EXHIBIT 10.22
February 4, 2000
Xxxxx X. Xxxxxxxxxx, Ph.D.
Esperion Therapeutics, Inc,
0000 Xxxxx Xxxxx Xx.
000 XXX Xxxxx
Xxx Xxxxx, XX 00000
Tel.: (734) 332-0506 ext. 213
Fax- (000) 000-0000
ESTH1000C: Service Agreement Valid for Thirty days
Service Agreement
______________________________________________________________________________
Formulation Transfer and Manufacturing of Phospholipid LUV for Injection
for Aseptically Manufactured Toxlcological Supplies
Background:
Esperion Therapeutics, Inc. ("Esperion") has requested that AAI perform a review
of their formulation and manufacturing process for phospholipid large
unilamellar vesicles (LUV) for injection. Upon completion of the review, AAI
will prepare aseptically manufactured toxicological supplies. AAI will deliver
to Esperion specifications for the product and the raw materials, development
reports (including weekly summaries), technical transfer document, manufacturing
support, product, batch records. Per the attached timeline, AAI estimates
delivery of the aseptically manufactured supplies 8 weeks after execution of the
contract and receipt of materials, methods and equipment.
Revision History:
Revision C Changes document to a Service Agreement, corrects typographical
error in terms section, provides table of activities and costs to
the terms section based on a go/no go decision after review of
particle size and sterility data from the lab scale up batch
(section II.B.), adds milestone payment schedule.
Revision B Incorporates changes requested by Esperion in e-mail from Esperion
on January 24 and 25 and additional environmental monitoring and
clarification of text requested by AAI.
Revision A Includes changes requested by Esperion in e-mail dated 1/19/2000
and additions following review by Xx. Xxxxx-Xxxxxx.
ESTH1000C
February 4, 2000
Page 2
Proposal:
AAI proposes to perform the following activities:
I. Definition
A. AAI WILL REVIEW PERTINENT INFORMATION SUPPLIED BY ESPERION SUCH AS
PREFORMULATION, FORMULATION AND METHOD OF MANUFACTURE.
B. ESPERION WILL PROVIDE PHOSPHOLIPID MATERIAL ALONG WITH MSDS AND
CERTIFICATE OF ANALYSIS.
C. ESPERION WILL PROVIDE TO AAJ, FOR USE IN THE ACTIVITIES OUTLINED BELOW,
AN AVESTIN EXTRUDER. AAI WILL ORDER ALL SPARE PARTS AND ASSOCIATED
COSTS WILL BE PASSED THROUGH TO ESPERION. THE EXTRUDER AND ALL SPARE
PARTS WILL BE RETURNED TO ESPERION UPON COMPLETION OF THE PROJECT OR
UPON ESPERION'S REQUEST.
D. ESPERION WILL PROVIDE A NICOMP FOR PARTICLE SIZE ANALYSIS. AAL WILL
ORDER ALL SPARE PARTS AND ASSOCIATED COSTS WILL BE PAID THROUGH TO
ESPERION. THE NICOMP AND ALL SPARE PARTS WILL BE PASSED THROUGH TO
ESPERION UPON COMPLETION OF THE PROJECT OR UPON ESPERIONS REQUEST.
E. AAI WILL SOURCE OTHER MATERIALS REQUIRED TO PERFORM THE ACTIVITIES
OUTLINED HEREIN.
F. AAI WILL SOURCE PACKAGE COMPONENTS TAKING IN TO CONSIDERATION WHAT HAS
BEEN PREVIOUSLY VALIDATED AT THE TRANSFER SITE FOR THE GMP SUPPLIES AND
WHAT IS CURRENTLY USED IN PHOSPHOLIPID PRODUCTS CURRENTLY ON THE
MARKET.
Estimated Cost (Section I.).......................................... No Charge
II. Formula Transfer
A. AAI WILL PREPARE UP TO 3 BATCHES OF THE PHOSPHOLIPID LUV FORMULATION
BASED ON THE FORMULA AND METHOD OF MANUFACTURE PROVIDED BY ESPERION.
