Document:

Exhibit 10.14

 

AMENDMENT NO.3 to WORK ORDER NO.2*

 

This Amendment No. 3 to Work Order No.2 is entered into on December 15, 2010 by and between Radius Health Inc., a Delaware Corporation, with its principal office at 300 Technology Square - 5th floor, Cambridge, MA 02139, United States of America (“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 Development and Manufacturing Services Agreement between RADIUS and Manufacturer dated October 16, 2007 (the “Agreement”). Capitalized terms in this Amendment will have the same meanings as set forth in the Agreement.

 

WHEREAS

 

RADIUS and Manufacturer are parties to Work Order No.2 executed January 15, 2010 under which Manufacturer had agreed to produce Product for use by Radius in a Phase III clinical study.

 

Manufacturer has produced excess product, which RADIUS wishes Manufacturer to purify to yield 100 grams of product (“Purified Product”) under this amendment.

 

Purified Product will be released, dispensed and packaged separately from Product.

 

NOW, THEREFORE, IT IS AGREED AS FOLLOWS:

 

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

 

Manufacturer will purify Product and release, dispense and package Purified Product hereunder suitable for use by RADIUS in a Phase III clinical study. Such work shall be performed in accordance with Exhibit A plus such additional requirements as discussed below. Prior to purification of Product, Manufacturer will (i) perform analytical testing of Product as identified in the first three bullet points of Section 5 of Exhibit A, (ii) provide Radius with (a) a report identifying the results of such testing and (b) Batch Documentation for the Product (collectively, (a) and (b) are the “Analytical Test Reports”) and (iii) obtain RADIUS’ written consent for Manufacturer to proceed with the remaining activities in this Amendment (“Consent to Purify”). The decision as to whether the analytical testing yielded satisfactory results and the Analytical Test Reports are acceptable will be at RADIUS’ sole and absolute discretion and RADIUS is under no obligation to provide any Consent to Purify.  Unless and until Consent to Purify is provided by RADIUS, no further Services under this Amendment shall be performed by Manufacturer.  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)                 Analytical testing will commence in the week of January 17, 2011. Purification will be initiated by the week of February 7, 2011.  The deliverables will include regular updates (status reports, conference calls), as requested by Radius, and Batch Documentation for the Purified Product.  Release specifications for Purified Product are listed in Exhibit B, 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), which may include Manufacturer Processes, Manufacturer Technology may be incorporated with the prior consent of RADIUS.

 

c)                 Upon completion of the purification activities described herein, Manufacturer will provide RADIUS with the Batch Documentation for the Purified Product for 

 

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

 

CONFIDENTIAL

 

1

 

RADIUS’ review.  No Purified Product will be shipped to RADIUS or its designee until it has received written approval to ship from RADIUS.

 

d)                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.  HDPE packaging is assumed. Upon request by RADIUS, Manufacturer will provide additional dispensing at additional charge to be communicated to RADIUS beforehand.

 

e)                 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.

 

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

 

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

 

2.                     Completion:

 

Analytical testing will be completed by January 21st, 2011. The Analytical Test Reports will be provided to RADIUS by January 21st, 2011.  Purification will be completed by week of 21st of March 2011 and API will be shipped to RADIUS by week of 4th of April 2011.

 

3.                     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

 

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

 

None

 

5.             RADIUS Equipment.

 

None

 

6.             Manufacturer Representative.

 

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

 

7.                     RADIUS Representative.

 

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

 

8.                     Compensation.  The total compensation due Manufacturer for proper performance of Services under this Amendment is €[*]. Such compensation will be paid  in installments as follows: [*]% of the fee listed above is due upon RADIUS providing Consent to Purify. The remaining amount will be invoiced to RADIUS upon acceptance of the Services and delivery of [*] grams of the Purified Product to RADIUS. For the

 

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

 

2

 

avoidance of doubt, no compensation will be due Manufacturer for any Services performed under this Statement of Work if RADIUS elects not to provide the Consent to Purify.  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 Amendment.  All undisputed payments will be made by RADIUS within [*] ([*]) days of receipt of invoice.

 

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

 

All other terms and conditions of the Agreement and Work Oder No. 2 will apply to this Amendment No.3.

 

 

	
AMENDMENT   AGREED TO AND ACCEPTED BY:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
RADIUS   HEALTH, INC.
    	
