Document:

Exhibit 10.8

 

STRICTLY CONFIDENTIAL

 

AMENDMENT N°2 TO PHARMACEUTICAL DEVELOPMENT*

AGREEMENT

 

BETWEEN

 

BEAUFOUR IPSEN INDUSTRIE S.A.S., a French corporation incorporated under the laws of France, located at rue d’Ethe Virton, 28100, France, duly represented by Jean-Pierre Dubuc, President,

 

hereinafter referred to as “Ipsen”, on the one hand,

 

AND

 

RADIUS HEALTH Inc., a United States corporation incorporated under the laws of the State of Delaware, United States, with its principal office at 300 Technology Square-5th Floor, Cambridge, MA, USA and formerly known as Nuvios, Inc., duly represented by Richard Lyttle, Chief Executive Officer,

 

hereinafter referred to as “Radius”, on the other hand.

 

WHEREAS

 

A.                                   Ipsen and Radius are parties to that certain License Agreement dated September 27, 2005 (the “License Agreement”).

 

B.                                     Within the framework of the License Agreement, Ipsen and Radius have entered into a pharmaceutical development agreement to develop a multidose injection for BIM 44058 dated as of January 2, 2006 (the “Pharmaceutical Development Agreement”) pursuant to which Ipsen performs certain research and development tasks and activities in view of developing a new formulation of Licensed Compound and/or Licensed Product.

 

C.                                     Ipsen and Radius have decided to further extend the duration and the scope of the Work Plan and to provide for the consideration relating to such an extension under an amendment to the Pharmaceutical Development Agreement ( “Amendment n°1”).

 

D.                                    Radius has requested, and Ipsen had agreed to manufacture some further stability batches and therefore to further extend the duration and the scope of the Work Plan under a second amendment to the Pharmaceutical Development Agreement (this “Amendment n°2”).

 

NOW, THEREFORE, in consideration of the premises and the performance of the covenants herein contained, IT IS AGREED AS FOLLOWS:

 

1.                                      In this Amendment n°2, unless otherwise expressly provided herein, the capitalized words and phrases shall have the same meaning as in the Pharmaceutical Development Agreement and in Amendment n°1.

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

 

2.                                      The May 31, 2007 deadline agreed upon for the performance by Ipsen or its subcontractors of all the work set out in the Extended Work Plan further to Amendment n°1 and its payment by Radius, is extended to December 31, 2012.

 

For sake of clarity, any reference to the date of December 31, 2006 in Article 10 of the Pharmaceutical Development Agreement and May 31, 2007 in the Amendment n°1 which relates to the performance of the Original Work Plan and the Extended Work Plan shall be replaced by and extended to December 31, 2012. The budget agreed upon in respect to all the work described in the Original Work Plan and the Extended Work Plan shall remain unchanged, except for the over overrun of €98,000 approved by Radius in Q4, 2006.

 

3.                                      The Work Plan is amended so as to include the work described in Appendix A to this Amendment n°2 (the “Second Extended Work Plan”). For clarity, all references to the Work Plan in the Pharmaceutical Development Agreement shall be deemed to include all work described in the Extended Work Plan, the Second Extended Work Plan as well as the work described in the Original Work Plan. Should Radius wish Ipsen to perform any other work in addition to the activities described in the Second Extended Work Plan, Radius and Ipsen shall enter into a new agreement or amendment.

 

4.                                      Timelines described in Appendix A are subject to the execution by Ipsen of an amendment to its existing agreement with Vetter.

 

5.                                      Activities related to the manufacture of Phase III clinical batches by Vetter and tested by Ipsen in the Second Extended Work Plan as identified in paragraphs 2, 4, 5 of Appendix A shall not be commenced by Ipsen unless authorized in writing by Nick Harvey, Chief Financial Officer of Radius or other representative designated in writing by Radius.

 

6.                                      Payments:

 

(a)                                  Subject to any modification of the budget included in the Second Extended Work Plan to be prior agreed in writing by the parties by Mike Dey, Vice-President, Pharmaceutical Development for Ipsen and by Nick Harvey, Chief Financial Officer to Radius or by any other representative designated by the relevant Party, the total amount to be paid by Radius to Ipsen in connection with the research activities and tasks pursuant to the Second Extended Work Plan and this Amendment n°2 shall be as specified in the here aftached Appendix A. Such total amount includes all costs in connection with such research activities, including costs of materials, supplies, services, personnel, subcontractors and overhead, regardless of whether such research activities are performed by Ipsen or by a subcontractor or both. The budget included in the Second Extended Work Plan as described in Appendix A to this Amendment n°2 shows the breakdown by calendar quarter of such total amounts in Euros.

 

(b)                                 Ipsen shall invoice Radius no later than thirty (30) days after the end of each calendar quarter for the amount corresponding to actual FTE time spent as per

 

2

 

timesheets incurred plus actual external cost bills received and approved by Ipsen during the elapsed quarter, as shall in each case be reported in reasonable detail on the invoice annex. Radius shall make payment of each invoice within thirty (30) days after receipt thereof in Euros.

 

(c)                                  Without the prior written consent of Radius, in no event shall Ipsen invoice Radius for an amount due in respect of any calendar year that is greater than the amount budgeted for such calendar year in the Second Extended Work Plan plus the ten percent (10%) limit defined in article 4(d) of this Amendment n°2. In addition, and notwithstanding anything expressed or implied in this Amendment n°2 to the contrary (including without limitation, the Second Extended Work Plan), in no event shall Radius have any obligation to make payments to Ipsen pursuant to this Amendment n°2 for any work done by Ipsen at any time after December 31, 2012 unless Radius shall have authorized in writing any such work.

 

Radius shall pay for all work in respect of which Ipsen has entered into legally binding commitments with subcontractors and which occurs before December 31, 2012, that may not be cancelled by Ipsen without incurring penalties, provided that all of such work is within the framework of the Second Extended Work Plan and the cost of such work is within the budget included in the Second Extended Work Plan.