EMPHASIS WILL BE ON FORMULA AND PROCESS OPTIMIZATION REQUIRED FOR
TRANSFER TO A GMP MANUFACTURING SITE. SEVERAL BATCHES WILL BE RUN TO
DETERMINE AND OPTIMIZE PROCESS PARAMETERS REQUIRED ACHIEVING A LUV
PARTICLE SIZE DISTRIBUTION OF 80 - 140 NM (DIAMETER). PREPARATION OF
THE BATCH WILL INCLUDE
ESTH1000C
February 4, 2000
Page 3
EVALUATION OF 2 VENDORS OF THE MILLIPORE PORETICS MEMBRANES, SEVERAL
PORE SIZES, STACKED, ETC. AAI WILL SELECT THE OPTIMAL MEMBRANE(S) TO
OBTAIN A PARTICLE SIZE X\\90\\ = 100 - 130 NM. THE BATCH WILL BE
OVERLAYED WITH ARGON. TESTING OF THIS BATCH WILL INCLUDE:
1. APPEARANCE
2. ETLC FOR POPC
3. VISCOSITY
4. PH
5. PARTICLE SIZE BY NICOMP
6. OSMOLARITY
7. CONCENTRATION
B. LABORATORY SCALE-UP BATCH MANUFACTURE
AAI will manufacture a laboratory scale-up batch to establish
processing and parameters, and specifications for in process and
finished product testing. This batch will be conducted as a trial
batch for the batches to be used in Esperion's toxicology studies.
Flow decay/bubble point will be conducted as a part of this batch or
as a part of the batches prepared in section II.A.
The following tests will be conducted on this batch:
1. APPEARANCE
2. HPLC FOR POPC
3. LHP
4. LAL
5. FILL VOLUME
6. VISCOSITY
7. PH
8. PARTICLE SIZE
9. PARTICULAR MATTER (MICROSCOPIC LIGHT OBSTRUCTION OR VISUAL)
10. STERILITY
Note: AAI will review all data, including 14 day sterility data, prior to
beginning activities described in section VLD.
C. ENVIRONMENTAL MONITORING FOR VIABLE PARTICULATES
AAI will perform one (1) evaluation for viable (RCS) and -non viable
particulates in the environment before manufacturing in the clean
environment, and perform 1 - 2 evaluations for viable particulates
(settling plates and RCS) during processing
ESTH1000C
February 4, 2000
Page 4
(2 to 3 total) of the laboratory scale batch. AAI will also verify
sterility of the argon gas.
D. ACCELERATED STABILITY PROGRAM - THE BATCH IN SECTION II.B. WILL BE
PLACED ON A SHORT-TERM ACCELERATED STABILITY PROGRAM, WITH TWO
CONTAINER ORIENTATIONS -UPRIGHT AND INVERTED:
Condition Timepoint
25(degree)C/60%RH Initial, 0.5 1, 2 and 3 months
40(degree)C/75%RH 0.5, 1, 2, and 3 months
30(degree)C/60%RH Test only if a problem arises at
40(degree)C/75%RH
5(degree) Control
Note: If testing of the 5(degree) or 30(degree)C/60%RH is deemed necessary, it
will be covered under a separate document.
The following tests may be conducted at each timepoint:
1. BPLC FOR POPC
2. LHP
3. PARTICLE SIZE
4. APPEARANCE
5. PH
6. VISCOSITY
7. PARTICULATE MATTER (MICROSCOPIC LIGHT OBSTRUCTION OR VISUAL)
E. MATERIAL CONTRACT STUDIES
These studies will be outlined and conducted under the most recent
signed revision of ESTH1003. In addition, Esperion has stated that
the material should be filtered using a polyethersulfone filter, that
the stopper used should be the same (if possible) as used for
Intralipid and that vials should be those validated by the
manufacturer that will be used for the GMP batches described in
ESTH1001.
F. OXYGEN SENSITIVITY STUDY
These studies will be outlined and conducted under the most recent
signed revision of ESTH1003.
G. REPORT PREPARATION
1. AAI WILL PROVIDE WEEKLY SUMMARIES, IN THE FORM OF MEETING
MINUTES, FOLLOWING CONFERENCE CALLS.
ESTH1000C
February 4, 2000
Page 5
2. AAI WILL PREPARE A SUMMARY REPORT OF THE RESULTS AND STUDIES
CONDUCTED HEREIN. A SUMMARY REPORT CONSISTS OF A SUMMARY, IN
TABULAR FORMAT WITH A SUCCINCT DISCUSSION OF THE EXPERIMENTAL AND
RESULTS. IF REQUESTED, AAI CAN SUPPLY A DETAILED SCIENTIFIC
REPORT OF STUDIES CONDUCTED. ACTIVITIES TOWARDS THE PREPARATION
OF A SCIENTIFIC REPORT WILL BE CONDUCTED IN A SEPARATE DOCUMENT.
Estimated Cost (Section II.)........................................... $87,100
III. ANALYTICAL SUPPORT OF THE PRODUCT
A. AAI WILL PROVIDE FULL RELEASE TESTING OF THE BULK PHOSPHOLIPID PER
SPECIFICATIONS PROVIDED BY ESPERION.