 
    	
LONZA   SALES LTD
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By
    	
/s/   B.N. Harvey
    	
 
    	
By
    	
/s/   Syed T. Husain
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print   Name 
    	
Nick   Harvey
    	
 
    	
Print   Name
    	
Syed   T. Husain
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title   
    	
CFO
    	
 
    	
Title
    	
Head   of Sales & BD
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date
    	
Dec.   14, 2010
    	
 
    	
Date
    	
15-Dec-10
    

 

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

 

3

 

Exhibit A

 

	
Radius
    	
 
    	
Page 1 of 3
    	
 
    	
LONZA
    
	
BA-058   (RDS-D01)
    	
 
    	
Version 1.1a
    	
 
    	
 
    

 

PROPOSAL

 

RADIUS

 

Product: BA-058

 

(Lonza Code: RDS-001)

 

Proposal for purification and Release of Overage ex C2 Campaign

 

([*] g NPW)

 

Version 1.1a

 

November 8, 2010

 

December 13, 2010

 

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

 

4

 

	
Radius
    	
 
    	
Page 2 of 3
    	
 
    	
LONZA
    
	
BA-058   (RDS-D01)
    	
 
    	
Version 1.1a
    	
 
    	
 
    

 

1) Introduction

 

The quotation provided herewith covers all activities which are required to purify and release the overage which resulted out of the C2 BA-058 campaign.  The target amount is [*] g NPW.

 

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

 

·      This quotation is based on the yields and results obtained in the [*]g NPW campaign produced in 2010.

·      The same purification process will be used as the one used for C2 campaign: two HPLC purifications (primary and secondary purifications) in order to meet the expected customer specifications.  As a consequence, a final HPLC purity of the API > [*]% is expected to be obtained (FG1 method).

·      Raw material prices: standard 2010 raw material prices were used in the cost calculation.  Only purification related raw materials are included in this quotation.

·      We expect a min. of [*] g peptide (NPW) to result out of this purification campaign.

 

4) Purification of C2 crude overage at [*]g NPW scale

 

	
Raw   materials (€)
    	
 
    	
[*]
    
	
Manpower   Downstream (€)
    	
 
    	
[*]
    
	
Manufacturing   facilities downstream (€)
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    
	
Total   Production (€)
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    
	
QA/QC   release (€)
    	
 
    	
[*]
    
	
 
    	
 
    	
 
    
	
TOTAL   (€)
    	
 
    	
[*]
    
	
Prices   per gram (€)
    	
 
    	
[*]
    

 

Timelines: [*] weeks; 1st purification line to become available in week [*] of [*].

 

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

 

5

 

	
RADIUS
    	
 
    	
Page 3 of 3
    	
 
    	
Lonza
    
	
BA-058 (RDS-001)
    	
 
    	
Version 1.1a
    	
 
    	
 
    

 

5) Activities to be performed prior to Purification (are all included in the quotation):

 

·      Analysis of the crude in IPC upstream HPLC release method, in order to check global purity.

·      LC-MS analysis in the same analytical method; comparison with the one available for the crude at t=0.

·      Assess potency of the crude by VG1 HPLC method before purification process.

·      Report of results as part of the purification batch record and review by Production and QA before purification.

·      Include decision point: apply C2 purification process, if there is no degradation. If there is degradation, include discussions to define a new process.

 

BK / RJM

11/08/10

12/13/10

 

6

 

Exhibit B

 

7

 

	
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
    

 

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

 

8Exhibit 10.19 

 

Change Order Form - Amendment 5*

 

Change order under Agreement dated: Development and Clinical Supply Agreement dated 19 June 2009

 

Between: Radius Health and 3M

 

Project Name: Radius Health proprietary compound BA058 and 3M proprietary microstructured transdermal system

 

Change requested by: Radius

 

Name:  Maria Grunwald

Company:  Radius Health, Inc

Date:   4 February 2011

 

Description of change:  Radius has asked 3M to prepare three Workplans that identify activities that could be initiated in [*].  These activities are summarized on the following Workplans:

 

Workplan #1 — Microscopic Evaluation of Clinical Supplies Workplan Summary

Workplan #2 — Residual Drug Analysis of Clinical Supplies Workplan Summary

Workplan #3 — Optimization of Ready-to-Coat Formulation and Process and Method  Development for Product Development Workplan Summary

Workplan #4 — DMF preparation for FDA response

 

In addition to the Workplans listed above, 3M will deliver responses to the FDA Advice/Information letter for the sMTS development received by Radius. These responses incorporate current testing plans (Workplan #[*], #[*], current manufacturing plan, in process controls, and the depth of penetration) & planned future development plan (i.e., DMFs development and sterile manufacturing process).  For the avoidance of doubt, 3M will provide Radius information on the depth of penetration studies funded by 3M at no charge to Radius.  The current responses to the FDA letter, and any authorized work, and reports conducted under the Workplans #[*] and #[*] will be completed by 3M and delivered to Radius by the end of [*] for Radius’ response submission.