 

The remaining samples from stability studies will be made available for Radius to ship to Radius nominated contract laboratory by December 31, 2012. Should Radius request in writing that Ipsen conduct work on Radius behalf, Ipsen will be under no obligation to conduct such work.

 

(d)                                 Should external costs incurred by Ipsen in relation to the performance of the activities described in the Second Extended Work Plan be more than as specified in Appendix A hereby attached for such activities, Radius shall reimburse Ipsen such additional costs up to a maximum of ten percent (10%) of the relevant annual amount described in Appendix A for the performance of the specific tasks that resulted in such additional costs. In addition, should internal costs incurred by Ipsen in relation to performance of the Second Extended Work Plan be more than as specified in Appendix A due to an increase in the number of FTE’s required (but not the cost per FTE), Radius shall reimburse Ipsen such additional costs up to a maximum of ten percent (10%) of the relevant annual amount described in Appendix A for the performance of the specific tasks that resulted in such additional costs. In either case, any reimbursement of costs in excess of such percentage will have to be prior agreed by Radius and, in the absence of any such prior agreement by Radius, shall be the responsibility of Ipsen. Ipsen shall use all reasonable efforts to avoid any such cost overruns.

 

7.                                      This Amendment n°2 shall enter into force retroactively upon its signature as of January 1st, 2009 and shall remain in full force and in effect until complete performance of the

 

3

 

Second Extended Work Plan or termination of the Pharmaceutical Development Agreement in accordance with its terms.

 

8.                                      All other terms and conditions of the Pharmaceutical Development Agreement shall remain in full force and effect and shall apply to this Amendment n°2 which is made part of the Pharmaceutical Development Agreement.

 

9.                                      This Amendment n°2 shall be governed by, interpreted and construed in accordance with the laws of the State of New York, U.S.A., without regard to the conflicts of law principles, and shall not be governed by the United Nations Conventions of International Contracts on the Sale of Goods (the Vienna Convention).

 

IN WITNESS WHEREOF, the Parties hereto have caused this Amendment n°2 to be duly executed by their respective duly authorized representatives:

 

	
Date:   January 30, 2009
    	
 
    	
Date:   January 17, 2009
    
	
 
    	
 
    	
 
    
	
SIGNED   by B.N. HARVEY
    	
 
    	
SIGNED   by Jean-Pierre Dubuc
    
	
CFO
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
/s/   B.N. Harvey
    	
 
    	
/s/   Jean-Pierre Dubuc
    
	
on   behalf of
    	
 
    	
as   President of
    
	
RADIUS   HEALTH Inc.
    	
 
    	
BEAUFOUR IPSEN INDUSTRIE S.A.S.
    

 

4

 

APPENDIX A

 

 

CMC Activities for BA058
 Phase III
 Radius / Ipsen

 

1 Stability Batches at Vetter

 

·                  Component Supply for 1.5ml Cartridge with new crimp cap + current bromobutyl stopper

·                  Stoppers available as standard stock item in Vetter.

·                  Standard RTS crimp caps require 12-14 weeks delivery; as already ordered, estimated delivery date week commencing 26th Jan 2009

·                  Machinability test (cartridges fill with new crimp caps and maximum filling volume and dimensional limits) Project work = [*]€

 

 

·                  Stability Batches Scheduled at Vetter in March 2009

	
·
    	
 
    	
BA058   placebo
    	
 
    	
 
    
	
·
    	
 
    	
BA058   2mg/ml solution
    	
 
    	
3,500   cartridges / batch
    
	
·
    	
 
    	
BA058   1mg/ml solution
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Uses   same equipment as used in Ph III
    	
 
    	
 
    
	
Manufacturing   starting date
    	
 
    	
March 09
    
	
Stability   studies start
    	
 
    	
April 2009
    

 

·                  Costs and Timings

 

Cartridge fill volume will be increased to maximum, to increase assurance of delivering 28 doses from each cartridge

 

	
Filling Stability/Technical batches
    	
 
    	
€ [*]
    

From €[*] for placebo & [*]€ for stability batches 1&2mg/ml, + [*]€ project management, microbiological validation [*]€, Closure container integrity test [*]€.

 

2 Clinical Batches 1.5 ml Cartridges

 

·                  Manufacturing of 3 Clinical Batches by Vetter and Tested by lpsen

·                  BA058 placebo

·                  BA058 2mg/ml solution 5,000 cartridges / batch

·                  BA058 1mg/ml solution

 

·                  Planned in May 2009 :

·                  Clinical studies start in July 2009

 

	
·
    	
 
    	
Costs
    	
 
    	
€ [*]
    

·                  From [*] per lot + [*]€ project management costs

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

 

3 Stability Testing of Phase III Preparation Lots

 

	
Activities
    	
 
    	
Duration
    	
 
    	
FTE*
    	
 
    	
FTE cost,
   (k€)**
    	
 
    	
External cost
   (k€)
    
	
Formulation   and Process Development
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
New   crimp caps Supply
    	
 
    	
14 weeks
    	
 
    	
—
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Sterile   filtration validation with new API (Millipore)
    	
 
    	
4 months
    	
 
    	
F: [*]
   A: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Stability   Studies
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Machinability   test & project work
    	
 
    	
1 month
    	
 
    	
—
    	
 
    	
[*]
    	
 
    	
[*]
    
	
36-month   ICH stability study (2 active + 1 placebo): manufacturing + stab study at 5°C   for 36months & 25°C for 6 months & stab-in-use + Mixing   study, filtration trials (Vetter) + μbio validation
    	
 
    	
43 months (including agreement) Final time point: 05/2012
    	
 
    	
F: [*]
   A: [*]
   μ: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
TOTAL
    	
 
    	
 
    	
 
    	
590
    	
 
    	
320
    

 

* F: formulation - A: Analytical - μ: Microbiology

** FTE rates of €[*] per year

 

4 Testing of Ph III Supplies

 

	
Activities
    	
 
    	
Duration
    	
 
    	
FTE*
    	
 
    	
FTE cost,
   (k€)**
    	
 
    	
External cost
   (k€)
    