Note: Should method development work be required for the use of any of the
methods required for release of the phospholipid, a description of
activities and associated costs will be covered under a separate
document.
B. ESPERION WILL TRANSFER THE FOLLOWING METHODS TO AAL PROTOCOLS WILL BE
GENERATED AND APPROVED BY ESPERION PRIOR TO TRANSFER OF EACH METHOD.
TRANSFER WILL CONSIST OF FIVE SAMPLE PREPARATIONS FROM A SINGLE AMPLE
AND ONE ANALYST ON THE SAME DAY.
1. IPLC FOR POPC
2. SPERTOPHOTOMETRIC FOR LIPID HYDROPEROXIDE ("LHP")
Note: Transfer and validation of the HPLC analytical methods is based on
looking at different classes of phospholipids, not fatty acids. AAI will
use HPLC with ELSD and is based on the method analyzing one or two
phospholipids. In addition, AAI will reevaluate testing prices upon
completion of the method transfers.
C. AAI WILL DEVELOP/VALIDATE THE FOLLOWING MICROBIOLOGICAL METHODS:
1. LAL
2. STERILITY VALIDATION
D. ANALYTICAL METHOD VALIDATION
1. AAI WILL PERFORM LIMITED VALIDATION (LINEARITY, ACCURACY,
RECOVERY AND PRECISION) IN SUPPORT OF THE HPLC FOR POPC METHOD.
ESTH1000C
February 4, 2000
Page 6
2. AAI WILL PERFORM LIMITED VALIDATION (LINEARITY, ACCURACY, RECOVERY
AND PRECISION) IN SUPPORT OF THE SPECTROPHOTOMETRIC ASSAY FOR
LIPID HYDROPEROXIDE.
E. CLEANING VERIFICATION SUPPORT
At this than AAI anticipates the use of dedicated equipment and hand
filling of the aseptically manufactured toxicological supplies. Based
on this, the need for analytical methodology for a direct sampling
technique for use in a cleaning validation program is not required.
F. RELEASE OF PACKAGE COMPONENTS
AAL will fully release test all package components required for the
project as described including those required for the fill of the
toxicology supplies. Esperion will provide AAI with label copy for
the toxicology supplies.
Estimated Cost (Section III.A - F.)..................................... $46,635
G. RELEASE TESTING OF THE PRODUCT - 4 LOTS:
1. APPEARANCE
2. HPLC FOR POPC
3. LHP
4. LAL
5. FILL VOLUME
6. VISCOSITY
7. PH
8. PARTICLE SIZE
9. PARTICULAR MATTER (MICROSCOPIC LIGHT OBSTRUCTION OR VISUAL)
10. STERILITY
Estimated Cost (Section III.G).......................................... $16,980
IV. PROJECT MANAGEMENT
The project team will consist of a team leader from AAI's Formulation
Development Laboratory (FDL), and appropriate representatives from other
disciplines involved in project execution.
A. AAI WILL PROVIDE A MANAGEMENT TEAM TO COMMUNICATE PROJECT PROGRESS AND
REVIEW ALL WORK FOR SCIENTIFIC INTEGRITY ACCORDING TO TIMELINES
MUTUALLY AGREED UPON BY AAI AND ESPERION.
ESTH1000C
February 4, 2000
Page 7
B. TELECONFERENCES WILL BE HELD, AT REGULAR INTERVALS, BETWEEN THE
PARTIES THAT ESPERION IDENTIFIES AND AAI.
V. CONSULATIVE PROJECT MANAGEMENT
AAI will provide on with a technical contact person for project
discussions and consultation in addition to up to six hours of weekly
conference calls. The time spent consulting with Esperion and providing
technical support (including regulatory support) will be invoiced to
Esperion at $165/hour. AAI estimates that this additional consultative
support may range from 2 to 4 hours per week.
Estimated Cost (Section V.)............................................ As Used
VI. ASEPTICALLY MANUFACTURED TOXICOLOGICAL SUPPLIES
A. PRODUCT TRANSFER
Activities that may be included as part of product technology transfer
are:
1. PREPARATION OF A MASTER BATCH RECORD
2. RAW MATERIAL, IN-PROCESS AND FINAL PRODUCT SPECIFICATIONS
3. BATCH RECORD REVIEW AND SIGN-OFF BY AAI AND ESPERION
B. RAW MATERIALS
AAI will release test all raw materials for use in the preparation of
the aseptically manufactured toxicological supplies.
C. ENVIRONMENTAL MONITORING FOR VIABLE PARTICULATES
AAI will perform one (1) evaluation for viable (RCS) and non viable
particulates in the environment before manufacturing in the clean
environment, and perform 1 -2 evaluations for viable particulates
(settling plates and RCS) during processing. (2 to 3 total).
