Document:

exh10_5.htm

 

Exhibit 10.5

 

 

 

	

March, 28 2012

 

 

Stephanie McSwain

Vice President, Manufacturing

Aeolus Pharmaceuticals, Inc.

26361 Crown Valley Parkway

Mission Viejo, CA 92681

 

 

Dear Stephanie,

 

Thank you for your continued interest in Johnson Matthey Pharma Services (JMPS).  As a follow-up to your recent request, we are pleased to provide Aeolus Pharmaceuticals (Aeolus) with this proposal for Solid Form Screening and Characterization of 2318.C.

 

Please contact me if I can provide additional information or be of additional service.  We appreciate the opportunity to support your chemistry service needs and look forward to your feedback on this proposal.

 

 

All the Best,

 

 

/s/ Todd Stark

Todd Stark, Ph.D.

 

Manager, Business Development

Johnson Matthey Pharma Services

 

978-496-7088

tstark@jmusa.com

 

 

  

  

  

 

	

 

Proposal for Solid Form Screening and Characterization of 2318.C

 

Appendix 3 to the Research and Manufacturing Agreement Dated:  February 16, 2011

 

Proposal Date:  March, 28 2012

 

Johnson Matthey Pharma Services (JMPS) is pleased to provide Aeolus Pharmaceuticals (Aeolus) with this proposal for Solid Form Screening and Characterization of 2318,C. JMPS will use commercially reasonable efforts to meet all milestones for the estimated fees as outlined in this proposal.  This proposal is based on technical information provided by Aeolus and other available technical information within the public literature and available at JMPS.

 

The project objective is to identify and characterize a desired form of 2318.C.  The table below provides a summary overview.

 

Summary

 

	
Proposal No:  AEO-120223-1166

	
Stage #

	
Description

	  	
Service Fee

	
Est. Direct Expenses*

	
Est. Duration

	
1

	
Oxidation State Studies

	  	
$[...***...]

	
[...***...]

	
[...***...]

	
2

	
Solid Form Screening

	  	
$[...***...]

	
[...***...]

	
[...***...]

	
3

	
Structural Elucidation

	  	
$[...***...]

	
[...***...]

	
[...***...]

	
3

	
Material Testing

	  	
$[...***...]

	
[...***...]

	  
	  	  	
Total

	
$[...***...]

	
$[...***...]

	
[...***...]

* Service Fee includes [...***...].

 

 

  

1

  

 

	

 

Introduction

 

	
1)  

	
[...***...] 12 3

 

 

 

 

 

 

 

 

 

 

 

 

 

  

[...***...]

  

[...***...]

  

[...***...]

 

 

  

2

  

 

	

 

[...***...]

 

Stage 1 - Oxidation State Studies

 

[...***...]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

3

  

 

	

 

 

Stage 2 – Solid Form Screening

 

Phase 1 - Batch Profiling and Design of Screening Experiments

 

The goal of this phase is to generate a comprehensive data package which fully characterizes the physical state of the starting solid and serve as a reference and baseline for the subsequent solid form screening work.  The following activities will be performed:

 

 

Phase 1-1- Characterization of the current lots that exist at JMPS

	
-  

	
Assessment of crystallinity by X-ray powder diffraction (XRPD)

	
-  

	
For each unique polymorph the following techniques will be used:

	
§  

	
Thermal analysis by Differential Scanning Calorimeter (DSC) and Thermal Gravimetric Analysis (TGA)

	
§  

	
Water content measurement

	
§  

	
Assessment of morphology using optical microscopy

	
-  

	
Evaluation of oxidation state on crystal structure (identified by XRPD)

 

Phase 1-2- Solubility assessment of starting solid

	
-  

	
A quantitative solubility assessment will be carried out in [...***...] solvents, with diverse properties, and at [...***...] different temperatures to provide information for crystallization experiments and design of solid form screening experiments.  The solvents that were used in the manufacturing of the solid will be included in the list.

