EXHIBIT 10.34
[CONFIDENTIAL TREATMENT REQUESTED] /*/ INDICATES MATERIAL THAT HAS BEEN OMITTED
AND FOR WHICH CONFIDENTIAL TREATMENT HAS BEEN REQUESTED. ALL SUCH OMITTED
MATERIAL HAS BEEN FILED WITH THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO
RULE 406 PROMULGATED UNDER THE SECURITIES ACT OF 1933, AS AMENDED.
CONFIDENTIAL
CTM AGREEMENT
THIS CTM AGREEMENT is made and entered into this 7th day of September,
2001 (the "EFFECTIVE DATE") by and between ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC,
having an address at ▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
("▇▇▇▇▇▇▇▇▇-▇▇▇▇▇") and Acusphere, Inc., having an address at University Park at
M.I.T., ▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇▇▇▇ ▇▇▇▇▇ ("Client") (each
individually a "PARTY" and collectively the "PARTIES").
WITNESSETH THAT
WHEREAS, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ has expertise, personnel, and experience in
conducting formulation and/or finishing of pharmaceutical products and has the
appropriate facilities to manufacture such products and is interested in
providing such manufacturing services to client companies in the pharmaceutical
area; and
WHEREAS, Client has a commercial interest in the manufacture of PLGA
Microspheres and AI-700 (hereinafter respectively the "Intermediate" and the
"Product") and is desirous of utilizing the services of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in a
phased program whereby ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will perform the "CTM Program" for Client
related to Clinical Phase III supplies of the Intermediate and Product in
compliance with All Applicable Laws and Regulations. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and Client
will negotiate in good faith to arrive at a mutually acceptable commercial
supply agreement for the Product.
NOW THEREFORE, in consideration of the mutual covenants contained
herein, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and Client hereby agree as follows:
ARTICLE 1
DEFINITIONS
The following terms, whether used in the singular or plural, shall have
the meanings assigned to them below for purposes of this CTM Agreement:
"All Applicable Laws and Regulations" shall mean all Federal, state and
local laws and regulations and, where applicable, guidance documents promulgated
by the FDA and being currently utilized within the pharmaceutical industry to
manufacture the applicable type of products(s) that apply to the Services being
provided hereunder by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, including, but not limited to, the
Federal Food, Drug, and Cosmetic Act (the "Act") as amended, and the regulations
promulgated thereunder, and the requirements of other domestic or foreign
governmental authorities made known to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ by Client, as all of such
laws, regulations or requirements may be amended or reenacted from time to time.
"Affiliate" shall mean any corporation or non-corporate entity which
directly or indirectly controls, is controlled by, or is under common control
with a Party. A corporation or non-corporate entity shall be regarded as in
control of another corporation if it owns or directly or indirectly controls at
least fifty percent (50%) of the voting stock of the other corporation or (a) in
the absence of the ownership of at least fifty percent (50%) of the voting stock
of a corporation or (b) in the case of a non-corporate entity, the power to
direct or cause the direction of the management and policies of such corporation
or non-corporate entity, as applicable.
"Agreement" means this agreement, as it may from time to time be
supplemented or modified by written amendment(s) signed by the parties.
"Batch" means a [CONFIDENTIAL TREATMENT REQUESTED] /*/ Unit size batch
of Product. One (1) batch of Product requires [CONFIDENTIAL TREATMENT REQUESTED]
/*/ of the Intermediate. [CONFIDENTIAL TREATMENT REQUESTED] /*/
"cGMP Regulation" means Current Good Manufacturing Practices and
Quality Systems Regulations, as defined from time to time under the Act, as
codified in 21 CFR parts 200 and 211 and any guidelines or guidances promulgated
by the FDA and being currently utilized within the pharmaceutical industry to
manufacture the applicable type of products(s).
"Chemicals and Materials" means the chemicals (other than the
Intermediate), and other materials such as vials required to manufacture and
bulk package the Product in accordance with the Product Specifications.
"Client's Technology Package" means such technical information to be
supplied by Client to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to permit ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to carry out its
obligations hereunder, including but not limited to, Client's raw material and
manufacturing component specifications, Intermediate and Product Specifications;
manufacturing and analytical testing equipment provided to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ by
Client, manufacturing equipment Installation Qualification (IQ) and Operation
Qualification (OQ) protocols, manufacturing and analytical testing equipment
standard operating procedures (SOP's), including cleaning procedures; analytical
method validation reports and analytical testing method transfer protocols
developed in conjunction with ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ which detail the specific
analytical testing methods to be used and the acceptance criteria
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ must satisfy to be qualified to perform such analytical testing
methods; manufacturing filter validation reports; Process Simulation
(Intermediate) / Media Fill (Product) Manufacturing Batch Production Records,
Intermediate and Product Manufacturing Batch Production Records; Intermediate
and Product Storage specifications, and Product bulk shipping and label
specifications.
