Cocrystals: A Regulatory Perspective. Scott L. Childs Renovo Research

Transcription

1 Cocrystals: A Regulatory Perspective Scott L. Childs Renovo Research

2 Outline FDA guidance EMA reflection paper Global regulatory strategies Potential for commercial impact

3 Summary of FDA Guidance Cocrystals are drug product intermediates (DPI) Cocrystal = API plus excipient (coformer = excipient) A cocrystal is the same API as a polymorph From a legal and regulatory perspective this is significant Cocrystal manufacturing (API/DP facilities) Cocrystal characterization

4 FDA Guidance: Positives The FDA has validated the use of cocrystals to some degree by providing final guidance Regulatory approach for coformers established The coformer is an excipient More flexibility in manufacturing site and manufacturing methods Switching to a cocrystal later in the development process can be easier

5 FDA Guidance: Negatives Industry does not favor this regulatory approach IP utility of a cocrystal is reduced Is cocrystal characterization still ambiguous? Will the industry shy away from cocrystal use because of the unknown aspects of the guidance? Questions about cocrystal manufacturing Questions about global regulatory conflicts Concerns about expiration dates with DPI label

6 Summary of EMA reflection paper Cocrystals are API Cocrystals are treated essentially the same as salts Sameness: based on effect on safety/efficacy Coformers with established use/tox are reagents Rational scientific explanation of their approach the classification of solid state APIs into salts or cocrystals is considered only of theoretical nature. Ultimately, the resulting material properties are the critical factors regardless of the molecular bonding involved. 6

7 Comparing regulatory approaches Classification FDA Drug Product Intermediate (DPI) EMA Active ingredient (API) Manufacturing Manufactured as DPI (or API) Manufactured as API Sameness Same API regardless of effect on efficacy Same as API unless demonstrated to have different efficacy Industry position Industry rejects/wants approach changed Industry will accept/ comments due 7

8 API or DPI: what s the difference? API (Active Pharmaceutical Ingredient) Manufacturing site: API facility Primary manufacturing method is from solvent/solution Well defined characterization requirements Expiration date of product NOT linked to API manufacture DPI (Drug Product Intermediate) Manufacturing site: Drug Product facility Use of solvent is typically very limited Different characterization requirements Expiration date of product linked to DPI manufacture 8

9 FDA approach to different forms Polymorphs Same API Salts Different API Per the current regulatory scheme, different polymorphic forms are considered the same active ingredients. Per the current regulatory scheme, different salt forms of the same active moiety are considered different active ingredients. 9

10 EMA approach to different forms Different API Safety, efficacy different Polymorphs Hydrates Salts Cocrystals Safety, efficacy same Same API different salts, esters, ethers, isomers, mixture of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance unless they differ significantly in properties with regard to safety and/or efficacy. Article 10.2.b of Directive 2001/83/EC

11 Cocrystal manufacturing options The selection of a manufacturing facility (either API or Drug Product) depends on: Solvent volumes and processes/equipment required/preferred to produce cocrystal Regulatory (and perhaps IP) strategy API manufact. site API (Drug Substance) Pure phase cocrystal (DPI) Drug product manufacturing site Formulated cocrystal (DPI) Final dosage form When limited solvent can be used API (Drug Substance) API manufacturing site Pure phase cocrystal (DPI as API) Drug product manufacturing site Formulated cocrystal (DPI) Final dosage form When crystallization from clear solution is preferred

12 Different development paths Cocrystal as DPI Cocrystal selection late in pre-formulation Use established process for API Manufacture cocrystal in DPI facility Integrate cocrystal as DPI into formulation Clinical trial material produced Decision making Cocrystal discovery: Timing and timelines Most suitable manufacturing process Strategy/role in drug product Legal considerations Regulatory considerations Regulatory strategy with global harmony: adopt either EMA or FDA guidance and then approach other agency with a request to make an exception Cocrystal as API Cocrystal selection early in solid form screening Develop API process for cocrystal Manufacture cocrystal in API facility Integrate cocrystal as API into formulation Clinical trial material produced