 

Phase 1-3- Design of the polymorph screening experiments

	
-  

	
Using the initial solubility data and structure of the molecule, up to [...***...] solvents will be selected for the screening experiments4.  These will include cooling, evaporative and anti- solvent crystallizations, thermal treatment if needed, slurry of starting material and the amorphous form.

Phase 2 - Polymorph Screening

 

In this phase, an array of scientifically crafted experiments will be employed to look for possible polymorphs, solvates and hydrates.  The diverse solvents and conditions are intended to increase the chance of finding various polymorphs.  In a thermodynamic solution mediated transition the less stable polymorph converts to a more stable one.  Therefore, starting with an amorphous solid, which is at the highest level of energy, could potentially result in formation and isolation of the least stable form.  The following activities will be performed:

 

 

Phase 2-1- Generation of amorphous material

	
-  

	
Various techniques such as rapid evaporation at high concentration will be employed in an attempt to make amorphous material.  Producing and characterizing the amorphous form is

  

4 Mahmoud Mirmehrabi and Sohrab Rohani, 2005, “An Approach to Solvent Screening for Crystallization of Polymorphic Pharmaceuticals and Fine Chemicals”, Journal of Pharmaceutical Sciences, vol. 94, No. 7, 1560-1576

 

 

  

4

  

 

	

 

important in terms of IP protection and also increasing the chance of finding metastable forms.

	
-  

	
The amorphous material will be characterized using XRPD, microscopy and DSC.

 

Phase 2-2- Screening experiments

The number and type of experiments are determined at Phase I.  These experiments will be conducted at mL scale consisting of:

	
-  

	
Evaporative crystallization

	
-  

	
Cooling crystallization

	
-  

	
Anti-solvent crystallization

	
-  

	
Thermal treatment for hydrates/solvates or enantiotropic/monotropic related forms

	
-  

	
Slurry of the starting material and the amorphous form (if applicable)

	
-  

	
Dry grinding and solvent drop grinding

During and after screening experiments, all of the recovered solids will be analyzed using XRPD.

 

Phase 3 - Polymorphs Characterization

 

At this point, sufficient quantities of each polymorph (up to [...***...] most promising ones) should be prepared to enable full characterization of the new forms.  The reproducibility of each crystal structure (based on XRPD) will be assessed at this scale-up effort.  The results of characterization are required for patent application and IP protection.  This data will also be needed to establish the relative stability of different polymorphs and for selection of the most stable form for development.  The following activities will be performed:

 

 

Phase 3-1- Scale up of new crystal forms

	
-  

	
About [...***...] of each of the new forms (up to [...***...]) will be produced and further characterized using the following techniques:

	
§  

	
Assessment of crystallinity by XRPD

	
§  

	
Thermal analysis by DSC and TGA

	
§  

	
Water content measurement

	
§  

	
Assessment of morphology using optical microscopy

	
§  

	
Assessment of the hygroscopicity using DVS

	
§  

	
Oxidation state

	
§  

	
Equilibrium solubility of forms in water

	
§  

	
Solid form stability at high humidity environment up to 7 days

 

Phase 3-2- Establish the thermodynamic relative stability of forms using one or all of the following techniques

	
-  

	
Comparison of thermal properties of anhydrous forms, e.g. heat of fusion and melting point

	
-  

	
Solubility differences

	
-  

	
Determining whether the forms are enantiotropically or monotropically related.

	
-  

	
Slurry stability of [...***...] relevant forms at [...***...] different temperatures and [...***...] solvents

 

 

  

5

  

 

	

 

Phase 3-3- Establishing the hydration state of the preferable solid form

	
-  

	
The most stable or otherwise preferable solid form will be freshly prepared from reaction mixture and then exposed to various levels of relative humidity to determine the equilibrium hydration state if such a state exists.

Stage 3 - Structural Elucidation

 

Several physico-chemical methods applicable for solid phase structural elucidation will be used to study the most desirable solid form of 2318.C.  These methods will provide “fingerprint” characteristics that could be used to evaluate the equivalency of any future 2318.C sample to this most favorable (standard) form.

 

[...***...]

