Exhibit 10.6

 

WORK ORDER NO. 4

 

THIS WORK ORDER NO. 4 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

 

Peptide Sequence:                    
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

 

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

 

Manufacturer will perform activities required for RADIUS’ filing of a new drug
application (“NDA”) in the United States with the FDA and similar applications
required by the European Medicines Agency (EMEA) and other Authorities,
excluding authorities in Japan, for BA058 including, but not limited to,
production of three (3) validation Batches. These activities will provide for
full process qualification and process validation and all required documentation
necessary for regulatory submissions of the NDA to the FDA and the NDA
equivalents to other Authorities.

 

Such work will be performed in accordance with Exhibits A and B of this Work
Order plus such additional requirements as discussed below. The Services are
identified in terms of a particular numbered activity (each, an “Activity”). All
Services under this Work Order, including Manufacture of any Batches, will be
conducted in compliance with standards suitable for an NDA filing by RADIUS. All
Batches will be Manufactured in compliance with cGMP, will conform to
Specifications provided to Manufacturer prior to commencement of the applicable
Batch, and the other requirements of the Agreement and this Work Order. Except
for Activities 1 and 6, Manufacturer will not proceed to a subsequent numbered
Activity until it provides a report to RADIUS with the status of and results of
the prior numbered Activity and RADIUS provides Manufacturer with written
authorization to proceed to the next Activity.

 

Activity 1: Development Work: The objective for this Activity is to define the
best conditions for the preparation of the BA058 peptide. As a first step,
Manufacturer will identify which parameters have influenced the unexpected high
yield in the C2 campaign. In addition, Manufacturer will investigate the
chemistry to ensure repeatability/reproducibility of such results. The criteria
to be evaluated and the deliverables to be provided are as set forth in
Section 4 of Exhibit B.

 

Activity 2: Pre-qualification activities: Manufacturer will challenge the
parameters identified as critical as a result of the performance of Activity 1
and identify working ranges for the parameters to ensure a robust process for
upstream and downstream activities. In addition, the studies identified in
Section 5 of Exhibit B will have to be conducted on different steps of the
process in order to define “holding points”. If conducted on any intermediate
products, all stability studies conducted by Manufacturer will be conducted in
accordance with the Manufacturer generated stability protocol to be approved by
RADIUS in writing.

 

1

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Activity 3: Qualification Campaign: Manufacturer will not commence this Activity
without the prior written consent of RADIUS. Manufacturer will Manufacture a
qualification Batch at a purification scale of NPW (net peptide weight) selected
by RADIUS from the table in Exhibit A; however, the assembly and cleavage
reaction that will lead to the crude will be performed at a scale of 180g NPW
equivalent. The Batch will be Manufactured in a 20L SPPS reactor. An amount
identified by RADIUS out of the crude that was Manufactured will be purified on
an LC150 HPLC column and lyophilized in a GT10 lyophilizer. The excess of crude
will be stored and will be purified by Manufacturer, if so requested by RADIUS
in writing (“Additional Purification”). These activities are further described
in Section 6 of Exhibit B.

 

Activity 4: Qualification Stability : Manufacturer will perform a stability
study from samples of the Product Manufactured pursuant to Activity 3 in
accordance with ICH requirements and the time points required by ICH
requirements (at a minimum, the following time points: 0, 3, 6, 9, 12, 18, 24,
36 months). The study will be performed according to a stability protocol to be
generated by Manufacturer and approved by RADIUS in writing.

 

Activity 5: Pre-validation activities: Based on pre-qualification Batches (C1
and C2 which were previously Manufactured) and the qualification Batch (C3 —
still to be produced), Manufacturer will prepare and deliver the reports and
protocols identified in Section 8 of Exhibit B.

 

Activity 6: Analytical Methods Validation: Manufacturer will validate the
analytical methods identified in Section 9 of Exhibit B and provide reports on
the analytical methods. These Services described in this Activity will commence
immediately. Completion dates are planned to allow the qualification Batch
described in Activity 3 to be tested with the required methods validated in this
Activity. In any event, all methods will be validated before the commencement of
Activity 7.