 

Radius authorizes 3M to work up to a maximum of [*] hours at a rate of $[*] per hour in February under this change order.  Radius will prioritize the Workplans #[*] and #[*], and in the case of Workplan  #[*], Radius will advise which tasks that it wishes 3M to commence in

 

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

 

1

 

February to complete the [*] authorized hours.  Radius understands that the deliverables accomplished under Workplan #[*] will correlate to the amount of work authorized by Radius.

 

In all other respects, the terms and conditions of the Agreement remain in full force and effect.

 

Requested task, dates and costs are approved by:

 

	
Company: Radius
    	
3M
    
	
Name: Nick Harvey
    	
Name:   Mary Mathisen
    
	
Signature:
    	
/s/   B.N. Harvey
    	
 
    	
Signature:
    	
/s/ Mary   Mathisen
    
	
Position:   CFO
    	
Position: Commercialisation Mgr
    
	
Date (dd/mm/yy): February 4,   2011
    	
Date   (dd/mm/yy):4 February 2011
    
					

 

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

 

2

 

Workplan #1

 

MICROSCOPIC EVALUATION WORK PLAN SUMMARY

 

Objective:

 

The objective of the work plan is to perform microscopic evaluation BA058-sMTS patches and arrays to assess for microneedle fracture, deformation of the needle, residual drug, or biological matter deposits following removal from dosed clinical subjects of Period 2, Protocol BA058-05-006.

 

Scope:

 

Approximately [*] patches (controls and samples) will be evaluated microscopically. Group 2a, Day [*] and Day [*] BA058-sMTS samples of each subject ([*]mcg) removed following dosing will be sent for residual drug analysis. Group 2b, Day [*] and Day [*] BA058-sMTS samples of each subject (Placebo and [*]mcg) removed following dosing will be send for residual drug analysis. Group 2c, Day [*] and Day [*] BA058-sMTS samples of each subject ([*]mcg) removed following dosing will be sent for residual drug analysis. Three BA058-sMTS unused samples from each dose (Placebo, [*]mcg, and [*]mcg) will be used as controls. Each BA058-sMTS will be examined at 100x power by microscope and assessed for microneedle fracture (breaks, cracks, and chips), deformation of the needle (bends and/or blunting), residual drug, or biological matter deposits.

 

Materials:

 

Forceps

Microscope, capable of 100x magnification and equipped with a digital camera

Control and sample patches (Placebo, [*]mcg, and [*]mcg) currently stored at 2-8°C.

 

Procedure:

 

Placebo Controls;

 

1.               Remove samples from 2-8°C and allow the sample to reach room temp. (about [*] hour).

 

2.               Carefully remove one of the BA058-sMTS placebo patches from the collar.

 

PATCHES THAT ARE DISLODGED FROM THE COLLAR DURING SHIPPING WILL NOT BE ASSAYED.

 

3.               Using 100x magnification examine the patch and array for microneedle fracture, deformation of the needle, residual drug, or biological matter deposits.

 

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

 

3

 

4.               Document observations on Attachment 2.

 

5.               Photograph the damaged needles.

 

6.               Repeat 1 through 5 for the other BA058-sMTS placebo controls.

 

Repeat the above for the BA058-sMTS Placebo samples, [*]mcg controls, [*]mcg samples, [*]mcg controls and [*]mcg samples.

 

Projected Hours

 

Visual testing of [*] arrays                 [*] hours

Preparation, review, and release of report        [*] hours

Total Hours           [*]

 

Deliverables

 

A summary report describing the type and frequency of observations.

 

Attachments:

 

Example Photo

Observations

Summary Observations

 

Example Photo

 

 

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

 

4

 

OBSERVATIONS

 

Sample ID:

 

 

Describe appearance of patch:

 

5

 

Enter code for damaged array on to chart.