	
Clinical   Supply
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Phase   III clinical batches manufacturing + release (2 active + 1 placebo)
    	
 
    	
9 months (including agreement)
    	
 
    	
F: [*]
   A: [*]
   μ: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Re-assay   program to verify stability
    	
 
    	
36months
    	
 
    	
A: [*]
   μ: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
IND
    	
 
    	
3 months
    	
 
    	
F: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
Project   Management
    	
 
    	
—
    	
 
    	
F: [*]
    	
 
    	
[*]
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    	
 
    	
TOTAL
    	
 
    	
455
    	
 
    	
218
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
673
    	
 
    	
 
    

 

* F: formulation - A: Analytical - μ: Microbiology

** FTE rates of €[*] per year

 

5 Phasing of Costs for Ph III Program

 

BA058 Phase III Quarterly breakdown for work plan activities

 

Drug Substance & Drug Product Program

 

	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
2009
    	
 
    	
2010
    	
 
    	
2011
    	
 
    	
2012
    	
 
    	
 
    
	
In   €000
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Q1
    	
 
    	
Q2
    	
 
    	
Q3
    	
 
    	
Q4
    	
 
    	
Total
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
External costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
540
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Internal costs
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
1,043
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
Total costs/Quarter
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    	
1,583
    

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

 

	
Total cost/year
    	
 
    	
1,182
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
173
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
136
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
92
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
1,583
    

 

API costs not included; API is supplied by Radius

 

 

6 API needed for Drug Product development activities

 

·                  Estimation based on available BA058 API available in stock on September, 2008

 

	
Activities
    	
 
    	
Units manufactured
    	
 
    	
API (pure)
   needed
    	
 
    	
API batch #
    
	
Stability   studies (ICH Current Formulation with new crimp caps [*]mg/ml &   [*]mg/ml
    	
 
    	
4,000   cartridges as 1 x 4,000 ea of 2mg/ml, 1mg/ml & placebo
    	
 
    	
[*]g   + [*]g = [*]g
    	
 
    	
Lonza   API in final cartridge CC and stopper at Vetter at scale for Ph III
    
	
Optimize/Validate   analytical Method
    	
 
    	
/
    	
 
    	
[*]   g
    	
 
    	
M12507   (Ipsen batch)
    
	
Finalise   API methods
    	
 
    	
/
    	
 
    	
[*]g
    	
 
    	
Lonza   API
    
	
Sterile   filtration validation
    	
 
    	
3,000mL
    	
 
    	
[*]g
    	
 
    	
Lonza   API to mimic Ph III process
    
	
Clinical batches for Ph III  
    Made to a suitable Validation protocol & to provide   stability lots for long-term storage
    	
 
    	
1 x 5,000 cart x 2mg/m1 + 1 x 5,000cart x 1mg/m1+1   x 5,000cart x placebo
    	
 
    	
(GMP   batch)
   [*]g
   [*]g
   [*]g
    	
 
    	
Two   strength to be manufactured at Vetter at Ph III scale
   1st lots mid 2009
   2nd lots end 2009
   3rd lots early 2010
    

 

· Total new API needed for Phase III activities = 96 g (pure peptide)

 

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.Exhibit 10.13

 

WORK ORDER NO. 2*

 

THIS WORK ORDER NO. 2 is by and between RADIUS HEALTH, INC. (“RADIUS”) and LONZA Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38, CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”), and upon execution will be incorporated into the Development and Manufacturing Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the “Agreement”).  Capitalized terms in this Work Order will have the same meanings as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.             API/Drug Substance and Product.

 

BA058

 

Nomenclature:   Chemical Name:  Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-GlyLys-Ser-IIc-GIn-Asp-Leu-Arg-Arg-GIu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2 [Glu22,25, Leu23,28,31, Aib29, Lys26,30] hPTHrP(1-34) NH2; The active pharmaceutical ingredient (API), BA058 API, is isolated with associated water and acetate.

 

2.             Services.  Manufacturer will render to RADIUS the following Services:

 

Manufacturer will produce Product hereunder for use by Radius in a Phase III clinical study.  Such work shall be performed in accordance with Exhibits A-C plus such additional requirements as discussed below.

 

Production:  Manufacturer will perform a solid-phase-peptide-synthesis process (SPPS) characterized by the stepwise addition of Fmoc-amino acids using Fmoc-Aas and coupling agents, followed by cleavage I deprotection and work-up in accordance with the “Proposal for the Manufacture of 50g and 100g, 150g and 200g of BA058 and upgrading of analytical methods to NDA filing levels for Radius Health, Inc.” attached hereto as Exhibit A).  Production will be performed in a 20L reactor.  Two purification steps will be performed by reverse phase HPLC, which is followed by isolation by means of lyophilization.  The purification will be monitored using the Manufacturer’s methods FG1 and VG1.

 

Analytical development:  As a first step, method comparability between TG1, VG1 and FG1 will be established in accordance with the “Analytical Development Proposal for BA058, API Project (Lonza RDS-001)” attached here as Exhibit B).  If needed, additional method development may be performed to identify the method of choice.  Once identified, the methods of choice (probably two) that are suitable for quantification of process impurities and supportive of ICH-stability studies will identified and agreed by the parties.  Resulting product will be greater than 97% pure as measured by the Manufacturer’s method FG1.  Release will be performed using the TG1 method, originally developed by Ipsen, unless otherwise agreed upon in advance based upon the outcome of the analytical method qualification.

 

Stability:  an ICH-stability study will be performed according to the requirements in “SP-RDS-001 Stability Protocol for BA058 API, an Analog of Human Parathyroid-related Peptide (PTHrP)” (Exhibit C).

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

CONFIDENTIAL

 

1

 

The above requirements, and any additional requirements that are agreed by the parties as contemplated above, shall be deemed part of the Specifications for the Product for purposes of the Agreement.

 

a)             Production will be initiated by the week of January 25, 2010.  Analytical development will commence in the week of January 18, 2010.  The deliverables will include regular updates (status reports, conference calls), as requested by Radius.  Release specifications are listed in Exhibit D, which for clarity shall be deemed part of the Specifications for the Product for purposes of the Agreement.  Modifications may be required, as the development status changes, and shall be agreed by the parties in writing.