 

Activity 7: Validation Campaign:

 

Manufacturer will Manufacture and release three (3) Batches of Product at a
scale of NPW (net peptide weight) selected by RADIUS from the table in
Exhibit A; however, the assembly and cleavage reaction that will lead to the
crude will be performed at a scale of 180g API equivalent. Manufacturer will
commence Manufacture of a Batch only with the prior written consent of RADIUS.
The excess of crude will be stored and Additional Purification will be performed
by Manufacturer, if so requested by RADIUS in writing. These activities are
further described in Section 10 of Exhibit B.

 

Activity 8: Validation Reports: Manufacturer will provide the following reports:

 

·                                          Upstream process validation reports

·                                          Downstream process validation report

 

Activity 9: Validation Stability               : Manufacturer will perform a
stability study from samples of the Product Manufactured pursuant to Activity 7
in accordance with ICH QIA requirements and the time points required by ICH
requirements (at a minimum, the following time points: 0, 3, 6, 9, 12, 18, 24,
36 months). The study will be performed in according to a stability protocol to
be generated by Manufacturer and approved by RADIUS in writing.

 

Activity 10: DMF Filing: Manufacturer will prepare, submit to applicable
Authorities identified by Radius, or to Radius for submission, and manage the
Drug Master File (DMF) using information about processes, equipment, facilities,
qualifications, controls and as needed. Manufacturer will provide the DMF to
Radius for review and approval prior to submission.

 

2

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For each Batch of Product Manufactured under this Work Order, Manufacturer shall
Manufacture, in accordance with cGMP and the Manufacturing Process, enough crude
to yield 180 grams (or such other amount specified by Radius in writing) of
Product.

 

The above requirements, including the yield 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)                                     Manufacturer will commence performance of
this Work Order by the week of January 2, 2012. The deliverables will include
regular updates (status reports, conference calls), as requested by RADIUS.
Release specifications will be provided by Radius, 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 identified above, which
may include Manufacturing Processes, Manufacturer Technology may be incorporated
with the prior written consent of RADIUS.

 

c)                                      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 teleconferences as needed. Audits of the
manufacturing plants and general customer visits may be scheduled as needed.

 

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

 

3.                                      Completion: Manufacturer will use
commercially reasonable efforts to complete the Services no later than the
following:

 

Activity 1: Development Work

Week of March 19, 2012

Activity 2: Pre-qualification activities

Week of May 28, 2012

Activity 3; Qualification Campaign

Week of June 29, 2012

Activity 4: Qualification Stability

Stability study to start by July 31, 2012 and continue according to protocol

Activity 5: Pre-validation activities

Week of Sept 24, 2012

Activity 6: Analytical Methods Validation

Week of May 30, 2012

Activity 7: Validation Campaign (Batch #1-3)

Batch #1 and #2: Week of Dec 26, 2012. Batch #3: Week of Feb 11, 2013 (or 2
weeks earlier, if small quantity has been requested).

Activity 8: Validation Reports

20 working days after completion of Validation Batch #3, or 20 days from date
requested by RADIUS

Activity 9: Validation Stability

Stability study to start within one month of batch purification and continue
according to protocol

Activity 10: DMF Filing

Within 40 working days of date requested by RADIUS, but not earlier than 3.5
months after the end of the Validation Campaign.

 

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

 

3

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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 Brenner, Senior Vice President and Chief Medical Officer

 

9.                                      Compensation. The total compensation due
Manufacturer for Services under this Work Order will not exceed €363,500 plus
the applicable charges for Activities 3 and 7, as shown in Exhibit A. The
reduced prices for validation Batch #2 and #3 will apply, if validation Batches
can be Manufactured simultaneously. The fees for the performance of the
Activities described above are set forth below.