"CTM" means Clinical Trial Material (product) to be used for clinical
trials, as opposed to product to be used for commercial sale.
"CTM Program" shall have the meaning set forth in Sections 2.1 and 2.9
of this CTM Agreement.
Page 2
"CTM Program Deliverables" means those deliverables as set forth in
Section 2.9 of this CTM Agreement. Included are specific confirmation,
qualification and validation activities related to the CTM Program as set forth
in Exhibit 1 and Exhibit 3 of this Agreement.
"CTM Program Facilities" means ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ manufacturing facility
located in Spokane, WA.
"Drug Substance" means the perfluorocarbon gas that is used in the
final processing step of the Product.
"FDA" means the United States Food and Drug Administration or any
successor organization and all agencies under their direct control.
"Information" shall have the meaning set forth in Section 4.1 of this
CTM Agreement.
"Intermediate" means with respect to the Product, PGLA Microspheres,
but shall not include other Chemicals and Materials.
"Manufacturing Process" means the process for manufacturing the
Intermediate and Product which is confirmed during the Manufacturing Program by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ under Sections 2.1 and 2.9 hereof using Client's Technology
Package as herein defined.
"Product" for the purposes of this CTM Agreement means Clinical Phase
III material of AI-700.
"Schedule" means the project timeline, milestones and deliverables as
set forth in Exhibit 3 of this Agreement.
"Specifications" means the specifications for the Intermediate and
Product which will be attached hereto as Exhibit 2 of this CTM Agreement and
made a part hereof, as determined and agreed upon in accordance with the CTM
Program using analytical methodology set forth therein, as such specifications
may be amended from time to time by mutual agreement of the Parties.
"Third Party" means any party other than Client, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and
their respective Affiliates.
"Unit" means a [CONFIDENTIAL TREATMENT REQUESTED] /*/fill of Product in
a [CONFIDENTIAL TREATMENT REQUESTED] /*/vial.
Page 3
ARTICLE 2
CTM PROGRAM
2.1 PROGRAM DEFINITION. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall, in compliance with
All Applicable Laws and Regulations, carry out the manufacturing program
outlined in Exhibit 1 of this Agreement hereto including any modifications and
additions thereto agreed upon by the Parties ("CTM Program") and in accordance
with the Schedule as set forth in Exhibit 3 of this Agreement shall (i) confirm
the Manufacturing Process, including the confirmation, qualification and
validation activities as specified in Exhibit 1 and Exhibit 3 of this Agreement,
(ii) confirm the Specifications for manufacturing the Intermediate and Product,
(iii) manufacture Batches in accordance with the requirements set forth in
Exhibit 1 of this Agreement, and (iv) confirm the analytical methodology used to
test the Intermediate and Product for compliance with the Specifications in
accordance with the acceptance criteria defined in analytical testing method
transfer protocols developed in conjunction with the Client. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
agrees to work with Client to attempt to minimize the number of Development
(Simulation) Batches required prior to the manufacturing of aseptic process
validation and manufacturing of CTM Batches. The CTM Program shall identify all
documentation (including regulatory documentation) and other deliverables to be
provided by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to Client pursuant to this Agreement and appended
hereto as Exhibit 4 ("the Documentation") of this Agreement. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
shall use its commercially reasonable best efforts to complete the CTM Program
in a timely fashion in accordance with the Schedule agreed upon by the Parties
and set forth in Exhibit 3 of this Agreement. If ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ is unable to
complete any stage of the CTM Program in the agreed times, it shall immediately
notify Client, in writing, of the delay, and the reason therefor.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall negotiate with Client a mutually acceptable date of
completion for the respective stage of the CTM Program, and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
shall use its commercially reasonable best efforts to complete the CTM Program
within such newly agreed upon time.
2.2 FACILITIES; STAFFING; SUPPLIES; EQUIPMENT
(i) Renovations to the CTM Program Facilities are
required to perform the CTM program. Such renovations will provide Client with
CTM and early commercial scale-up capability for manufacturing the Intermediate.