 

b)            In the activities outlined in (a) and (b), which may include Manufacturer Processes, Manufacturer Technology may be incorporated with the prior consent of RADIUS.

 

c)             RADIUS will specify the number and size of aliquots to be produced and notify the Manufacturer.  The material can be stored at the Manufacturer’s site for up to three (3) months after release free of charge.  It will be shipped after notification of RADIUS by Manufacturer.  Amber glass packaging is assumed.  Upon request by RADIUS, Manufacturer will provide additional dispensing at additional charge to be communicated to RADIUS beforehand.

 

d)            A project team will be formed which will work closely with the team at RADIUS.  The project team will include technical project leaders as well as the appropriate QC, QA, and Regulatory personnel.  Communications with RADIUS will include weekly teleconferences as needed.  Audits of the manufacturing plants and general customer visits may be scheduled as needed.

 

e)             For further details, please refer to Exhibits A, B and C attached hereto.

 

f)             All Services hereunder will be conducted in compliance with analytical standards suitable for NDA filing and in compliance with cGMP for Phase III product.

 

3.             Completion:

 

Production will be completed by week of 26th April 2010 and API will be shipped to RADIUS by week of 3rd of May 2010.

 

	
Preparation:
    	
 
    	
week   of December 11, 2009
    
	
Start   of Upstream:
    	
 
    	
week   of January 25, 2010 (week 4)
    
	
Global   deprotection:
    	
 
    	
week   of February 15, 2010 (week 7)
    
	
Start   of Downstream:
    	
 
    	
week   of February 22, 2010 (week 8)
    
	
Lyophilisation   step:
    	
 
    	
week   of March 15, 2010 (week 11)
    
	
API   QC/QA release:
    	
 
    	
week   of April 26, 2010 (week 17)
    
	
Shipment   of API:
    	
 
    	
week   of May 3, 2010 (week 18)
    

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

2

 

4.             Facilities.  The Services described above will be rendered at the Facility unless another facility of Manufacturer is indicated below:

 

Lonza S.A., Chausée de Tubize 297, B-1420 Braine l’Alleud, Belgium

 

5.             RADIUS Materials.  RADIUS will provide to Manufacturer the following materials to be used by Manufacturer to perform the Services:

 

None

 

6.             RADIUS Equipment.

 

None

 

7.             Manufacturer Representative.

 

Raimund Miller, Director, Sales and Business Development, Lonza Custom Manufacturing

 

8.             RADIUS Representative.

 

Louis O’Dea, Senior Vice President and Chief Medical Officer

 

9.             Compensation.  The total compensation due Manufacturer for Services under this Work Order is €341,500.

 

	
 
    	
 
    	
Gram
    	
 
    	
€/gram
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
[*]g
    	
 
    	
$[*]
    	
 
    	
€
    	
 
    
	
Raw Materials
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
Production (incl. SPPS, IPC, DSP)
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
QC, QA release
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
HPLC methods comparability
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
Additional method development (optional)
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
HPLC method qualification
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
ICH-stability
    	
 
    	
 
    	
 
    	
 
    	
 
    	
[*]
    	
 
    
	
TOTAL cost
    	
 
    	
 
    	
 
    	
 
    	
 
    	
341,500
    	
 
    

 

Such compensation will be paid in installments.  20% of the costs listed above are due upon, signing of this Work Order.  The remaining payments are due upon completion of the Services and delivery of the resulting material.  RADIUS and Manufacturer must agree in advance of either party making any change in the compensation due hereunder.  Manufacturer will invoice RADIUS to the attention of Nick Harvey, SVP and CFO, for Services rendered under this Agreement.  Manufacturer will invoice RADIUS for all amounts due under this Work Order.  All undisputed payments will be made by RADIUS within thirty (30) days of receipt of invoice.

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

3

 

10.          Insurance will be provided as required by the Agreement.

 

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

	
RADIUS   HEALTH, INC.
    	
 
    	
LONZA   SALES LTD
    
	
 
    	
 
    	
 
    
	
By
    	
/s/   B. N. Harvey
    	
 
    	
By
    	
/s/   Raimund Miller
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print   Name
    	
Nick   Harvey
    	
 
    	
Print   Name
    	
Raimund   Miller, PhD.
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title
    	
CPO
    	
 
    	
Title
    	
Director,   Sales & BD
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date
    	
Jan   15, 2010
    	
 
    	
Date
    	
Jan.   15, 2010
    

 

4

 

Exhibit A

 

Proposal for the Manufacture of 50g and 100g, 150g and 200g of BA058 and upgrading of analytical methods to NDA filing levels for Radius Health, Inc.

 

5

 

 

PROPOSAL for the MANUFACTURE of 50g and 100g, 150g and 200g

of BA058 (Lonza Designation:  RDS-001)

and upgrading of analytical methods to NDA filing levels

for RADIUS Health, Inc.

(As per the March 19 and April 06, ‘09 RFPs)

1st Amendment dated April 28, ‘09

(all new text in blue)

2nd Amendment dated April 30, ‘09

(all new text in dark yellow)

3rd Amendment dated Nov. 30, ‘09 and Dec. 01, ‘09, and Dec. 3, ‘09

(for 50g and 100g; all new text in red)

 

 

Prepared for:

Maria Grunwald, Ph.D., MBA

Director, Business Development

Radius

300 Technology Square, 5th Floor

Cambridge, MA 02139

 

 

Prepared by:

Raimund J. Miller, PhD.

Director, Sales & Business Development

Lonza Custom Manufacturing

25 Commerce Drive

Allendale, NJ 07401

 

 

Date:

April 20, 2009

April 28, 2009

April 30, 2009

Nov. 30, 2009, Dec. 01, ‘09, Dec. 3, ‘09

 

DISCLAIMER

 

THIS DOCUMENT IS ISSUED BY LONZA FOR DISCUSSION PURPOSES ONLY.  IT IS NOT INTENDED TO CONSTITUTE ANY SORT OF OFFER OR TO CREATE ANY LEGAL RELATIONS BETWEEN LONZA AND ANY OTHER PARTY.