 

 

 

€

 

Activity 1: Development Work

 

50,000

 

Activity 2: Pre-qualification activities

 

80,000

 

Activity 3: Qualification Campaign

 

See Exhibit A

 

Activity 4: Qualification Stability

 

35,000

 

Activity 5: Pre-validation activities

 

30,000

 

Activity 6: Analytical Methods Validation

 

71,000

 

Activity 7: Validation Campaign, Batch #1-3

 

See Exhibit A

 

Activity 8: Validation Reports

 

22,500

 

Activity 9: Validation Stability

 

35,000

 

Activity 10: DMF Filing

 

40,000

 

 

In addition, the prices for the Additional Purification, as described in
Activity 3 and 7, are identified in Exhibit A.

 

To the extent that a regulatory approval process is substantially different from
FDA or EMEA and requires additional effort as part of Activity 10, an additional
fee may apply as may be agreed to in writing by the parties.

 

Invoicing: Compensation will be paid in installments as follows: Twenty percent
(20%) of the fee listed above for an Activity (or in the case of Activity 3 and
7, the applicable Batch or Additional Purification) will be invoiced upon
commencement of such Activity; the remaining fee for the Activity will be
invoiced upon completion of all Services for such Activity including, but not
limited, delivery to RADIUS of the resulting material, if applicable.

 

Expenses: Radius will be invoiced €22,500 for a stationary phase of an HPLC
column used by Manufacturer in the Manufacture of the Product. This stationary
phase will become the property of Radius

 

4

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upon payment to Manufacturer of the applicable invoice.

 

General: 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.

 

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/ Nick Harvey

 

By

/s/ Rachel Corder

 

 

 

 

 

 

 

 

 

 

Print Name

Nick Harvey

 

Print Name

Rachel Corder

Title

CFO

 

Title

Senior Legal Counsel

Date

Dec 22, 2011

 

Date

Dec 23, 2011

 

 

 

 

 

 

 

 

By

/s/ John Eley

 

 

 

 

 

 

 

 

 

 

 

 

 

Print Name

John Eley

 

 

 

Title

Legal Counsel

 

 

 

Date

Dec 23, 2011

 

 

[g65771lc01i001.gif]

 

5

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Exhibit A

 

Pricing for Activity 3 and Activity 7

 

Pricing is identified below for several options which Radius may elect for the
Activities identified below.

 

Activity 3, Qualification Campaign

 

 

 

First Purification (after synthesis at a scale of
180g NPW equivalent)

 

Additional

 

 

 

 

Purification

 

 

 

50g

 

100g

 

150g

 

180g

 

50g

 

Qualification Batch

 

€

217,000

 

€

243,000

 

€

264,000

 

€

274,500

 

€

99,500

 

per gram

 

€

4,340

 

€

2,430

 

€

1,760

 

€

1,525

 

€

1,990

 

 

Activity 7, Validation Campaign

 

 

 

First Purification (after synthesis at a scale of 180g
NPW equivalent)

 

Additional

 

 

 

 

Purification

 

 

 

50g

 

100g

 

150g

 

180g

 

50g

 

Validation Batch #1

 

€

226,750

 

€

252,750

 

€

273,750

 

€

284,250

 

€

99,500

 

per gram

 

€

4,535

 

€

2,528

 

€

1,825

 

€

1,579

 

€

1,990

 

Validation Batch #2

 

€

209,000

 

€

235,000

 

€

256,000

 

€

266,500

 

€

97,750

 

per gram

 

€

4,180

 

€

2,350

 

€

1,707

 

€

1,481

 

€

1,955

 

Validation Batch #3

 

€

209,000

 

€

235,000

 

€

256,000

 

€

266,500

 

€

97,750

 

per gram

 

€

4,180

 

€

2,350

 

€

1,707

 

€

1,481

 

€

1,955

 

 

6

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Exhibit B

 

Proposal

RADIUS

Product: BA-058

(Lonza Code: RDS-001)

Proposal for Pre-Validation and Validation Activities (Regulatory Roadmap)

(Version 1.7)

 

7

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[g65771lc05i001.jpg]

 

PROPOSAL

RADIUS

Product: BA-058

(Lonza Code: RDS-001)

Proposal for Pre-Validation and Validation Activities

[Regulatory Roadmap]

Version 1.5

July 20, 2010

September 29, 2010

October 6, 2010

October 13, 2010

October 18, 2010

October 25, 2010

October 18, 2011 (version 1.5)

October 21, 2011 (version 1.6)

December 05, 2011 (version 1.7)

 

8

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CONFIDENTIAL

 

This proposal contains information proprietary to Lonza Sales AG, and must not
be copied or otherwise distributed other than for the purpose of review by
RADIUS in accordance with the terms of our existing CDA.