D. MANUFACTURE OF LUV FOR INJECTION WITH THE FOLLOWING ASSUMPTIONS:
Manufacture of up to four lots of 25 -L batch size to provide 4 kg of
material following samples being removed for release testing, retains
and stability. Sampling of package components during manufacture to
be used as controls. Filling of finished product into 50ml glass
bottles
Labeling for both stability and toxicology studies
ESTH1000C
February 4, 2000
Page 8
Estimated Cost (Section VI.)........................................... $47,900
Note: The aseptic fill process has not validated.
VII. Storage and Testing of the Aseptically Manufactured Toxicology Supplies
AAI will piece one of the four aseptically manufactured batches on the
following accelerated stability program. Materials will be set in both
the upright and inverted configurations, only one configuration will be
tested.
Condition Timepoint
23(degree)C/60%*RH Initial, 3, 6, 9, 12, 18, 24 and 36 months
40(degree)C/750% 1, 3 and 6 months
30(degree)C/60%RH Test only if a problem arises at
40(degree)C/75%RH
5(degree)C Control
Note: If testing of the 5(degree)C or 30(degree)C/60%RH is deemed necessary, it
will be covered under a separate document.
The following tests will be conducted at each timepoint:
A. HPLC for POPC
B. LHP
C. Particle size
D. Appearance
E. Viscosity
F. Particulate matter (microscopic light obstruction or visual)
X. XXX (6 months at 40(degree)C/75%RH and 12, 24 and 36 months at
25(degree)C/60%RH)
H. Sterility (6 months at 40(degree)/75%RH and 12, 24 and 36 months at
25(degree)C/60%RH)
Note: Esperion may elect to not conduct a stability study on the aseptically
manufactured batch. If Experion elects not to conduct this stability
study, there will be no charges for activities not conducted.
Estimated Cost (Section VII.)................................... $39,015
VIII. Regulatory Support
Esperion may elect to utilize AAI's regulatory affairs group during the
development of their product. Should Esperion elect to do so, AAI's
regulatory consulting services will be charged at a rate of $165 per
hour. Services would not be conducted without prior authorization from
Esperion.
Estimated Cost (Section VIII.).............................Hourly, if requested
ESTH1000C
February 4, 2000
Page 9
Terms and Conditions:
At this time, it is estimated that all activities outlined above will cost
$237,720. Should Esperion elect to terminate the program following completion
of testing of the lab scale up batch described in section II.B. the following
schedule describes activities and costs that will have been completed by that
date.
Early Termination Schedule
for decision to terminate the project following receipt of results from Section
II.B.
----------------------------------------------------------------------------------------------------------
Service Estimate Description Completion date Estimated Cost
Section (assumes 2/8/00
signature date)
----------------------------------------------------------------------------------------------------------
I Project Definition February 11, 2000 No Charge
----------------------------------------------------------------------------------------------------------
II.A., B., C., G.1. Formula Transfer March 22, 2000 $51,155
(thru termination) including testing in
section II.B.
----------------------------------------------------------------------------------------------------------
III.A., B., C., D., F. Analytical Support March 24, 2000 $46,635
----------------------------------------------------------------------------------------------------------
V. Consultative Project N/A As described, if used
Management
----------------------------------------------------------------------------------------------------------
Based on a decision to proceed:
----------------------------------------------------------------------------------------------------
Service Estimate Description Completion date Estimated Cost
Section (assumes 2/8/00
signature date)
----------------------------------------------------------------------------------------------------
II.D., G.1., G.2. Stability, weekly and June 5, 2000 $35,945
final report
----------------------------------------------------------------------------------------------------
III.G. Release of up to 4 lots April 24, 2000 $16,980
----------------------------------------------------------------------------------------------------
V. Consultative Project N/A As described, if used
Management
----------------------------------------------------------------------------------------------------
VI. Aseptically April 25, 2000 $47,990
manufactured Supplies
----------------------------------------------------------------------------------------------------
VII. Stability April 28, 2003 $39,015
----------------------------------------------------------------------------------------------------
The project will be initiated upon Esperion acceptance of this proposal,
assignment of a purchase order number, and prepayment in the amount of $32, 500.
Prepayments shall be credited against the first two invoices until the
prepayment is exhausted Unless otherwise agreed, according to the following
milestone schedule:
ESTH1000C
February 4, 2000
Page 10
Milestone Schedule
-----------------------------------------------------------------------------------------------------------
Milestone Deliverable Estimated Invoice Date Milestone Payment
-----------------------------------------------------------------------------------------------------------
1 Up front payment With signature $32,600
-----------------------------------------------------------------------------------------------------------
2 Test report for laboratory scale April 1, 2000 $34,855
batch as described in section II.B.