13 Guidance is not written in stone Pharma prefers a single regulatory approach applicable on a global scale How flexible will FDA and/or EMA be? Industry will resist adopting the FDA Guidance and embrace the concept of cocrystals as DPI Continuing efforts will focus on creating alignment Industry would like the FDA to adjust their position Existing guidance notes that: You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. 13

14 Conclusions/Summary FDA guidance EMA reflection paper Global regulatory strategies Potential for commercial impact

15 Thank You! Scott L. Childs Renovo Research 749 Moreland Ave SE Suite A201 Atlanta, GA

16 Questions/Discussion What are the key determinants for solid state stability of cocrystals? Does it matter if a compound is cocrystal or salt? When does shelf life of cocrystals begin? Are the sponsors expected to submit both API and cocrystal stability data? What if API cannot be isolated? What does one need to demonstarate disproportionation of cocrystals before the site of action. Could you comment on characterization of cocrystals How do we address compounds that contain is a mix of salt and cocrystal? What is the future of cocrystals?

17 Embracing the Guidance: New opportunities for cocrystals The guidance is significantly enabling in the right context Cocrystal formulation The guidance views a cocrystal as a formulated material Cocrystal manufacturing Shift cocrystal synthesis from Drug Substance to Drug Product facilities The use of greener (and non-traditional) synthesis methods is possible

18 pk data (ng/ml) dissolution (mg/ml) pk data (ng/ml) dissolution (mg/ml) Danazol cocrystal formulation results Not Formulated cocrystal danazol:vanillin cocrystal 10X Formulated polymorph in vivo in vitro (a) 1.7X (a) (b) AUC increase in vivo (b) in vitro Hypothesis: Cocrystals must be formulated appropriately in order to compete with existing solutions to the bioavailability problem. Mol. Pharmaceutics, 2013, 10 (8), pp DOI: /mp400176y Funding: NSF SBIR Phase I Grant IIP

19 Cocrystals are one option within an array of available technologies Competing technologies Amorphous dispersion API Properties Hot Melt Extrusion Self-emulsifying/lipids Particle size Cosolvent/surfactant Production Process Performance Stability Safety Regulatory Formulation Complexation Cocrystal formation Excipients/ Dosage Form

20 Cocrystal Manufacturing Process Coformer (excipient) Surfactant, polymer (excipients) Filler, binder, etc (excipients) API (Drug Substance) Pure phase cocrystal (DPI) Formulated cocrystal (DPI) Final dosage form Solvent type/volume and Processing Conditions

21 Cocrystal synthesis and solvent use High % solvent (fully dissolved) Crystallization from clear solution Jacketed reactors (cooling or anti-solvent addition) Slurry conversion: flowing suspension Stirred suspension (high flow) High shear mixing/emulsification Slurry conversion: Wet mass processing Stirred paste (low flow/thick consistency) Wet granulation, roller compaction, milling or high shear blending of semi-solids No solvent (solid mixture) Dry or non-solvent based processing Dry milling process (i.e. ball mill) Hot melt extrusion

22 Integration concept summary Positive: Cocrystal investigations can be investigated in parallel with amorphous dispersions and other solubilizing approaches on the same timeline Cocrystal as DPI does not disrupt existing API manufacturing Scale-up of cocrystal can be faster, greener and more cost effective The approach is more consistent with FDA Guidance Negative: Pharma wants cocrystal to be API Pharma disagrees with the Guidance Pharma associates cocrystals with risk FDA is not responsive to questions

23 Key commercial concerns Cannot be applied generally Duplicates existing approaches Regulatory guidance issues/ema conflict No precedence with FDA yet Toxicity/mass of coformer Scale-up (costs, facility, equipment, expiration) Effect of processing/storage (wet granulation) Requires additional R&D ($+risk)