Cocrystals: A Regulatory Perspective

Scott L. Childs

Renovo Research

Outline

• FDA guidance

• EMA reflection paper

• Global regulatory strategies

• Potential for commercial impact

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

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

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

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

Comparing regulatory approaches

7

FDA EMA Classification Drug Product

Intermediate (DPI)

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

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

FDA approach to different forms

• “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

Polymorphs Same API

Salts Different API

EMA approach to different forms

• “… 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

Polymorphs

Hydrates

Salts

Cocrystals

Safety,

efficacy

different

Safety,

efficacy

same

Same

API Different

API

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

Formulated cocrystal

(DPI)

Final dosage

form

Pure phase cocrystal

(DPI as API)

API (Drug

Substance)

Formulated cocrystal

(DPI)

Final dosage

form

Pure phase cocrystal

(DPI)

API (Drug

Substance)

API manufact. site Drug product manufacturing site

Drug product manufacturing site API manufacturing site

When limited solvent can be used

When crystallization from clear solution is preferred

Different development paths

• 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

Clinical trial material produced

Integrate cocrystal as DPI into formulation

Manufacture cocrystal in DPI facility

Use established process for API

Cocrystal selection late in pre-formulation

Clinical trial material produced

Integrate cocrystal as API into formulation

Manufacture cocrystal in API facility

Develop API process for cocrystal

Cocrystal selection early in solid form screening

Cocrystal as API Cocrystal as DPI

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

Conclusions/Summary

• FDA guidance

• EMA reflection paper

• Global regulatory strategies

• Potential for commercial impact

Thank You!

Scott L. Childs

Renovo Research 749 Moreland Ave SE

Suite A201 Atlanta, GA 30316

404-377-7876 schilds@renovoresearch.com

www.renovoresearch.com

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?

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

Danazol cocrystal formulation results

Hypothesis: Cocrystals must be formulated appropriately in order to compete with existing solutions to the ‘bioavailability problem’.

Mol. Pharmaceutics, 2013, 10 (8), pp 3112–3127 DOI: 10.1021/mp400176y

Funding: NSF SBIR Phase I Grant IIP-1143108

in vivo in vivo

in vitro in vitro

10X

1.7X

dis

solu

tio

n (

mg

/ml)

dis

solu

tio

n (

mg

/ml)

pk

dat

a (

ng

/ml)

pk

dat

a (

ng

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(a) (b) (b) (a) AUC increase

cocrystal

polymorph

Not Formulated Formulated danazol:vanillin cocrystal

Cocrystals are one option within an array of available technologies

• Competing technologies

– Amorphous dispersion

– Hot Melt Extrusion

– Self-emulsifying/lipids

– Particle size

– Cosolvent/surfactant

– Complexation

– Cocrystal formation

Performance Stability Safety

Regulatory

API Properties

Production Process

Excipients/ Dosage Form

Formulation

Cocrystal Manufacturing Process

Formulated cocrystal

(DPI)

Pure phase cocrystal

(DPI)

API (Drug

Substance)

Coformer (excipient)

Surfactant, polymer

(excipients)

Filler, binder, etc (excipients)

Solvent type/volume and Processing Conditions

Final dosage

form

Cocrystal synthesis and solvent use

• 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

• Dry or non-solvent based processing – Dry milling process (i.e. ball mill) – Hot melt extrusion

High % solvent (fully dissolved)

No solvent (solid mixture)

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

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)