----------------------------------------------------------------------------------------------------------
3 Method Validation reports, test April 1, 2000 $30,335
reports
----------------------------------------------------------------------------------------------------------
Remaining schedule with decision to proceed:
--------------------------------------------------------------------------------------------------
Milestone Deliverable Estimated Invoice Date Milestone Payment
--------------------------------------------------------------------------------------------------
4 Up front payment With decision to proceed $ 33,600
--------------------------------------------------------------------------------------------------
5 Stability data and final summary Upon delivery of final $ 24,745
report report
--------------------------------------------------------------------------------------------------
6 Release test report (CofA's for 4 May 1, 2000 $ 5,780
batches)
--------------------------------------------------------------------------------------------------
7 Aseptic batches submitted for final April 5, 2000 $ 36,790
testing
--------------------------------------------------------------------------------------------------
8 Initiation of stability, 1 month Upon completion of testing $ 10,945
pull
--------------------------------------------------------------------------------------------------
9 Following each stability pull - Upon completion of testing $4,010 per pull
delivery of data
--------------------------------------------------------------------------------------------------
$237,720
---------------------------------------------------------------------------------------------------
This cost estimate is based on the information available and AAIs
experience with the procedures involved. AM reserves the right to review this
estimate should the scope of the project change or should unforeseen
difficulties arise. Any changes in the scope or the nature of the work covered
by this Service Agreement must be mutually agreed to and confirmed by a written
"Change Order".
In addition, Esperion will be charged for all out-of-pocket costs and/or
expenses associated with the activities outlined herein. Such costs and expenses
shall include required materials, travel and shipping expenses, and lab supplies
such as columns, standards and chemicals unavailable from Esperion. AAI shall
notify Esperion prior to incurring any unusual cost or expense exceeding $1,500.
Stability setup and storage charges are due i id payable upon Initiation of
the study. Any revisions to the stability protocol made after the initiation of
the stability study will be billed at $125 per hour for changing the protocol.
Esperion shall be entitled to terminate the project at any time on thirty
(30) days' prior written notice. In the event of cancellation, Esperion will be
obligated to pay only the cost of work, materials and services (exclusive of
stability setup and storage charges) used for the
February 4, 2000
Page 11
project through the effective date of the cancellation, as well as AAI's cost of
all materials and services previously acquired or contracted for and which
cannot be utilized in other day-to-day
AA1 Proprietary Technology:
Esperion recognizes that in conducting the feasibility study described in
this Service Agreement, AM may utilize fonnulation technology that is
proprietary to AAI ("AAI Proprietary Technology"). Notwithstanding anything
contained herein to the contrary, Esperion shall own all inventions,
discoveries, improvements on data (collectively, "Inventions") reduced to
practice by AAI or Esperion in connection with this Service Agreement, including
data resulting from AAI conducting such feasibility study. AAI shall fully
cooperate with Esperion in obtaining, at Esperion's sole costs and expense, any
patent and/or other protection as may be available with respect to such
Inventions and shall execute all documents deemed reasonably necessary by
Esperion for purposes of procuring such patent and/or other protection. AAI
agrees that it shall contractually ensure the prompt disclosure to Esperion by
any employee of any Inventions arising hereunder, as well as their cooperation
in securing patent and/or other protection as set forth herein. No right, title
or interest to any such AAI Proprietary Technology is granted to Esperion under
this Service Agreement except as otherwise provided herein. For the avoidance of
doubt, the Inventions shall not be deemed AAI Proprietary Information. In the
event Esperion chooses to further develop and/or commercialize a formulation
comprising, in part or in whole, AAI Proprietary Technology, Esperion will
obtain a license from AAI to use such AAI Proprietary Technology, in thc form of
a license agreement, such agreement which shall be memorialized in a separate
writing and negotiated in good faith by AAI and Esperion. Such agreement should
provide the right to Esperion to make, use, sell, and import a pharmaceutical
product using AAI Proprietary Technology with a right to sublicense, in a
territory, and with financial terms, to be mutually agreed upon, but AAI shall
retain all right, title, and interest to any and all United States and/or
international patent applications and/or issued patents claiming such AAI
Proprietary Technology.