 

9

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Company: RADIUS

From:

Raimund Miller

 

 

 

 

 

Paul Tastenhoye

 

 

 

To:

Date:

Oct. 18, 2011

 

 

 

Maria Grunwald, PhD

 

 

 

 

 

E-mail:

Page(s): 10

 

 

mgrunwald@radiuspharm.com

 

 

 

Subject: Regulatory Roadmap

Copy:

 

Dear Maria,

 

On behalf of Lonza, we are pleased to provide you with our proposal for
Pre-Validation and Validation Activities [Regulatory Roadmap] for your BA-058
(Lonza Code: RDS-001).

 

We would like to thank you for giving us the opportunity to quote for these
activities. We sincerely hope that this proposal will win your confidence, as
Lonza is highly committed to meet your requirements to the fullest extent.

 

Kind regards,

 

/s/ Raimund Miller

 

/s/ Eric Bironneau

 

 

 

Raimund Miller

 

Eric Bironneau

Director, Sales & BD

 

Head of Business Development - Peptides

Lonza Inc.

 

Lonza Sales Ltd.

Lonza Custom Manufacturing

 

Lonza Custom Manufacturing

 

10

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1)        Introduction

 

The quotation provided herewith covers all activities which are required prior
to NDA filing of the BA-058 peptide; these activities are in addition to the two
development campaigns, C1 and C2 (50 g and 300 g respectively), which were
already run and which supported Radius’ product requirements for Ph II and Ph
III clinical trials. These regulatory road-map activities comprise the following
steps:

 

·                  Development work

·                  Pre-qualification activities

·                  Qualification campaign at 50g NPW scale

·                  Pre-validation documentation

·                  Analytical methods validation

·                  Validation campaigns - 3 batches at 50g NPW scale

·                  Post-validation documentation

·                  Master validation report

·                  DMF Filing

 

2)        Peptide Sequence

 

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

 

3)        Assumptions / Remarks

 

·                  The prices quoted are based on the yields and results
obtained in the C2 campaign produced in 2010.

·                  The full SPPS strategy is the only strategy considered.

·                  The chemical assembly/cleavage process will be followed by
two HPLC purifications (primary and secondary purifications) in order to meet
the customer specifications. As a consequence, an expected final HPLC purity of
the API > 97% will be obtained (by the FG1 method).

·                  Raw material prices: standard 2012 raw material prices were
used in the cost calculations.

 

11

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4)        Development Work (all quotations are in Euros €; (pro memoriam, as of
Oct. 14, ‘11, the US $ / € exchange rate was 1.38)

 

·                  Objective: Define the best conditions for the preparation of
BA-058 peptide.

 

First of all, Lonza will have to define clearly which parameters have influenced
the unexpected high yield in the C2 campaign. Moreover, Lonza needs to
investigate the chemistry to ensure repeatability / reproducibility of such
results for future campaigns. Various criteria will have to be evaluated.

 

1.              Concerning raw materials:

 

·                  In order to achieve the same quality for future campaigns,
Lonza will have to test different resin suppliers and qualify at least two of
them.

·                  Specifications of the starting resin should then be modified
in order to fit the defined parameters.

 

2.              Concerning process, Lonza will have to challenge the different
steps.

 

·                  Loading:

 

a)             use of preloaded resin or in-house loading?

b)             working range of loading. It has to be defined in terms of
productivity and quality of the resulting crude material.

 

·                  Assembly:

 

a)             Identification of critical impurities in the crude coming from
mono deletion or double addition. This analysis will be performed based on
impurities present in C1 and C2 materials.

 

·                  Cleavage:

 

a)             Define the best conditions of cleavage in order to minimize
impurities linked to this step (almost 15% HPLC area for two impurities formed
during this cleavage step).