The renovations will create a manufacturing area dedicated to Client. Excess
capacity of this dedicated area not utilized by Client may be used by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ upon written approval from Client. Such approval will not be
unreasonably withheld. Client's equipment, as defined in Article 2, Section
2.2(iii), may not be used by other ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ clients.
(ii) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall maintain at all times
sufficient staffing, supplies and equipment necessary for it to perform the CTM
Program in accordance with the terms of this Agreement. Client, in accordance
with this Agreement, shall provide and/or disclose to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ certain
materials, equipment and know-how, defined as the Client's Technology Package.
Page 4
(iii) Equipment. As part of the consideration for the CTM
Program provided hereunder, Client shall provide ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ with the use of
certain analytical and manufacturing equipment ("the Equipment") as listed in
Exhibit 5 of this Agreement.
(a) During the term of this CTM Agreement,
Client shall, at its expense and in a timely manner, deliver the Equipment to
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ for installation and use solely in performing the CTM Program.
The Parties shall cooperate in the installation, calibration, confirmation,
qualification, validation, maintenance, cleaning and handling of the Equipment.
As and to the extent reflected in Exhibits 1 and 9 of this Agreement hereto, the
calibration of the Equipment will be at ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ cost, but Client shall
have the right to review and approve all installation, calibration,
confirmation, qualification, validation, maintenance, operation and cleaning
procedures and data for the Equipment as stated in Exhibit 1 of this Agreement.
Costs for maintenance and any requalification/revalidation of the Equipment
during the term of this Agreement shall be borne by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ except for
such costs which are associated with the condition of the Equipment when it was
delivered to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, which costs shall be borne by Client. During the
term of this Agreement, the Equipment shall be exclusively dedicated to the
performance of the CTM Program.
(b) At all times Client shall retain all legal
and equitable title to the Equipment. While the Equipment is located at
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ premises, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall promptly notify Client of any
damage to the Equipment. Any cost to repair Equipment that is damaged while in
the custody of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, except to the extent caused by Client, will be
at ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ sole cost and expense. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ must receive oral
approval from Client, which will not be unreasonably withheld, conditioned or
delayed, before any repairs to the Equipment are performed. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will
provide timely, written documentation to Client detailing the repairs made to
the Equipment. Upon Client's written request, or any termination or expiration
of this Agreement, the Equipment and Equipment-related documentation (including
all calibration certificates and reports, use and cleaning logs, confirmation,
qualification, validation and maintenance documents) shall be promptly returned
to Client in good condition, usual wear and tear excepted. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall
make its premises and personnel available during normal business hours to assist
with the removal and return of the Equipment, along with all Equipment-related
documentation. Client shall be responsible for all costs and expenses of such
removal as set forth in Section 8.6 hereof. The Parties shall reasonably
cooperate with regard to the restoration of the CTM Program Facilities. While
the Equipment is located in the Premises, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall" (i) at its sole
expense, safeguard and care for the Equipment, subject to normal wear and tear,
(ii) not grant any person a security interest, lien or any other rights or
interest in or to the Equipment; and (iii) not remove, deface, alter, obscure or
obliterate any ▇▇▇▇, tag or other information or identification or statement of
ownership placed on the Equipment by Client.
2.3 PROGRAM COST. The parties have defined the costs that are to
be incurred during the execution of this CTM Program, such costs are set forth
in Exhibit 1 and 9 hereof. Such costs ("Cost") have been estimated based on
anticipated manpower and overhead requirements for the
Page 5
tasks set forth in Exhibit 1 and 9 of this Agreement and the anticipated cost of
Chemicals and Materials, but excluding the cost of polymer, phospholipid and
perfluorocarbon raw materials, all of which shall be procured by Client and
provided by Client to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ at Client's sole expense. Client shall pay
or reimburse ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ for the costs described in Exhibit 1 and 9 in the
amounts set forth in Section 2 of Exhibit 9 hereto and in accordance with the
procedures set forth in Exhibit 9 and Section 2.4 below. In addition, Client
shall, for such expenses and costs that are expressly authorized in writing in
advance by Client, separately pay ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, on an as-costs-are-incurred
basis in accordance with Section 2.4, (i) for all reasonable and necessary
travel and lodging expenses incurred in the performance of this Agreement which
have been requested or approved by Client, (ii) for ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ cost of
auditing any supplier of Chemicals or Materials not currently on
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ list of approved suppliers, and (iii) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ cost
for any specialized equipment or tooling associated with equipment changes
required at the Facility to manufacture the Product. In the event Client and
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ agree that additional manufacturing activities are necessary to
complete the CTM Program, the Cost shall be negotiated in good faith by the
Parties.