Indemnification:
Esperion shall indemnify and hold AAI and AAI's affiliates harmless against
any claims asserted or suits brought against AAI or AAIs affiliates arising out
of; or connected with, materials provided to AAI by Esperion except where such
claim or suit is a direct result of AAI or AAI's affiliates gross negligence in
the performance of any obligation imposed hereunder. Provided, however, that AAI
or AAI's affiliates will promptly notify Esperion of any such claim or suit, and
at Esperion's discretion and cost, permit Esperion's attorneys to handle and
control such claims or suits exclusively so long as Esperion's attorneys
actively pursue the defense of the same.
AAI shall indemnify and hold Esperion and Esperion's affiliates harmless
against any claims asserted or suits brought against Esperion or Esperion's
affiliates arising out of, or connected with the gross negligence of AAI in the
performance of any obligation imposed hereunder. Provided, however, that
Esperion or Esperion's affiliates will promptly notify AAI of any such claim or
suit, and at AAI's discretion and cost, permit AAI's attorneys to handle arid
February 4, 2000
Page 12
control such claims or suits exclusively so long as AAI's attorneys actively
pursue the defense of the same.
In no event shall either party be liable to the other for any special,
indirect or consequential damages, including lost profit.
Nondisclosure:
AAI agrees that it will not itself use, or provide to, disclose to, or
permit any third party to use any Esperion Confidential Information (as defined
below). Except as otherwise provided herein, AAI shall retain all right, title
and interest to its proprietary trade secrets, know-how, inventions, whether
patentable or not, and other intellectual property ("AAI Technology"). All
Esperion Confidential Information will be maintained in secrecy by AAI, and AAI
will use all reasonable diligence to prevent use or disclosure of any such
information for a period of five (5) years from the date hereof. This obligation
of confidentiality will survive termination of this estimate. As used herein,
"Esperion Confidential Information" means any and all trade secrets and
proprietary information (in any and every form and media) of Esperion or any of
its Affiliates, including, without limitation, (a) information, data, documents,
or other items which were developed or generated by AAI pursuant to this
Agreement, (b) information relating to existing or contemplated products,
services, technology, designs, processes, formulae, research and development (in
any and all stages) of Esperion or any of its Affiliates, and (c) information
relating to business plans, methods of doing business, sales or marketing
methods, customer lists, customer usage's and/or requirements and supplier
information of Esperion or any of its Affiliates. As used herein, "Affiliate"
means any person or entity that directly, or indirectly through one or more
intermediaries, controls or is controlled by or is under common control with
Esperion.
Excluded Materials:
Notwithstanding the nondisclosure section set forth above, information,
data, or documents developed or generated by AAI solely for its internal use or
for persons other than Esperion is not restricted by the ownership rights to be
transferred to Esperion herein.
Compliance with Laws:
AAI hereby covenants and agrees to perform all of its obligations pursuant
hereto in compliance with (a) all applicable laws, rules and regulations,
including standards of Good Manufacturing Practices, (b) all standards and
practice generally accepted in the industry, and (c) protocols provided by
Esperion to AAI from time to time.
Return of Material:
Upon termination of this Agreement by Esperion (which termination may be
effected by Esperion upon thirty days written notice at AAI), AA shall return to
Esperion all Esperion Confidential Information and all other property provided
by Esperion to AAI pursuant hereto.
February 4, 2000
Page 13
Insurance:
AAI agrees to maintain and name Esperion as an additional insured under
such insurance policies and in such amounts as Esperion shall reasonably request
from time to time.
FDA Inspection:
In the event that AAI receives a Notice of Inspection (hereinafter
"Notice") from the U.S. Food and Drug Administration (the "FDA") which relates
in any way to this Service Agreement, AAI shall (a) promptly notify Esperion in
writing of the Notice, (b) keep Esperion informed of the progress of the
inspection, and (c) provide a copy to Esperion of any documents produced to the
FDA pursuant to the Notice.
Announcements:
No announcement, oral presentation or publication relating to any matter
described herein shall be made without the prior written approval of Esperion,
which approval may be granted or withheld by Esperion in its discretion.
Non Debarment:
AAI warrants and represents that AAI has never been and is not currently
(a) debarred by the FDA, or an employer, partner, shareholder, member,
subsidiary or affiliate of any person or entity debarred by the FDA, from
providing services in any capacity to a person or entity that has an approved or
pending drug product application; or (b) a person or entity that has been
debarred by the FDA from submitting or assisting in the submission of an
abbreviated new drug application (a Debarred Entity") or an employer, partner,
shareholder, member, subsidiary or affiliate of a Debarred Entity.
AAI further represents and warrants to Esperion that AAI has no knowledge
of any circumstances which may affect the accuracy of foregoing representations
and warranties, including, but not limited to, FDA investigations of, or
debarment proceedings against, AAI or any person or entity performing services
or rendering assistance relating to activities taken pursuant hereto.