 

Codes: R — break, C — chip, K — crack, D — bend, L — blunt, B — biological matter, F — partial fill, S - residual drug

 

Add sequence number for digital image.

 

SUMMARY OBSERVATIONS

 

	
Sample
   ID
    	
 
    	
Microneedle fracture
   (breaks, cracks, and
   chips)
    	
 
    	
Deformation of
   the needle (bends
   and/or blunting)
    	
 
    	
Residual
   drug
    	
 
    	
Biological
   matter
   deposits
    	
 
    	
Digital
   Photo
    (√)
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    

 

6

 

	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Breaks
    	
 
    	
Cracks
    	
 
    	
Chips
    	
 
    	
Bends
    	
 
    	
Blunting
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    

 

7

 

Workplan #2

 

RESIDUAL DRUG ANALYSIS WORK PLAN SUMMARY

 

Objective:

 

The objective of the work plan is to perform residual drug analysis of BA058-sMTS arrays following removal from dosed clinical subjects of Period 2, Protocol BA058-05-006 to assess residual drug remaining on the array.

 

Scope:

 

Approximately [*] arrays (controls and samples) will be evaluated for residual drug. Group 2a, Day [*] and Day [*] BA058-sMTS samples of each subject ([*] mcg) removed following dosing will be sent for residual drug analysis. Group 2b, Day [*] and Day [*] BA058-sMTS samples of each subject (Placebo and [*]mcg) removed following dosing will be send for residual drug analysis. Group 2c, Day [*] and Day [*] BA058-sMTS samples of each subject ([*] mcg) removed following dosing will be sent for residual drug analysis. Three BA058-sMTS unused samples from each dose (Placebo, [*] mcg, and [*] mcg) will be used as controls. Each BA058-sMTS will be analyzed in accordance with Method-07-001836.

 

Materials:

 

Forceps

Snap-cap polypropylene sample vials (5mL, Nalgene Part 6250-0005)

BA058-sMTS Control and sample patches (Placebo, [*] mcg, and [*] mcg) stored at -20°C.

 

Procedure:

 

Prepare the controls and samples as follows;

 

7.               Remove samples from -20°C storage and allow to reach room temp. (approx. [*] hours).

 

8.               Carefully remove one of the BA058-sMTS patches from the collar.

 

PATCHES THAT ARE DISLODGED FROM THE COLLAR DURING SHIPPING WILL NOT BE ASSAYED.

 

9.               Separate the large circular adhesive from the hard plastic disc containing the micro array needles by holding the array patch across the patch diameter with the thumb and finger.

 

DO NOT TOUCH THE MICRO ARRAY.

 

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

 

8

 

10.         Pinch the thumb and finger together to bend the patch away from the array. (Figure A).

 

Figure A.               Use the forceps to grab the array from the bent adhesive patch.

 

 

11.         Use a forceps to grasp the array and to peel the array from the patch (Figure A).

 

12.         Place the disc containing the micro array into a labeled plastic snap cap container (needles-down orientation) and seal.

 

13.         Analyze each in accordance with Method-07-001836.

 

Projected Hours

 

	
HPLC analysis and review of data for [*] patches
    	
 
    	
[*]   hours
    
	
Preparation, review, and release of report
    	
 
    	
[*]   hours
    
	
Total
    	
 
    	
[*]   hours
    

 

Deliverables

 

Summary report describing residual BA058 content of arrays.

 

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

 

9

 

Workplan #3

 

RTC Process Development and Analytical Methods WORK PLAN SUMMARY

 

Objective

 

Determine operating conditions for RTC mixing and filtration that provide a robust process for preparing sterile, homogeneous ready-to-coat (RTC) formulation.  Following these experiments, the process and parameters for preparing RTC should be finalized.

 

Some method development efforts are also addressed below.

 

Background

 

[*]

 

Process efficiency is currently about [*]%.  Variations in filtration media and devices will be investigated to improve this number.

 

Scope

 

Observed response variables for the mixing experiments are average content, variance of the content, and viscosity.  Two mixing methods will be investigated: [*] (the current method) and [*], a [*] method [*].  For [*], three times ([*], [*], [*] min) prefiltration and four times ([*], [*],[*],[*] minutes) postfiltration will be tested.  For [*], three times will be investigated prefiltration ([*], [*], [*] minutes) and four times postfiltration ([*], [*], [*], and [*] minutes).    To investigate the effect of the RTC concentration, mixing will be performed with [*]% and [*]% bulk drug substance (w/w).  The current manufacturing process uses [*]% w/w.