 

THE SUPPLY OF THIS DOCUMENT IN ELECTRONIC FORM IS STRICTLY ON THE UNDERSTANDING THAT NO AMENDMENTS WILL BE MADE TO IT WHICH ARE NOT EXPLICITLY DRAWN TO LONZA’S ATTENTION EITHER BY MARKING THE CHANGES IN THE TEXT ITSELF OR OTHERWISE IN WRITING.  LONZA DOES NOT AGREE TO ANY AMENDMENT

 

CONFIDENTIAL

 

1

 

WHICH IS NOT SO EXPLICITLY BROUGHT TO OUR ATTENTION.

 

1)            Background

 

On March 19, ‘09 Dr. Maria Grunwald asked for a cost proposal + timelines for upgrading the analytical methods, which were employed in the 1st BA-058 campaign, to NDA filing levels.  This was followed by a request for proposal on April 6, ‘09 for pricing for a 150g Ph III / cGMP campaign.  On April 29, ‘09 Radius placed a request to include pricing for a 200g as well.  The 04/30/09 2nd proposal amendment provides pricing for the 200g. On Nov. 23, ‘09 Radius requested a proposal for a 50g batch for Phase 3 (requiring manufacture to GMP standards).  On Nov. 30, ‘09 Radius requested that pricing be added for a 100g campaign as well.  On Dec. 3, ‘09, Radius requested a “break” on the 100g price which Lonza is willing to give in support of Radius’ program.

 

In mid 2008 Lonza Braine performed the 1st BA-058 campaign (C1 campaign) which yielded [*]g peptide corresponding to [*]g net peptide.  An extra quantity of [*]g powder weight was generated during this first campaign.

 

Campaign summaries were provided in Process Analytical reports which were sent to Radius on March 2, ‘09 (PAR-S-RDS-001-103 C1, concerning upstream process description) and on March 9, ‘09 (PAR-P-RDS-001-Campaign 1-Lot 8AG1, concerning downstream process description).

 

To date (April 20, ‘09) the following shipments were made out of this C1 campaign:

 

1) In February ‘09, 40.0g (8 x 5.0g powder weight) were sent to Vetter Pharma (Germany).

 

2) In March ‘09, 4.0g (1 x 1.5g + 1 x 2.5g powder weight) were sent to Charles River Laboratories (Canada)

 

2)            BA058—the Product

 

The BA058 (RDS-001) Peptide is an amide 34 mer with one non natural AA: H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

 

General Information

 

Nomenclature

 

	
Chemical   Name:
    	
 
    	
Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-ALa-NH2 [GIU22,25, Leu23,28,21, Aib29, Lys26,30] hPTHrP(1-34)-NH2
    
	
 
    	
 
    	
 
    
	
USAN   Name:
    	
 
    	
Not   assigned
    
	
 
    	
 
    	
 
    
	
Research   Names:
    	
 
    	
BA058
    	
(Radius   Code)
    

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

2

 

	
CAS   Registry
    	
 
    	
247062-33-5,   512206-66-5, 506422-98-6
    
	
Numbers:
    	
 
    	
 
    

 

Structure

 

The structure of BA058 peptide is depicted in Figure 1.

 

Figure 1:               Structure of BA058 Peptide

 

 

The active pharmaceutical ingredient (API), BA058 API, is isolated with associated water and acetate.

 

3)            Process:

 

The manufacturing process which Radius asked Lonza to quote on for the 1st campaign was outlined in the 4/17/07 RFP.  The process is a solid-phase-peptidesynthesis process (SPPS) characterized by the [*] amino acids [*] and coupling agents, followed by cleavage, deprotection and work-up; the purification is performed by reverse phase HPLC which is followed by isolation by means of lyophilization.

 

In the course of the feasibility study performed by Lonza Braine in early ‘08, two different analytical methods were developed in order to properly monitor purification of the peptide.  These two methods provide much better resolution than the one received from Radius using a TFA based system.

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

3

 

During the C1 campaign, these methods were used for the monitoring of the primary purification of the peptide.  This has resulted in an 00C (out of criteria), as the min. of 97.0% purity was not reached at the end of this step of purification.

 

In an internal meeting, it was decided to implement a second step of purification using acetic acid medium in order to increase the purity of fractions.  At the same time, Radius requested to use the TFA method for the QC lot release.  Lonza proposed to add one of our methods for supportive data during this release.

 

By using Lonza’s analytical method, it was possible to produce an extra pure lot at 99.1% HPLC purity (Radius method).  This means also that recovery and productivity were low due to a secondary step of purification and recycling to reach the required purity.

 

The new pricing is based on yields and recoveries obtained during the C1 campaign, which should not be considered as a representative campaign.

 

For the future C2 campaign, norms to reach will be performed in TFA method (using the Radius HPLC method).

 

Concerning change of equipment, assembly of the peptide on the resin during C1 campaign has been performed in a 20 L-Pepsynloop reactor.  For a batch size of 150g NPW API, a bigger reactor will be used, such as a 50L-Pepsynloop reactor.  The upstream process will not be changed as the same technology is used in either reactor.

 

For the sake of this 1st amendment of the April 20th proposal all quantities to be produced have been revised, and the entire campaign has been recalculated.  The final quantity to be produced is 150g net peptide weight at 97.0% HPLC purity (by the Radius method) which is unchanged.  The upstream will be performed in two small-scale SPPS reactors (2 x 20 L) in parallel vs. a single 50 L reactor in the initial proposal.

 

For the sake of the 2nd amendment a totally new production concept has been worked up and costed.  In this case we can use mid-scale equipment:  one run in 50 L SPPS reactor and LC200 for downstream; considerably less manpower is required in this production scenario resulting in considerable cost savings vs. a 150g campaign.