 

Summary of Objectives:

 

	
·  

	
Stage 1, to better understand the control of oxidation state prior to investigating different polymorphic forms of 2318.C

	
·  

	
Stage 2, design and screen for different forms of 2318.C followed by isolation of the identified forms with polymorphic characterization

	
·  

	
Stage 3, to better elucidate the structure for the identified most favorable form

Deliverables:

 

	
·  

	
Weekly (or bi-weekly) updates

	
·  

	
Final report with a list of all experiments performed, data interpretation, conclusions and, recommendations

 

 

 

  

6

  

 

	

 

Timeline:

 

	
·  

	
Stage 1: [...***...]

	
·  

	
Stage 2: [...***...] - starts after Stage 1

	
·  

	
Stage 3: [...***...] - starts after Stage 2

JMPS will use commercially reasonable efforts to achieve the deliverables as outlined in this proposal.  This estimate is based on a specific scope of work that was developed using technical information provided by Aeolus.  Project objectives or technical details may differ from those assumed in this estimate.  If a significant difference occurs from the originally proposed scope of work or with the actual technical details from those assumed, JMPS will assess the impact of such a change and inform Aeolus.  JMPS and Aeolus will promptly and in good faith develop and agree to a modified project plan to ensure that project delays are avoided or minimized.  If these changes result in additional cost, Aeolus must authorize the additional cost in writing prior to implementation.

 

JMPS will schedule resources and order materials upon acceptance of this proposal.  Scheduling is contingent on prevailing staff commitments, raw material, and equipment availability.  Aeolus will be notified of the expected start date as soon as is practical.  JMPS will appoint a project leader to oversee the work and serve as the primary technical liaison with Aeolus.  Project updates will be submitted weekly and conference calls will be arranged on a frequency agreed upon by both parties.

 

JMPS offers to perform Stage 1 and Stage 2 on a Fixed Fee basis.  Stage 3 is provided on a Fixed Fee basis for labor plus direct expenses for outsourced materials testing.  For clarity, the fees for Stages 1 and 2 are fixed as is the labor fee for Stage 3.  The materials testing portion of Stage 3 is variable and we have provided an estimate of its cost here.  The direct expenses for Stage 3 material testing will be billed as direct expenses at cost.

 

Notwithstanding anything to the contrary, upon acceptance of this proposal, Aeolus will be invoiced a deposit of [...***...]% in the amount of $[...***...].  Deposits will be credited proportionally against the final invoice for each stage.  Invoices for fixed fee work are issued upon completion of stage deliverables.  Direct expenses not included in the fixed fees will be invoiced monthly.  Invoices are payable within thirty (30) days from the date of issuance.  Materials will be shipped from JMPS’s facility F.C.A (Incoterm 2010) within 30 days of project completion.

 

All work specified in this proposal is subject to the Research and Manufacturing Agreement between Johnson Matthey Pharma Materials dba Johnson Matthey Pharma Services and Aeolus Pharmaceuticals dated February 16, 2011.  This proposal is valid for thirty (30) days from the preparation date.

 

 

  

7

  

 

	

 

AUTHORIZATION

 

Appendix 3 to the Research and Manufacturing Agreement Dated:  February 16, 2011

 

Proposal for Solid Form Screening and Characterization of 2318.C

 

AEO-120223-1166

 

This proposal, including all work and material provided by JMPS hereunder, shall be governed by the Research and Manufacturing Agreement between Johnson Matthey Pharma Materials dba Johnson Matthey Pharma Services and Aeolus Pharmaceuticals.  By its signature below, Aeolus Pharmaceuticals hereby authorizes Johnson Matthey Pharma Services to perform the work detailed in this proposal subject to the Research and Manufacturing Agreement dated February 16, 2011.

 

For:  Aeolus Pharmaceuticals

 

	  	  
	
/s/ John L. McManus

	
Date:  4/30/12

	

Signature

	  
	  	  
	
John L. McManus

	  
	

Printed Name

	  
	  	  
	  	  

 

For:  Johnson Matthey Pharmaceutical Materials, Inc. d/b/a Johnson Matthey Pharma Services

 

	  	  
	
/s/ Jayachandra Reddy, Ph.D.