 

Materials

 

[*] g BA058

Miscellaneous lab supplies

 

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

 

10

 

Procedure

 

For each mixing technique, the prefiltration experiments will be performed.  The best prefiltration mixing time will be used for the postfiltration experiments.  The procedure will be repeated for the two concentrations of BA058.

 

The average and variance of the content will be determined by taking multiple samples from each mixing experiment and assayed using a validated HPLC method (Method-07-001836).   Viscosity of the RTC following each experiment will be tested using a Rheosense m-VROC.

 

Each experiment will use [*]  mL of RTC ([*] g of bulk drug substance).  [*].  The [*] g figure is considerably larger than previously quoted.  The previous quote assumed material could be saved by using the RTC from the mixing experiments to begin the coating process experiments.  Of course, unused RTC from this work will be saved for future use.

 

To determine the optimal approach to sterile filtration, a solution of BSA will be prepared with a viscosity similar to that of the current RTC.  This solution will be used to test filtration setups for easy of use and efficiency.  Once a suitable configuration is found, it will be tested by sterile filtering RTC and checking for changes in viscosity, purity, and content.

 

Projected Hours

 

Mixing Process Development

 

	
Perform   mixing and take samples
    	
 
    	
[*]   hours
    
	
HPLC   analysis
    	
 
    	
[*]   hours
    
	
Viscosity   measurements
    	
 
    	
[*]   hours
    
	
Prepare   report
    	
 
    	
[*]   hours
    
	
Mixing   Process Total
    	
 
    	
[*]   hours
    

 

Filtration Process Development

 

	
Trial   filtration runs
    	
 
    	
[*]   hours
    
	
Confirm   filtration parameters
    	
 
    	
[*]   hours
    
	
Prepare   reports
    	
 
    	
[*]   hours
    
	
Filtration   Process Total
    	
 
    	
[*]   hours
    
	
RTC   Process Development Total
    	
 
    	
[*]   hours
    

 

Deliverables

 

1.               Summary report describing mixing experiments

2.               Summary report describing filtration experiments

3.               Master Batch Record for the ready to coat

4.               Updated specifications for the ready to coat

 

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

 

11

 

Analytical Method Development

 

The following analytical method development activities are proposed. Method development covers laboratory activities intended to define the method. Authoring of method development reports and validation activities are separate and not included in the estimates given here.

 

	
Identification   method
    	
 
    	
Uses   current HPLC method, mix 1:1 sample with reference material, show that only   one peak elutes from HPLC. Update method document.
    	
 
    	
[*] hours
    
	
Aggregation   method
    	
 
    	
Develop   size exclusion chromatography method to characterize any formation of   aggregates in drug product
    	
 
    	
[*] hours
    
	
Release   Method
    	
 
    	
Explore   and develop method for release testing of microneedle patches.
    	
 
    	
[*] hours
    
	
Pouch   Integrity
    	
 
    	
Adapt   ASTM method to microneedle patches
    	
 
    	
[*] hours
    
	
Patch   Adhesion
    	
 
    	
Adapt   ASTM method to microneedle patches
    	
 
    	
[*] hours
    

 

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

 

12

 

Workplan #4

 

FDA RESPONSE WORK PLAN SUMMARY

 

Objective:

 

Respond to FDA’s questions regarding 3M’s manufacturing process and controls.

 

Scope:

 

A DMF will be prepared with information about 3M’s sMTS manufacturing process and controls.

 

Materials:

 

Not Applicable

 

Procedure:

 

Not Applicable

 

Projected Hours

 

	
Prepare,   review, and submit DMF
    	
 
    	
[*]   hours
    

 

Deliverables

 

1)              DMF will be filed with FDA.

2)              Radius will be provided with the DMF number and a letter of access.

 

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

 

13

 

3M DRUG DELIVERY SYSTEMS CONTACT INFORMATION

 

For inquiries related to the proposal, please contact:

 

[*]

[*]

3M Drug Delivery Systems

3M Center, Bldg. 260-4N-12

St. Paul, MN 55144

Tel:  [*]

Fax:  [*]

Cell: [*]

E-Mail: [*]

 

[*]

[*]

3M Drug Delivery Systems

3M Center, Bldg. 275-3E-10

St. Paul, MN 55144

Tel:  [*]

Cell: [*]

E-Mail: [*]

 

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

 

14

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