 

For the sake of the 3rd amendment and as the request concerns the same batch size as for C1 campaign, we can use the same size equipment.  This means, small-scale SPPS reactor (20 L) and LC150 for downstream.  All improvements needed, coming from know-how acquired during C1 campaign, will be implemented in this new campaign.

 

4

 

4)            Price Proposal and Assumptions for new 50q and 100q cGMP campaigns.  The Quotation is in Euros (pro memoriam:  the 11/30/09 US$ / Euro exchange rate is 1.5035):

 

	
 
    	
 
    	
50g
    	
 
    	
100g
    	
 
    
	
Raw Materials
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
Production (incl. SPPS, IPC, DSP)
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
QC, QA release
    	
 
    	
[*]
    	
 
    	
[*]
    	
 
    
	
TOTAL cost of 50g campaign
    	
 
    	
Euros 210,000
    	
 
    	
Euros 275,700
    Euros 257,750
    	
 
    

 

A 50g campaign is not well suited to the smallest reactor which we will have to use.  A 100g campaign is much better suited.

 

The target quality of the 50g and 100g campaigns (NPW, net peptide weight) will be 97.0% (HPLC, Radius method).

 

In terms of timing, synthesis + purification + QA/QC release are estimated to take 14 weeks for the 50g, 17 weeks for the 100g campaign.

 

5)            Price Proposal and Assumptions for a new 150q cGMP campaign.  The Quotation is in Euros (pro memoriam:  the 04/28/09 US$ / Euro exchange rate is 1.3153):  [SECTION 4 AND PRICING OF 150G REMAINS UNCHANGED IN THE 2ND AMENDMENT]

 

Prior to the start of production, specific raw material purchasing and their QC/QA release have to be scheduled.  These tasks are estimated to take six weeks.

 

Production of 150g (NPW, net peptide weight) at 97.0% (HPLC, Radius method), including upstream, downstream, QC and QA release of the GMP lot.

 

Price :  €350,000 (all inclusive of raw materials, production, and margin)

 

This cost does NOT include Reference Standard qualification on this lot.  New internal QA guideline is a separate RS from the batch (extra pure one, which means:  two separate lyophilisation steps, 2 distinct QC releases and so on).  Associated costs have been calculated as follows:

 

Assumptions :

 

	
·
    	
[   Extra pure API (part of the purification lot)
    
	
·
    	
Lyophilisation
    
	
·
    	
QC   release ]
    	
 
    	
[*]   €
    
	
·
    	
5g   net peptide weight
    	
 
    	
[*]   €
    

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

5

 

Total costs for a new reference standard:  €32,500

 

6)            Price Proposal and Assumptions for a new 200q cGMP campaign.  The Quotation is in Euros (pro memoriam:  the 04/30/09 Euro / US$ exchange rate is 1.3205):

 

Prior to the start of production, specific raw material purchasing and their QC/QA release have to be scheduled.  These tasks are estimated to take six weeks.

 

Production of 200g (NPW, net peptide weight) at 97.0% (HPLC, Radius method), including upstream, downstream, QC and QA release of the GMP lot.

 

Price :  €285,000 (all inclusive of raw materials, production, and margin; excluding the €[*]  cost for the new stationary phase for the larger column)

 

This cost does NOT include Reference Standard qualification on this lot.  New internal QA guideline is a separate RS from the batch (extra pure one, which means:  two separate lyophilisation steps, 2 distinct QC releases and so on).  Associated costs have been calculated as follows:

 

Assumptions :

 

	
·
    	
[   Extra pure API (part of the purification lot)
    
	
·
    	
Lyophilisation
    
	
·
    	
QC   release ]
    	
 
    	
[*]   €
    
	
·
    	
5g   net peptide weight
    	
 
    	
[*]   €
    

 

Total costs for a new reference standard:  €26,335

 

7)            Price Proposal for Upgrading of Analytical Methods to NDA filing levels.  The Quotation is in Euros (pro memoriam:  the 04/17/09 Euro / US$ exchange rate is 1.3043):

 

1.             Analytical activities (this should be performed in parallel of the GMP campaign, concerning validation methods.  For additional testing 3 extra weeks are needed after the release of the lot).

 

·      Validation of analytical methods :  Price €100,000

 

·      HPLC / M-009-RDS-001TG1 (QC release method)

·      HPLC / M-009-RDS-001 FG1 (QC release method)

·      Acetate and Trifluoroacetate content in API

·      Water content

·      GC-Headspace (complement to general method)

·      Direct GC (complement to general method)

·      Specific rotation

·      Peptide content (Nitrogen)

·      HPLC for in-process control upstream and downstream (3 methods).

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

6

 

·      Additional testing requested for NDA filling :  Price:  €25,000

 

·      LC-MS profiles of one lot + one lot in stability study (study of degradation of API:  impurity profile).

·      Comparability study for lots coming from different suppliers

·      Heavy metals

·      General properties:  polymorphism, solubility, pH (isoelectric point), appearance, etc...

 

For all this analytical work, [*] g powder weight of API is needed.  We still have [*] g powder weight of lot 8AG1 in stock.  We will be able to use this material if Radius so decides.  Otherwise, we will have to use an extra quantity to be made available from this lot (this one has not been paid yet by Radius).  This will be discussed with Radius when necessary.

 

Total price:  €125,000

 

2.             Regulatory activities

 

NDA filing.  Price:  €57,500

 

15 weeks will be needed to finalize the NDA writing and associated corrections.

 

8)            Terms and Conditions

 

·      Proposal Validity:  May 31, ‘09.  After the expiry of the validity Lonza reserves the right to revisit all assumptions taken and outlined in this proposal.

·      Proposal Validity for 3rd Amendment:  May 31, ‘10.

·      Payment Terms:  a min. 30% upfront payment is required upon commencement of project related lab activities.

·      Packaging:  Lonza standard packaging is assumed.  Should any non-standard packaging be required, additional costs associated with this change will be charged separately.

·      INCO-terms:  FCA Lonza Braine.