 

·                  Purification:

 

a)             Assessment of the potential impact of upstream development work
on the purification process.

b)             Development of UPLC method for in process control corresponding
to FG1 method (analysis time reduction).

 

·                  Deliverables:

 

Upstream (7 to 8 weeks)

 

·                  Development work - experimental part € 36,4000

·                  Process development report — Compilation of the process
knowledge (C1, C2, and development work) € 3,600

 

Downstream (2 to 3 weeks)

 

·                  Development work - experimental part € 8,000

·                  Process development report — Compilation of the process
knowledge (C1, C2, and development work) € 2,000

 

In order to reach Radius target in terms of price and timing, it has been
decided to reduce tests performed during this development work.

 

Quotation for development activities (in Euros €): € 50,000 (Breakdown: see
quotation for each activity; duration: almost 2.5 months with activities
performed in parallel).

 

12

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5)        Pre-qualification Activities

 

·                  Objective: ensure we have a robust process by challenging
parameters defined as critical for both upstream and downstream.

 

In order to ensure we have a robust process before running the qualification
campaign, parameters defined as critical will have to be “challenged” in order
to obtain a suitable working range for these parameters. Moreover, some
stability studies will have to be conducted on different steps of the process in
order to define “holding points”, such as:

 

For upstream part (2 weeks) price € 10,000:

 

a)             stability of the peptide resin

b)             stability of the crude in neat TFA

c)              stability of the crude during evaporation step

d)             stability of the crude after precipitation

e)              stability of the crude during drying step

f)               stability of the crude upon storage, etc...

 

For downstream part (3 weeks) price €30,000:

 

Potential critical parameters such as column loading, gradient, chemical
stability of fractions in purification and peptide concentration, tray volume,
powder homogeneity in lyophilization will have to be assessed and challenged.

 

·                  Deliverables (4 weeks):

 

Upstream €20,000

 

·                  Qualification parameter protocols

·                  Qualification parameter - experimental part

·                  Qualification parameter reports

·                  Definition of critical parameters Upstream

·                  Parameter List

·                  Robustness Testing

 

Downstream € 20,000

 

·                  Qualification parameter protocols

·                  Qualification parameter experimental

·                  Qualification parameter reports

·                  Definition of critical parameters Downstream

·                  Parameter List

·                  Robustness Testing

 

Quotation for pre-qualification activities (in Euros €): € 80,000 (Breakdown:
37.5% upstream, 62.5% downstream; duration: 9 weeks with activities performed in
parallel).

 

By reducing development work, less experiment needed for this part of the
roadmap.

Costs have been decreased accordingly.

 

13

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6)        Quotation for Qualification Campaign at 50g NPW scale (in Euros)

 

·                  Objective: Qualify the parameters defined as critical for
both upstream and downstream for the preparation of BA-058 peptide.

 

Lonza will run the qualification campaign at a scale of 50g NPW; however, the
assembly and cleavage reaction that will lead to the crude will be performed at
a scale of 180g API equivalent, since this is the minimum scale at which the
process can be validated later. The assembly will be performed in a 20L SPPS
reactor. Only part of the crude (50g NPW out of 180g NPW) will be purified on an
LC150 HPLC column and lyophilized in a GT10 lyophilizer. The excess of crude
will be stored and can be purified later. Excellent 18M stability data of the
crude are currently available.

 

The price is given for the first 50g NPW production (including the full cost of
the crude at a scale of 180g NPW API equivalent), as well is for the later
processing of the excess crude (without crude processing cost and per 50g NPW
API):

 

 

 

 

 

50 g Price

 

First

 

First

 

Full

 

 

 

First 50 g

 

without cost

 

100 g

 

150g

 

180g

 

Quotation

 

NPW

 

of crude

 

NPW

 

NPW

 

NPW

 

Raw Materials

 

12,000

 

4,500

 

13,000

 

13,750

 

13,900

 

Production:

 

 

 

 

 

 

 

 

 

 

 

·       Crude (at scale of 180 g API equivalent)

 

105,000

 