	
Date:  April 30, 2012

	

Jayachandra Reddy, Ph.D.

General Manager

	  

 

 

8exh10_6.htm

 

 

Exhibit 10.6

 

 

	

 

March, 28 2012

 

Stephanie McSwain

Vice President, Manufacturing

Aeolus Pharmaceuticals, Inc.

26361 Crown Valley Parkway

Mission Viejo, CA 92681

 

 

Dear Stephanie,

 

 

Thank you for your continued interest in Johnson Matthey Pharma Services (JMPS).  As a follow-up to your recent request, we are pleased to provide Aeolus Pharmaceuticals (Aeolus) with this proposal for Scale-up Development and cGMP Manufacture of 2318.C.

 

Please contact me if I can provide additional information or be of additional service.  We appreciate the opportunity to support your chemistry service needs and look forward to your feedback on this proposal.

 

All the Best,

 

/s/ Todd Stark

Todd Stark, Ph.D.

 

Manager, Business Development

Johnson Matthey Pharma Services

 

978-496-7088

tstark@jmusa.com

 

 

  

  

  

 

	

 

Proposal for Scale-up Development and cGMP Manufacture of 2318.C

 

 

Appendix 4 to the Research and Manufacturing Agreement Dated:  February 16, 2011

 

 

Proposal Date:  March, 28 2012

 

Johnson Matthey Pharma Services (JMPS) is pleased to provide Aeolus Pharmaceuticals (Aeolus) with this proposal for scale-up development and cGMP manufacture of 2318.C.  JMPS will use commercially reasonable efforts to meet all milestones for the fees as outlined in this proposal.  This proposal is based on technical information provided by Aeolus and other available technical information within the public literature and available at JMPS.

 

 

Summary

 

	
Proposal No:  AEO-120223-1167

	  	  
	
Stage #    

	
Description

	
Service Fee*

	
Estimated Timeline        

	
1

	
Scale-up Development

	
$[...***...]

	
[...***...]

	
2

	
Kilo-Lab Demonstration

	
$[...***...]

	
[...***...]

	
3

	
cGMP Manufacture

	
$[...***...]

	
[...***...]

	  	
Total

	
$[...***...]

	
[...***...]

*Includes [...***...].

 

JMPS will use commercially reasonable efforts to achieve the deliverables as outlined in this proposal.  This proposal is based on a specific scope of work that was developed using technical information provided by Aeolus.  Project objectives or technical details may differ from those assumed in this proposal.  If a significant difference occurs from the originally proposed scope of work or with the actual technical details from those assumed, JMPS will assess the impact of such a change and inform Aeolus.  JMPS and Aeolus will promptly and in good faith develop and agree to a modified project plan to ensure that project delays are avoided or minimized.  If these changes result in additional cost, Aeolus must authorize the additional cost in writing prior to implementation.

 

JMPS will schedule resources and order materials upon acceptance of this proposal.  Scheduling is contingent on prevailing staff commitments, raw material, and equipment availability.  Aeolus will be notified of the expected start date as soon as is practical.  JMPS will appoint a project leader to oversee the work and serve as the primary technical liaison with Aeolus.  Project updates will be submitted weekly and conference calls will be arranged on a frequency agreed upon by both parties.

 

 

  

1

  

 

	

 

 

JMPS offers to perform this work on a Fixed Fee basis.  Notwithstanding anything to the contrary, upon acceptance of this proposal, Aeolus will be invoiced a deposit of [...***...]% in the amount of $[...***...].  Deposits will be credited proportionally against the final invoice for each Stage.  Invoices are payable within thirty (30) days from the date of issuance.  Materials will be shipped from JMPS’s facility F.C.A (Incoterm 2010) within 30 days of project completion.

 

All work specified in this proposal is subject to the Research and Manufacturing Agreement between Johnson Matthey Pharma Materials dba Johnson Matthey Pharma Services and Aeolus Pharmaceuticals dated February 16, 2011.  This proposal is valid for thirty (30) days from the preparation date.