 

KB / RJM

04 / 20 / 09

04 / 28 /09

04 /30 / 09

11 / 30 /09; 12/01/09; 12/03/09

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

7

 

Grunwald, Maria

 

	
From:
    	
 
    	
Miller   Raimund - Allendale [raimund.miller@Ionza.com]
    
	
Sent:
    	
 
    	
Thursday,   December 17, 2009 10:07 AM
    
	
To:
    	
 
    	
Grunwald,   Maria
    
	
Cc:
    	
 
    	
Bouget   Karine - Braine
    
	
Subject:
    	
 
    	
New   Price offer for 75g
    

 

Hello Maria,

 

Per our telecon on Tuesday, Dec. 15, we are herewith re-quoting for a new 75g campaign which will produce 97% material by the FG1 method.  The 10% which were added to our Dec. 8, ‘09 quote for the same quantity, are to cover raw material supply and recycling steps during purification to reach the targeted purity.

 

Price Proposal and Assumptions for new 75q cGMP campaign.

 

The Quotation is in Euros (pro memoriam:  the 12/17/09 US$ / Euro exchange rate is 1.437):

 

	
 
    	
 
    	
75g
    	
 
    
	
Raw Materials
    	
 
    	
[*]
    	
 
    
	
Production (incl. SPPS, IPC, DSP)
    	
 
    	
[*]
    	
 
    
	
QC, QA release
    	
 
    	
[*]
    	
 
    
	
TOTAL cost of 75g campaign
    	
 
    	
Euros 258,500
    	
 
    

 

Assumptions:  same as in the most recent proposal dated Dec. 3, ‘09.

 

Thanks,

Raimund

 

Raimund J. Miller, PhD.

Lonza Custom Manufacturing

Lonza Inc.

25 Commerce Drive

Allendale, NJ 07401

Tel+1-201-316-9322

Cell +1-201-233-2006

Fax+1-201-696-3530

 

Lonza

raimund.miller@lonza.com

www.lonza.com

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

1

 

Exhibit B

 

Analytical Development Proposal for BA058, API project (Lonza RDS-001)

 

6

 

 

Analytical Development Proposal For BA058, API Project
 (Lonza RDS-001)

 

Development proposal

 

The development proposal is divided into 3 steps that should be conducted prior to the next API batch release.

 

1.             HPLC methods comparability

 

A first step will be to establish method comparability between TG1, VG1 and FG1 HPLC methods, in order to understand the capabilities and pitfalls of these methods for true process impurities, including [3-34] and [4-34] truncated peptides.  The HPLC data will be backed up by LC/MS data to support identification of impurities and methods comparability in case of co-elution of impurities (either with the main peak or with other impurities).

 

This will also allow building a rationale for method change in future API release specifications.

 

This method comparability would be based on Lonza samples (including previously manufactured lots 5AG1R and 8AG1, [3-34] and [4-34] impurity markers, as well as DSP side fractions containing process impurities).  Should it be of interest to Radius, samples of BA058, API from other sources could also be added to this study in order to bridge these materials with the current Lonza material (8AG1).

 

Requirement:  Samples from Radius (if needed)

Timeline:  4 weeks

Deliverable:  Comparability report between 3 HPLC methods, including LC/MS identification of impurities.

Price:  €15,000

 

2.             Additional method development

 

Based on the above assessment, additional HPLC method development may have to be performed, in order to identify the method of choice (separate the critical [3-34] and [4-34] from the other process impurities), in addition to the identified HPLC method that will be used to assess overall purity and individual impurities.

 

For this, we could use alternative stationary phases (eg HILIC) or even move to UPLC (more resolution power than HPLC)

 

Timeline:  4 weeks

Deliverable:  HPLC method Development report

Price:  €15,000

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

 

 

3.                                      HPLC methods qualification

 

Once identified, the methods of choice (probably two) found suitable for their intended purposes (quantitation of process impurities, and stability-indicating to support ICH stability studies of API and DP) will be qualified.  One of these methods could also be used to determine the API content in the powder (against an external reference standard), should this be a requirement from Radius.  This method qualification work will have to be completed before initiation of the next campaign release.

 

Timeline:  5 weeks (assuming 2 methods qualified in parallel)

Deliverable:  HPLC method Qualification protocol and report

Price:  €18,000 per method (in line with any previous proposal for method qualification)

 

JMP / KB / RJM

01/08/10

 

 

Exhibit C

 

SP-RDS-001 Stability Protocol for BA058 API, an Analog of Human Parathyroid-related Peptide (PTHrP)

 

7

 

SP-RDS-001-8AG1

 

BA058 API, an Analog of Human Parathyroid-related Peptide
 (PTHRP)/RDS-001

 

 

Table of Contents

 

	
1.
    	
OBJECTIVE
    	
3
    
	
2.
    	
INTRODUCTION
    	
3
    
	
3.
    	
STABILITY   STUDY DESCRIPTION
    	
3
    
	
3.1
    	
Equipment   description
    	
3
    
	
3.2
    	
Containers   for stability samples
    	
3
    
	
3.3
    	
Analytical   tests to be performed
    	
4
    
	
3.4
    	
Acceptance   criteria
    	
4
    
	
3.5
    	
Testing   schedule
    	
4
    
	
3.5.1
    	
Material   required for each test per station and storage condition
    	
4
    
	
3.5.2
    	
Material   sampling per station and storage condition
    	
4
    
	
3.5.3
    	
Material   inventory
    	
5
    
				

 

 

1.                                      OBJECTIVE

 

This protocol describes the experiments to be performed in order to assess the stability of batch 8AG1 of BA058 Active Pharmaceutical Ingredient (API), as produced in the current manufacturing process.

 

2.                                      INTRODUCTION

 

This study will be performed in different storage conditions up to 36 months.

 

The conditions meet the requirements of the International Conference for Harmonization, as described in Q1A(R2) “Stability Testing of New Drug Substances and Products”.