2.4 INVOICES AND PAYMENT. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will submit invoices to
Client reflecting the work completed in accordance with applicable milestones,
such milestones ("the Milestones") being described in Exhibit 9. Client shall
pay all uncontested ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ invoices issued pursuant to this Agreement
within thirty (30) days of the dates thereof. Client shall, within this thirty
(30) day period notify ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ regarding any contested amounts or
questions regarding an invoice or invoice item. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ agrees to
respond to requests by Client to clarify questions on any invoice or invoice
item, and Client agrees that it will use its best efforts to resolve contested
invoice items in a timely fashion. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ acknowledges and agrees that
Client is not obligated to pay such contested amounts otherwise due and payable
within the thirty (30) day period until such time as the contested issues are
resolved to the satisfaction of both Parties, and that Client will not be
subject to any penalty or finance charge for such withheld payments. All
payments due hereunder to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall be sent to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ at
the times set forth herein by wire transfer of funds via the Federal Reserve
Wire Transfer System to such financial institution as ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ may
designate to Client in writing from time to time in accordance with Section 10.1
hereof. Prior to the value date of each transfer, Client shall notify such
person as ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ may designate to Client from time to time in
accordance with Section 10.1 hereof. Not withstanding the foregoing, if Client
does not raise at least [CONFIDENTIAL TREATMENT REQUESTED] /*/ in new funds
prior to the scheduled delivery date of any CTM batch then Client shall pay for
such batch upon delivery.
All amounts not paid when due, with the exception of contested invoices
as described herein, shall bear interest from the due date at the rate of one
and one-half percent (1.5%) per month (or such other percentage, if lower, as
shall not exceed the maximum rate permitted by law).
The Cost does not include sales, use, consumption, or excise taxes of
any taxing authority. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall notify Client of any such tax at the
execution of this Agreement,
Page 6
or upon learning that such taxes are applicable to any of the Product or
Services contemplated by this Agreement. The amount of such taxes, if any, will
be added to the Cost and shall be reflected in the invoices submitted to Client
by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ pursuant to this Agreement. Client shall pay the amount of
such taxes to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in accordance with the payment provisions of this
Agreement.
2.5 CLIENT'S RESPONSIBILITIES. To assist ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in its
performance of this Agreement, Client shall provide ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, in a timely
fashion, with all relevant information, documentation and data in the Client's
Technology Package and as set forth in Exhibit 1 of this Agreement necessary or
appropriate for ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ performance hereunder, including without
limitation the information, documentation and data set forth in Exhibit 1 of
this Agreement. Client shall ensure that all Chemicals and Materials supplied to
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ by or on behalf of Client (as may be set forth in Exhibit 1 of
this Agreement) are suitable for use under this Agreement, comply with All
Applicable Laws and Regulations (including without limitation those relating to
the import of such materials) and receive all required governmental and
regulatory approvals, including without limitation customs and FDA approvals. If
requested by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to provide the support or information referred to
in the first sentence of this paragraph, Client shall provide such support or
information (or a reasonable explanation for any delay and a projected date by
which such support or information will be provided) within five (5) business
days of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ request. In the event Client is to review or approve
any information, documentation, data or samples prepared or supplied by or on
behalf of Client, it shall complete such review and approval process within five
(5) business days, unless additional time is requested by Client based upon a
reasonable explanation provided to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ within such five (5) day
period. Client shall cooperate with ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in the performance of this
CTM Agreement and shall deal honestly and in good faith with ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
2.6 ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ RESPONSIBILITIES. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall
provide Client, in a timely fashion, with all relevant information,
documentation and data necessary or appropriate for Client's performance
hereunder, including without limitation any ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ information,
documentation and/or other materials as may be set forth in Exhibits 1 and 4 of
this Agreement. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall ensure that all Chemicals and Materials
supplied by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ on behalf of the Manufacturing Program (as may be
set forth in Exhibit 1 of this Agreement) are suitable for use under this
Manufacturing Agreement, comply with All Applicable Laws and Regulations
(including without limitation those relating to the import of such materials)
and receive all required governmental and regulatory approvals, including
without limitation customs and FDA approvals. If covered by Exhibits 1 and 4 of
this Agreement hereof, and if, requested by Client to provide the support or
information referred to in the first sentence of this paragraph, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
shall provide such support or information (or a reasonable explanation for any
delay and a projected date by which such support or information will be
provided) within five (5) business days of Client's request. In the event
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ is to review or approve any information, documentation, data or
other materials prepared or supplied by or on behalf of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, it
shall complete such review and approval process within five (5) business days,
unless additional time is requested by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ based upon a reasonable
explanation
Page 7
provided to Client within such five (5) day period. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall
cooperate with Client in the performance of this Agreement and shall deal
honestly and in good faith with Client.