Reports:
AAI shall provide Esperion with weekly written reports describing with
specificity AAI's performance of its obligations hereunder.
Entire Agreement:
This Service Agreement constitutes the entire agreement between Esperion
and AAI and shall supersede all previous communications, representations,
agreements or understandings, whether oral or written, between Esperion and AAI
with respect to the subject matter hereof.
February 4, 2000
Page 14
Assignment:
This Service Agreement shall not be assigned (whether by sale, stock
transfer, merger or otherwise) by either party without the prior written consent
of the other party. Notwithstanding anything herein to the contrary, in the
event Esperion merges with another entity, is acquired by another entity, or
sells all or substantially all of its assets to another entity, Esperion may
assign its rights and ob1i~ations hereunder to, in the event of a merger or
acquisition, the surviving entity, and in the event of a sale, the acquiring
entity, without AAI's consent so long as: (a) Esperion is not then in material
breach of this Agreement; and (b) AAI receives from the proposed assignee, in
writing, (i) reaffirmation of the terms of this Agreement; (ii) an agreement to
be bound by the terms of this agreement; and (iii) an agreement to perform the
obligations of Esperion under this Agreement.
February 4, 2000
Page 15
AGREED AND ACCEPTED:
AIA: ESPERION
/s/ Xxxxxxx X. Xxxxxxx /s/ Xxxxx X. Xxxxxx
------------------------------------ -------------------------------------
Xxxxxxx X. Xxxxxxx Signature
Manager, Technical Marketing Group
2-8-00 President/CEO
------------------------------------ -------------------------------------
Date Title
/s/ Xxxxx X. Straight 2/8/00
------------------------------------ -------------------------------------
Xxxxx Xxxxxxxx Date
Global Contracts Director
2/8/00
------------------------------------ -------------------------------------
Date Purchase Order Number
For questions concerning this document, please contact:
Xxxxxxx X. Xxxxxxx, Manager
Technical Marketing Group
AAI
0000 Xxxxx 00/xx/ Xxxxxx
Xxxxxxxxxx, XX 00000
Phone (000) 000-0000
Fax (000) 000-0000
March 31, 2000
Xxxxx X. Xxxxxxxxxx, Ph.D.
Esperion Therapeutics, Inc.
0000 Xxxxx Xxxxx Xx.
000 XXX Xxxxx
Xxx Xxxxx, XX 00000
Tel.: (734) 332-0506 ext. 213
Fax: (000) 000-0000
XXXX0000X.xx
Change Order
________________________________________________________________________________
Formulation Transfer and Manufacturing of Phospholipid for Aseptically
Manufactured Supplies Changes to Scope
Background:
Esperion Therapeutics, Inc. ("Esperion") has requested that AAI perform a
review of their formulation and manufacturing process for phospholipid large
unilamellar vesicles (LUV) for injection. Upon completion of the review, AAI
will prepare aseptically manufactured toxicological supplies. AAI will deliver
to Esperion specifications for the product and the raw materials, development
reports (including weekly summaries), technical transfer document, manufacturing
support, product, batch records. This document includes additional activities
either completed, in progress or planned based on the information and process
provided by Esperion.
Revision History:
Revision b Removes LAL testing of 3 lots of material supplied by Esperion,
redistributes milestone payments.
Revision a Includes clarification of activities and associated costs.
March 31, 2000
Page 2
Changes in Scope by Service Estimate Section:
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Activities: Section Changed: Estimated Cost
------------------------------------------------------------------------------------------------
7 TOC samples of the pressure vessels II. $ 455
------------------------------------------------------------------------------------------------
Media run of the aseptic fill process including sterility II. $ 5,300
testing of the media
------------------------------------------------------------------------------------------------
Hydration evaluation at RT and 37(degrees)C evaluation of II.A. $ 14,790
up front homogenization, filter evaluation, flow decay
conducted at 3 pressures using a 0.22 filter, flow decay
conducted at 3 pressures using a 0.45 and 0.22 filter
stacked, bubble point on the argon gas, LHP testing and
fill volume. Testing not conducted includes HPLC for
POPC.
------------------------------------------------------------------------------------------------
Additions to testing on scale up batch include: II.B. $ 4,150
concentration (3), TLC, osmolality, headspace GC, MLT
(2). Deletions to testing include: RPLC for POPC and
viscosity.
