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:  [*]; 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 [*]g and [*]g, [*]g and
[*]g 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 [*]% 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).

 

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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 [*].  Analytical
development will commence in the week of [*].  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 [*] ([*]) 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 [*] and API will be shipped to RADIUS by
week of [*].

 

Preparation:

 

week of [*]

Start of Upstream:

 

week of [*] (week [*])

Global deprotection:

 

week of [*] (week [*])

Start of Downstream:

 

week of [*] (week [*])

Lyophilisation step:

 

week of [*] (week [*])

API QC/QA release:

 

week of [*] (week [*])

Shipment of API:

 

week of [*] (week [*])

 

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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 €[*].

 

 

 

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

 

 

 

 

 

[*]

 

 

Such compensation will be paid in installments.  [*]% 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 [*] ([*]) days of receipt of
invoice.

 

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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

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Exhibit A

 

Proposal for the Manufacture of [*]g and [*]g, [*]g and [*]g of BA058 and
upgrading of analytical methods to NDA filing levels for Radius Health, Inc.

 

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[g127871kp01i001.gif]

 

PROPOSAL for the MANUFACTURE of [*]g and [*]g, [*]g and [*]g

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 [*]g and [*]g; 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

 

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CONFIDENTIAL

 

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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 [*]g Ph III / cGMP campaign.  On April 29, ‘09
Radius placed a request to include pricing for a [*]g as well.  The 04/30/09
2nd proposal amendment provides pricing for the [*]g. On Nov. 23, ‘09 Radius
requested a proposal for a [*]g batch for Phase 3 (requiring manufacture to GMP
standards).  On Nov. 30, ‘09 Radius requested that pricing be added for a [*]g
campaign as well.  On Dec. 3, ‘09, Radius requested a “break” on the [*]g 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, [*]g ([*] x [*]g powder weight) were sent to Vetter Pharma
(Germany).

 

2) In March ‘09, [*]g ([*] x [*]g + [*] x [*]g powder weight) were sent to
Charles River Laboratories (Canada)

 

2)            BA058—the Product

 

The BA058 (RDS-001) Peptide is an [*]

 

General Information

 

Nomenclature

 

Chemical Name:

 

[*]

 

 

 

USAN Name:

 

Not assigned

 

 

 

Research Names:

 

BA058

(Radius Code)

 

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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

 

[g127871kp01i002.gif]

 

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.

 

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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 [*] % 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 [*]% 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
[*]g 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 [*]g net peptide weight at [*]% 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 [*]g 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.

 

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

 

 

 

[*]g

 

[*]g

 

Raw Materials

 

[*]

 

[*]

 

Production (incl. SPPS, IPC, DSP)

 

[*]

 

[*]

 

QC, QA release

 

[*]

 

[*]

 

TOTAL cost of [*]g campaign

 

Euros [*]

 

Euros [*]
Euros [*]

 

 

A [*]g campaign is not well suited to the smallest reactor which we will have to
use.  A [*]g campaign is much better suited.

 

The target quality of the [*]g and [*]g campaigns (NPW, net peptide weight) will
be [*]% (HPLC, Radius method).

 

In terms of timing, synthesis + purification + QA/QC release are estimated to
take [*] weeks for the [*]g, [*] weeks for the [*]g campaign.

 

5)            Price Proposal and Assumptions for a new [*]q 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 [*]G 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 [*]
weeks.

 

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

 

Price :  € [*] (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

 

[*] €

 

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Total costs for a new reference standard:  € [*]

 

6)            Price Proposal and Assumptions for a new [*]q 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 [*]
weeks.

 

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

 

Price :  € [*] (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:  € [*]

 

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 [*]
extra weeks are needed after the release of the lot).

 

·      Validation of analytical methods :  Price € [*]

 

·      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).

 

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·      Additional testing requested for NDA filling :  Price:  € [*]

 

·      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:  € [*]

 

2.             Regulatory activities

 

NDA filing.  Price:  € [*]

 

[*] 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. [*]% 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

 

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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 [*] g

 

Hello Maria,

 

Per our telecon on Tuesday, Dec. 15, we are herewith re-quoting for a new [*] g
campaign which will produce [*] % material by the FG1 method.  The [*] % 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 [*] q cGMP campaign.

 

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

 

 

 

[*] g

 

Raw Materials

 

[*]

 

Production (incl. SPPS, IPC, DSP)

 

[*]

 

QC, QA release

 

[*]

 

TOTAL cost of [*] g campaign

 

Euros [*]

 

 

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

 

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Exhibit B

 

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

 

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[g127871kp03i001.gif]

 

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:  [*] weeks

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

Price:  €[*]

 

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:  [*] weeks

Deliverable:  HPLC method Development report

Price:  €[*]

 

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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:  [*] weeks (assuming 2 methods qualified in parallel)

Deliverable:  HPLC method Qualification protocol and report

Price:  € [*] per method (in line with any previous proposal for method
qualification)

 

JMP / KB / RJM

01/08/10

 

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Exhibit C

 

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

 

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SP-RDS-001-8AG1

 

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

 

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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

 

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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 [*] 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

 

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

 

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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

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

+ 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)

 

[*] mg

·

 

Water content by coulometric KF

 

 

 

 

(M-048)

 

[*] mg

·

 

Peptide content, overall purity and related substances

 

 

 

 

(M-009-RDS-001TG1)

 

[*] mg

·

 

Overall purity and related substances by SEC-HPLC

 

 

 

 

(M-009-RDS-001FG1)

 

[*] mg

·

 

M-022 by nitrogen analysis

 

 

 

 

(M-022)

 

[*] mg

 

3.5.2                     Material sampling per station and storage condition

 

One HDPE bottle container containing [*] mg (all tests in duplicate analyses).

 

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

 

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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

 

[*]

 

[*]

 

[*]

Long term

 

- 20°C

 

[*]

 

[*]

 

[*]

Witness sample

 

Below - 25°C

 

[*]

 

[*]

 

[*]

Initial

 

NA

 

[*]

 

[*]

 

[*]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[*]

 

This study will require [*] HDPE bottles containing [*] mg of powder.

 

A total quantity of [*] g of peptide powder is requested for this stability
study

 

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

 

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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

 

> [*]%, area %

< [*]%

< [*]% 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

 

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

 

8

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