0

 

105,000

 

105,000

 

105,000

 

·       Purification and Lyophilisation

 

80,000

 

80,000

 

105,000

 

125,250

 

135,600

 

QC/QA Release

 

20,000

 

15,000

 

20,000

 

20,000

 

20,000

 

Total Quote

 

217,000

 

99,500

 

243,000

 

264,000

 

274,500

 

Price / g

 

4,340

 

1,990

 

2,430

 

1,760

 

1,525

 

 

·                  Lead time: 14 weeks

·                  Deliverables: see point 8

·                  Following Lonza SOP a Development Manufacturing Report will
be issued after qualification, considered as engineering batch. In case of no
change between this batch and validation batches, this is possible after an
equivalency report to use this batch as commercial supply. Moreover, this batch
may be use for clinical trials as far as API specifications are met, as for C1
and C2 campaigns material.

 

7)        Qualification stability: 0, 6, 12, 24, 36 months

 

€ 21,600

 

14

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8)   Pre-validation Activities

 

·      Objective: prepare validation campaigns

 

·      Deliverables:

 

·                  Update Process development report — Compilation of the
process knowledge (pre-qualification and qualification batch)

·      Master validation protocol

·      Upstream and Downstream process validation protocols

 

·      Cost:

 

·      Process development report upstream

·      Master validation protocol

·      Upstream process validation protocol

·      Process development report downstream

·      Downstream process validation protocol

 

Quotation for pre-validation activities (in Euros €): € 30,000

 

·      Expected time needed: ± 20 working days (upstream and downstream
activities in parallel).

 

9)   Analytical Methods Validation

 

·      These activities should start at least 6 months before the first batch of
validation.

 

·      Validation of analytical methods :

 

·      Acetate and Trifluoroacetate content in API € 12,000

·      Water content € 5,000

·      GC-Headspace (complement to general method) € 12,000

·      Direct GC (complement to general method) € 12,000

·      Specific rotation € 3,000

·      Peptide content (Nitrogen) € 6,000

·                  HPLC for in-process control upstream and downstream (3
methods). Need for HPLC methods will be discussed with Radius.

·                  HPLC for in-process control downstream : 2 methods (FG1 and
VG1) € 3,000 each method

·                  HPLC for in-process control upstream : 3 methods: loading €
4,000, short method cleavage € 6,000, long method cleavage € 8,000

 

Quotation for analytical methods validation (in Euros €): € 71,000

 

Additional testing (if needed):

 

· LCMS comparability:

 

LC-MS analysis by TG1 method: € 800 per sample

 

Comparability report: € 500

 

· reference standard [assuming 2 lots and 250mg of each minimum]

 

Sequencing by ES/MS/CAD/MS: € 3000 for 2 samples

 

Amino acid analysis: € 1600 for 2 samples

 

15

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Limit test for residual amino acids: € 1600 for 2 samples

 

Secondary counter ions: € 1000 for 2 samples

 

· Heavy metals (USP/EP level)

 

€ 900 per test sample (same method as for lot 4AI1) + $ 22,500 for specific
method validation (Sn, Cr, Hg, Pb, As, Cd per ICH guidelines)

 

· General properties:

 

Solubility: € 175 per test sample

 

pH: € 150 per test sample

 

isoelectric point: € 275 per test sample

 

10)  Quotation for Validation Campaign at 50 g NPW scales (in Euros)

 

Lonza will ran do the validation campaign at a scale of 50g NPW; however, as for
the qualification campaign, the assembly and cleavage reaction that will lead to
the crude, will be performed at a scale of 180g API equivalent, since this is
the minimum scale at which the process can be validated.