 

 

Assumptions:

 

	
1.  

	
The deliverables and associated effort described herein are based on the current process and yields.

	
2.  

	
JMPS will use USP analytical methods or their equivalents for some tests and may outsource these tests to qualified testing facilities.

	
3.  

	
It is assumed that Compound 2318.C and its intermediates are non-potent (Category 2 out of 4 on a Safebridge scale) and will be handled using typical containment/isolation techniques.

 

Stage 1:  Scale-up Development

 

JMPS will perform scale-up development activities prior to the non-GMP demonstration run.

 

1. Cleaning method development

[...***...]

2. Preparation of 2318.A with complete exclusion of air

[...***...]

 

 

Deliverables for Stage 1:

 

· A summary report.

· A cleaning protocol for 2318.A.

· A recommendation on how to implement air oxidation on scale (if required).

 

 

  

2

  

 

	

 

Stage 2:  Non-GMP Kilo-lab Demonstration

 

JMPS will perform a kilo-lab demonstration of the developed process by running a single batch of each step in 72-liter and 100-liter glass equipment.  [...***...]  The process will be documented in non-GMP batch records, and the material will be tested according to the current specifications.

 

	
1.  

	
Write non-GMP batch records (3) to fit the equipment being used for this campaign

	
2.  

	
Process approximately [...***...] of aldehyde

	
3.  

	
Evaluate IPC methods

	
4.  

	
Co-mil/screen final API

	
5.  

	
Prepare Certificate of Testing for 2318.C

 

Deliverables for Stage 2:

 

· A brief (1-2 page) report summarizing the process and yields at each step.

· Copies of executed non-GMP batch records.

· Any material produced as a result of this stage accompanied by a COT.

 

Stage 3:  cGMP Manufacture

 

Upon completion of the kilo-lab campaign, JMPS will perform a plant scale demonstration of the process in a 100-Gallon / 200-Gallon equipment train.  [...***...]  The process will be documented in cGMP batch records, and the material will be tested according to the current specifications.

 

The overall manufacturing plan is outlined in Table 1.

 

Table 1

 

	
Step Description

	
Equipment

	
No. of Batches

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

	
[...***...]

 

 

  

3

  

 

	
1.  

	
Write and review batch records (3) to fit the equipment being used for this campaign

	
2.  

	
Process approximately [...***...] of aldehyde

	
3.  

	
Prepare Certificate of Analysis, BSE/TSE documents and Certificate of Compliance for 2318.C

 

Deliverables for Stage 3:

 

· Approximately [...***...]  batch of 2318.C under cGMP.

· A brief (1-2 page) report summarizing the process and yields at each step.

· Copies of executed cGMP batch records.

· COA, BSE/TSE and COC.

 

JMPS offers to perform this work on a Fixed Fee basis.

 

  

4

  

 

	

 

AUTHORIZATION

 

 

Appendix 4 to the Research and Manufacturing Agreement Dated:  February 16, 2011

 

 

Scale-up Development and cGMP Manufacture of 2318.C

 

 

AEO-120223-1167

 

This proposal, including all work and material provided by JMPS hereunder, shall be governed by the Research and Manufacturing Agreement between Johnson Matthey Pharma Materials dba Johnson Matthey Pharma Services and Aeolus Pharmaceuticals.  By its signature below, Aeolus Pharmaceuticals hereby authorizes Johnson Matthey Pharma Services to perform the work detailed in this proposal subject to the Research and Manufacturing Agreement dated February 16, 2011.

 

 

For:  Aeolus Pharmaceuticals

 

/s/ John L. McManus                                                                 Date:  4/30/12                                                     

Signature

John L. McManus                                                      

Printed Name

 

For:  Johnson Matthey Pharmaceutical Materials, Inc. d/b/a Johnson Matthey Pharma Services

 

/s/ Jayachandra Reddy                                                                Date:  April 30, 2012                                                     

Jayachandra Reddy, Ph.D.

General Manager

 

5

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