 

3.                                      STABILITY STUDY DESCRIPTION

 

3.1                               Equipment description

 

·                                         Freezer at - 78°C ± 8°C
 Such as THERMO (Forma -86C ULT freezer)

 

Temperature records in Freezer at - 78°C ± 8°C :

·                                          Digital thermometer for permanent record

·                                          Manual record of temperature twice-weekly

·                                          The temperature uniformity is checked at least annually

 

·                                         Freezer at - 20°C ± 5°C
 Such as Elbanton LTV650.

 

·                                         Cold room at + 5°C ± 3°C
 Such as refrigerator WEISS

 

Temperature records in Freezer at - 20°C ± 5°C and in the cold room :

·                                          GTO monitoring for continuous monitoring and permanent record.

·                                          Manual record of temperature every day.

 

3.2                               Containers for stability samples

 

Stability samples will be stored in 8 mL HDPE bottle with suitable closure of the same quality as those used for bulk storage.

 

Two samples will be stored at below - 25°C as witness samples

 

 

3.3                               Analytical tests to be performed

 

	
Tests
    	
 
    	
Methods
    
	
Powder   appearance by visual examination
    	
 
    	
M-001
    
	
Water   content by coulometric KF
    	
 
    	
M-048
    
	
Overall   purity and related substances
    	
 
    	
M-009-RDS-001TG1
    
	
Overall   purity and related substances
    	
 
    	
M-009-RDS-001FG1
    
	
Peptide   content
    	
 
    	
M-022
    

 

3.4                               Acceptance criteria

 

The norms set in the current specifications are applied to the stability results obtained at the recommended storage temperature (- 20°C ± 5°C).

 

3.5                               Testing schedule

 

	
Months
    	
 
    	
0
    	
 
    	
1
    	
 
    	
3
    	
 
    	
6
    	
 
    	
9
    	
 
    	
12
    	
 
    	
18
    	
 
    	
24
    	
 
    	
36
    	
 
    
	
+   5°C ± 3°C
    	
 
    	
—
    	
 
    	
A
    	
 
    	
A
    	
 
    	
A
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
-   20°C ± 5°C
    	
 
    	
A
    	
 
    	
—
    	
 
    	
A
    	
 
    	
A
    	
 
    	
A
    	
 
    	
A
    	
 
    	
A
    	
 
    	
A
    	
 
    	
A
    	
 
    

 

3.5.1                     Material required for each test per station and storage condition

 

	
Tests & Methods
    	
 
    	
Quantity by test
    
	
·
    	
 
    	
Powder   appearance by visual examination
    	
 
    	
 
    
	
 
    	
 
    	
(M-001)
    	
 
    	
10 mg
    
	
·
    	
 
    	
Water   content by coulometric KF
    	
 
    	
 
    
	
 
    	
 
    	
(M-048)
    	
 
    	
30 mg
    
	
·
    	
 
    	
Peptide   content, overall purity and related substances
    	
 
    	
 
    
	
 
    	
 
    	
(M-009-RDS-001TG1)
    	
 
    	
20 mg
    
	
·
    	
 
    	
Overall   purity and related substances by SEC-HPLC
    	
 
    	
 
    
	
 
    	
 
    	
(M-009-RDS-001FG1)
    	
 
    	
20 mg
    
	
·
    	
 
    	
M-022   by nitrogen analysis
    	
 
    	
 
    
	
 
    	
 
    	
(M-022)
    	
 
    	
20 mg
    

 

3.5.2                     Material sampling per station and storage condition

 

One HDPE bottle container containing 200 mg (all tests in duplicate analyses).

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

 

3.5.3                     Material inventory

 

The following table displays the material inventory required for this stability study :

 

	
 
    	
 
    	
Storage
   condition
    	
 
    	
Control time
   points
    	
 
    	
Reserve sample
    	
 
    	
Total number
    
	
Short   term
    	
 
    	
+ 5°C
    	
 
    	
3
    	
 
    	
2
    	
 
    	
5
    
	
Long   term
    	
 
    	
- 20°C
    	
 
    	
7
    	
 
    	
4
    	
 
    	
11
    
	
Witness   sample
    	
 
    	
Below - 25°C
    	
 
    	
—
    	
 
    	
2
    	
 
    	
2
    
	
Initial
    	
 
    	
NA
    	
 
    	
1
    	
 
    	
—
    	
 
    	
1
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
19
    

 

This study will require 19 HDPE bottles containing 200 mg of powder.

 

A total quantity of 4.1g of peptide powder is requested for this stability study

 

 

Exhibit D

 

	
Batch Analysis of BA058 API
    

 

	
Test
    	
 
    	
Specification
    
	
Appearance
    	
 
    	
White   to off-white powder
    
	
Identification:  HPLC
    	
 
    	
Co-Elutes   with reference
    
	
Identification:  TLC
    	
 
    	
Single   spot with Rf similar to reference
    
	
Assay   Peptide content (HPLC) Peptide   content (HPLC, anhydrous, free base basis)
    	
 
    	
> [*] (w/w)   [*] to [*]%
    
	
Purity   BA058 (HPLC) Total related impurities Individual related impurities
    	
 
    	
> 97.0%, area   %

< 3.0%

< 1.0% area %
    
	
Purity   by Mass Spectrometry 44117D(3-34 analog) 44116D (4-34 analog)
    	
 
    	
Not   detected**

Not   detected
    
	
Acetate   Content
    	
 
    	
< [*]% (w/w)
    
	
Water   Content
    	
 
    	
< [*] % (w/w)
    
	
TFA   Content
    	
 
    	
Report
    
	
Specific   Optical Rotation (anhydrous free base corrected)
    	
 
    	
Report
    
	
Residual   Solvents
    	
 
    	
Methanol   <[*]% w/w

Acetonitrile   <[*]% w/w

Ethyl   Acetate <[*]% w/w

Triisopropylsilane   <[*]% w/w

Dimethylformamid   <[*]% w/w
    
	
Microbial   content Bacteria Yeasts and Molds LAL
    	
 
    	
Report   (cfu/g)

Report   (cfu/g)

<   [*]UI/mg
    

 

* Confidential Treatment Requested by the Registrant.  Redacted Portion Filed Separately with the Commission

 

8

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