late stage of development Or after introduction to market

35. Can polymorph screening be done ”too soon” in regard to IPR? “The inventiveness of a novel polymorph form of a pharmaceutically active compound will be acknowledged only if the novel polymorph form is associated with an unexpected pharmaceutical activity ” I.e. “different properties” is not enough

36. Polymorph screening – How?

37. Screen: To select, reject, consider, or group (people, objects, ideas, etc.) by examining systematically ”How” according to ICH guideline =Stage is free

38. Setting up the screening Challenge: To select relevant conditions – as it is not possible to test ”all”. The larger the risk – the more extensive the screening Purpose: To ”stress” the system in order to crystallise ”all” in order to crystallise ”all” possible polymorphic forms of the API Purpose: To ”stress” the system in order to crystallise ”all” in order to crystallise ”all” possible polymorphic forms of the API

39. How to create different polymorphic forms… At a given temperature and pressure, one of these forms is the stable form.

40. How to create different polymorphic forms… Imagination?

41. How to create different polymorphic forms… Imagination? Polar end Non-polar end Crystallisation: High ”local” concentrations Solvent mediated

42. How? Newpolymorph? Solvents Wet/dry PressureSpecialmanufac-turingconditions Temperature

43. Case study Well known API used to ”test” simple polymorph screening set-up –3 solvents (very different properties) –3 temperatures (hot/cold/intermediate) –Pressure –Humidity Case study

44. Results: 5 polymorphic forms/solvates found 6 polymorphic forms known from literature: Using a very basic set-up almost all forms were reproduced! Case study If ”the right” conditions are selected, the extent of the screening might be reduced

45. Setting up ”slim” screening procedure Choose a number of solvents with very different properties Examine effect of temperature, pressure and humidity Examine all known ”risks” from manufacturing process

46. All ”precipitates” analysed by XRD – crystalline? Crystallisation: Concentration Temperature Evaporation rates Pressure All forms analysed by TGA: True polymorphic forms or solvates?

47. Only crystalline material has a diffraction patternOnly crystalline material has a diffraction pattern All polymorphic forms have unique patternAll polymorphic forms have unique pattern A new polymorphic form is identified by XRD

48. A ”pure” polymorph are distinguished from a solvent by TGA Weight loss upon heatingWeight loss upon heating Reveals ”loosely bound” componentsReveals ”loosely bound” components  Solvates (hydrates) are identified Solvates (hydrates) are identified

49. Relative stability of polymorphs After initial screening: Examination of stability Most stable = lowest solubility Relative stability might change with temperature …. but independent on solvent Solvates might ”slur” the picture A metastable form will always transform into the stable form – but it might take time…..

50. Why does the stable form not always precipitate?  Local concentration  Orientation in solvent due to solvent properties  Solvent ”mediated” crystallisation  Kinetics determines the transformation rate Metastable polymorphs are formed due to optimal crystallisation conditions

51. Why is it difficult to find all forms? Mix acetone and acetonitril 1:1 and add 1.5% of water. Heat it to 39  C for 3 minutes and cool it with liquid nitrogen. Dry the sample for >24 hours at 100  C. Expose the sample to EtOH vapor. Dissolve the the sample in MeOH and leave for stirring for 10 hours at RT To find “all” forms a very extensive polymorph screening is required… What is the propability that these forms are more stable ”Unpredictable” Design of Experiment (e.g. MODDE) very difficult

52. Dissolution Need for quantification of polymorphic form? Yes….. If a high risk of transformation exist (remember to include examination of the excipients)If a high risk of transformation exist (remember to include examination of the excipients) If a possible transformation has high influence on bioavailabilityIf a possible transformation has high influence on bioavailability Does the manufacturing process routinely give a single polymorph? Yes – Qualitative Control (IR, etc) No – Quantitative Control (XRD, etc) Methods: XRD, FTIR, DVS, dissolution, DSC ICH 10: Identify sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation;

53. Dissolution Need for quantification of polymorphic form? Methods: XRD, FTIR, DVS, dissolution, DSC ICH Q10: “Identify sources of variation affecting process performance and product quality for potential continual improvement activities to reduce or control variation” ICH Q10: Demonstrate product and process understanding, including effective use of quality risk management principles (e.g., ICH Q8 and ICH Q9). Opportunity to: facilitate science based pharmaceutical quality assessment; enable innovative approaches to process validation; establish real-time release mechanisms.

54. Dissolution Need for ID of polymorphic form in final product Methods: XRD, FTIR, DVS, dissolution, DSC Q6A: “It is generally technically very difficult to measure polymorphic changes in drug products. A surrogate test (e.g., dissolution) (see Decision tree 4(3)) can generally be used to monitor product performance, and polymorph content should only be used as a test and acceptance criterion of last resort. Not true If I know I produce the same form each time – and it is the stable polymorph there is no need for testing?

55. Does your surrogate test assure crystalline purity? Dissolution tests are generally not validated in order to predict possible variations in vivo A dissolution test of polymorphic changes should be tested in relevant biological media (pH 1.5 – 7)

56. Need for ID of polymorphic form in final product Methods: XRD, FTIR, DVS, dissolution, DSC Down to 3-5% “crystalline impurity” can be detected by XRD - Even lower with DVS (amorphous) A surrogate test (dissolution) is generally much less sensitive in detecting polymorphic changes Interations with excipients can cause changes from stable to metastable form! Identity of crystalline form in final product should always be validated! (i.e. compatibility study)

57. Summary What? Why? When? How? All API’s exist in different crystal forms with different properties At some time point a spontaneous transformation between metastable forms and the stable form will occur A polymorph screening will lead to ”increased control”

58. Summary What? Why? When? How? Cases from real life show the need for screening for polymorphs: Transformation of polymorphic form might affect patient safety and consequences should be evaluated The requirement is stated in ICH Q6A

59. Summary What? Why? When? How? Risk assessment! Never too early, but the extent should correspond to the risk

60. Summary What? Why? When? How? New polymorphic forms can be formed by changing the surroundings No such a thing a a ”full” screening exist – but risk of transformation can be minimized

61. Particle Analytical ApS www.particle.dk kli@particle.dk