 

In order to make use of potential efficiencies, Radius asked for scenarios
whereby validation batches V2 and V3 are performed in parallel. The quotes for
these scenarios are presented in the table below:

 

·                  Validation batch 1 (V1) performed alone, no change in price

·                  Validation batches V2 and V3 performed in parallel in
synthesis but not for purification

·                  2 releases in parallel for V2 and V3

 

The price is given for the first 50g NPW production (including the full cost of
the crude at a scale of 180g NPW API equivalent), as well is for the later
processing of the excess crude (without crude processing cost and per 50g NPW
API):

 

Validation 1:

 

 

 

 

 

50 g Price

 

First

 

First

 

Full

 

 

 

First 50 g

 

without cost

 

100 g

 

150g

 

180g

 

Quotation

 

NPW

 

of crude

 

NPW

 

NPW

 

NPW

 

Raw Materials

 

12,000

 

4,500

 

13,000

 

13,750

 

13,900

 

Production:

 

 

 

 

 

 

 

 

 

 

 

·       Crude (at scale of 180 g API equivalent)

 

105,000

 

0

 

105,000

 

105,000

 

105,000

 

·       Purification and Lyophilisation

 

80,000

 

80,000

 

105,000

 

125,250

 

135,600

 

QC/QA Release

 

20,000

 

15,000

 

20,000

 

20,000

 

20,000

 

Homogeneity Study

 

9,750

 

 

 

9,750

 

9,750

 

9,750

 

Total Quote

 

226,750

 

99,500

 

252,750

 

273,750

 

284,250

 

Price / g

 

4,535

 

1,990

 

2,527.5

 

1,825

 

1,580

 

 

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Validations 2 and 3:

 

 

 

 

 

50 g Price

 

First

 

First

 

Full

 

 

 

First 50 g

 

without cost

 

100 g

 

150g

 

180g

 

Quotation

 

NPW

 

of crude

 

NPW

 

NPW

 

NPW

 

Raw Materials

 

12,000

 

4,500

 

13,000

 

13,750

 

13,900

 

Production:

 

 

 

 

 

 

 

 

 

 

 

·       Crude (at scale of 180 g API equivalent)

 

89,000

 

0

 

89,000

 

89,000

 

89,000

 

·       Purification and Lyophilisation

 

80,000

 

80,000

 

105,000

 

125,250

 

135,600

 

QC/QA Release

 

18,250

 

13,250

 

18,250

 

18,250

 

18,250

 

Homogeneity Study

 

9,750

 

 

 

9,750

 

9,750

 

9,750

 

Total Quote

 

209,000

 

97,750

 

235,000

 

256,000

 

266,500

 

Price / g

 

4,180

 

1,955

 

2,350

 

1,707

 

1,480

 

 

Lead time: 17 weeks (3 validation campaigns)

 

Total price for the 3 validation campaigns at 50 g: 1 x €226,750 + 2 x €209,000
= €644,750

 

Concerning homogeneity, this study in plates is performed during
prequalification activities. In the case of the validation batches, defined as
the most representative material compared to commercial batches, the homogeneity
study is performed on bulk material during dispensing. This work will be done on
all validation batches and will assay water content, acetonitrile content and
acetate content (€9,750 per batch). This is the reason why validation batches
are a bit more expensive than qualification batches. No experience gain is
expected between qualification and validation batches at that scale: same
equipments, same scale.

 

11)  Validation Reports

 

·      Upstream process validation reports:         € 10,000 (20 working days)

·      Downstream process validation report:     € 12,500 (20 working days)

 

Quotation for Validation reports:        €22,500

 

12)  Validation stability: ICH (0, 3, 6, 9, 12 etc. months)

 

€ 35,000 per batch

 

17

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13)  Stationary phase HPLC column

 

5kg of stationary phase of the HPLC column will be charged to Radius. This
stationary phase is fully dedicated to BA-058 and cannot be used anymore for
other products in case the RDS-001 project would stop for any reason. Therefore,
it is now common practice at Lonza to sell the full amount of the phase directly
to the customer at the start of a project. Once Radius has paid for it, it
becomes Radius property.

 

€ 22,500€.

 

14)  DMF Filing

 

Quotation for DMF filing: €40,000

 

15)  Validity of Proposal

 

The validity of this proposal expires on December 31, 2011.

 

BK / RJM

07/20/10; 09/29/10; 10/06/10; 10/13/10; 10/18/10; 10/25/10.

 

PT/RJM

10/18/11; 10/21/11; 12/05/11

 

18

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