------------------------------------------------------------------------------------------------
3 month scale up batch stability II.D. ($21,305)
------------------------------------------------------------------------------------------------
Identification, LAL and appearance of three lots of POPC III.A. $ 5,735
API, including LAL validation of API
------------------------------------------------------------------------------------------------
Full release of one lot of POPC API III.A. ($3,800)
------------------------------------------------------------------------------------------------
TLC identification method transfer, including translation III.B. $ 3,500
of the method provided by Esperion
------------------------------------------------------------------------------------------------
Transfer of the concentration method III.B. $ 2,500
------------------------------------------------------------------------------------------------
Transfer of HPLC for POPC method III.B. ($2,000)
------------------------------------------------------------------------------------------------
Partial validation of the TLC identification test III.D. $ 10,000
------------------------------------------------------------------------------------------------
Partial validation of the concentration test III.D. $ 10,000
------------------------------------------------------------------------------------------------
Partial validation of the HPLC for POPC method ffl.D. ($16,800)
------------------------------------------------------------------------------------------------
Additions to release testing include: concentration, TLC, III.G. $ 2,540
osmolality, headspace GC, deletions include HPLC for
POPC, viscosity.
------------------------------------------------------------------------------------------------
Charges associated with increased batch size (double) for VI.D. $ 27,400
the aseptically manufactured batches.
------------------------------------------------------------------------------------------------
Changes to stability of aseptically manufactured VII. ($1,180)
supplies, per protocol approved by Esperion
------------------------------------------------------------------------------------------------
$ 40,655
------------------------------------------------------------------------------------------------
Terms and Conditions:
The additional cost for the activities described above are $40,655 plus
$120/organism identification conducted by microbiology.
Unless otherwise agreed, AAI will invoice Esperion according to the
following milestone schedule:
March 31, 2000
Page 3
Milestone Schedule
Milestone Deliverable Estimated Invoice Date Milestone Payment
--------------------------------------------------------------------------------------------------
1 Up front payment With signature $ 32,600
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2 Test report for laboratory April 17, 2000 $ 40,655
scale batch as described in
section II.B.
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3 Method validation reports June 1, 2000. $ 34,765
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4 Batch record April 10, 2000 $ 8,815
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5 Release test report (CofA's May 8, 2000 $ 50,975
for 4 batches)
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6 Aseptic batches submitted for April 17, 2000 $ 67,360
final testing
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7 Initiation of stability, 1 Upon completion of testing $ 22,486
month pull
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8 Following each stability pull Upon completion of testing per $4,143.80 per pull
-- delivery of data stability pull (5 pulls)
--------------------------------------------------------------------------------------------------
$ 278,375
--------------------------------------------------------------------------------------------------
This cost estimate is based on the information available and AAI's
experience with the procedures involved. AAI reserves the right to revise this
estimate should the scope of the project change or should unforeseen
difficulties arise. Any changes in the scope or the nature of the work covered
by this Service Agreement must be mutually agreed to and confirmed by a written
"Change Order".
In addition, Esperion will be charged for all out-of-pocket costs and/or
expenses associated with the activities outlined herein. Such costs and
expenses shall include required materials, travel and shipping expenses, and lab
supplies such as columns, standards and chemicals unavailable from Esperion.
AAI shall notify Esperion prior to incurring any unusual cost or expense
exceeding $1,500.
Stability setup and storage charges are due and payable upon initiation of
the study. Any revisions to the stability protocol made after the initiation of
the stability study will be billed at $125 per hour for changing the protocol.
Esperion shall be entitled to terminate the project at any time on thirty
(30) days' prior written notice. In the event of cancellation, Esperion will be
obligated to pay only the cost of work, materials and services (exclusive of
stability setup and storage charges) used for the project through the effective
date of the cancellation, as well as AAI's cost of all materials and services
previously acquired or contracted for and which cannot be utilized in other day-
to-day operations.
All activities will be conducted as described in the terms and conditions
in ESTH1000C.
March 31, 2000
Page 4
AGREED AND ACCEPTED:
AIA: ESPERION
/s/ Xxxxxxx X. Xxxxxxx /s/ Xxxxx X. Xxxxxx
---------------------------------- ------------------------------------
Xxxxxxx X. Xxxxxxx Signature
Manager, Technical Marketing Group
3-31-00 President/CEO
---------------------------------- ------------------------------------
Date Title
/s/ Xxxxxx Xx Xxxxxxx March 31, 2000
---------------------------------- ------------------------------------
Xxxxxx Xx Xxxxxxx Date
Global Contracts Director
3-31-00
---------------------------------- ------------------------------------
Date Purchase Order Number
For questions concerning this document, please contact:
Xxxxxxx X. Xxxxxxx, Manager
Technical Marketing Group
AAI
0000 Xxxxx 00/xx/ Xxxxxx
Xxxxxxxxxx, XX 00000
Phone (000) 000-0000
Fax (000) 000-0000