2.7 COOPERATION. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall provide all reasonable
cooperation with Client's representatives in order that Client may from time to
time confirm ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ compliance with the provisions of this Agreement,
including, but not limited to, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ due and reasonable care in the
storage of Chemical and Materials and components, Intermediate and Product
Batches, and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ compliance with All Applicable Laws and
Regulations, and any applicable guidance documents or other standards which are
agreed upon by the Parties.
2.8 MANUFACTURING. (i) Upon the completion of each batch of the
Intermediate and Product, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall submit copies (certified as
accurate and complete by authorized ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Quality Assurance personnel)
of all documents and test data for that batch, including documents and test data
pertinent to the CTM Program facilities and utilities involved in the
manufacture of that batch as set forth in Section 2.9 of this Agreement.
(ii) Prior to initiating any aseptic process validation
and CTM Batch manufacturing, the Parties shall prepare and agree upon Master
Batch Production and Control Records for the Intermediate and Product, which
when prepared and agreed upon by the Parties shall be appended as Exhibit 6 of
this Agreement and deemed incorporated into the Specifications.
(iii) Prior to initiating any aseptic process validation
and CTM Batch manufacturing, the Parties shall prepare and agree upon Master
Quality Control analytical testing methods and procedures for testing the
Chemicals and Materials, Intermediate and Product for conformance to the
Specifications, which when prepared and agreed upon by the Parties shall be
appended as Exhibit 7 of this Agreement. In addition, the Parties shall prepare
and agree upon Master Quality Control analytical testing method transfer
protocols that detail the specific analytical testing methods to be transferred
and the acceptance criteria ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ must satisfy to be qualified to
perform such analytical testing methods, which when prepared and agreed upon by
the Parties shall be appended as Exhibit 8 of this Agreement.
(iv) Prior to initiating any aseptic process validation
and CTM Batch manufacturing, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will provide Client with a list of
all applicable standard operating procedures, including revision numbers, for
the equipment, utilities, facilities or other systems related to the
manufacturing, inspection, testing, bulk packaging and storage of the
Intermediate and Product. Client will review all applicable standard operating
procedures and any revisions thereto related to the equipment, utilities,
facilities or other systems related to the manufacturing, inspection, testing,
bulk packaging and storage of the Intermediate and Product.
Page 8
2.9 DELIVERY OF CTM PROGRAM DELIVERABLES. In accordance with the
manufacturing milestones established by the Parties in Exhibits 1, 3 and 9 of
this Agreement, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall produce and deliver the CTM Program
Deliverables to Client. In all cases, unless otherwise directed in writing, CTM
Program Deliverables shall be: (i) delivered in single shipments at the option
and request of Client using a carrier expressly approved in writing by the
Parties, and pursuant to Client's shipping requirements as defined in Exhibit 1
of this Agreement and using ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ bulk shipping container(s), and at
Client's expense, three (3) to six (6) QA released, unlabeled, bulk packaged
Batches of Product produced in accordance with the CTM Program. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
shall retain appropriate representative samples, as agreed upon in writing by
the Parties, from each batch of Intermediate and Product for record keeping,
testing and regulatory purposes. The amount of samples retained will be twice
the quantity required to carry out all of the tests required, with the exception
of sterility and LAL testing, to determine if the Intermediate and Product meet
Specifications; (ii) accompanied by a certificate executed by authorized
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Quality Assurance personnel that such CTM Program Deliverables
meet applicable Specifications and were otherwise produced in accordance with
this CTM Agreement, and all pertinent test data and results; (iii) accompanied
by a copy of the Manufacturing Batch Production Records for the delivered batch
of Product and the batch of Intermediate used to manufacture such batch of
Product, all of which are to be certified and stamped by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Quality
Assurance personnel as being accurate and complete and in accordance with this
CTM Agreement. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ may, at its sole discretion, transmit the
information specified in subsection (iii) separately from other project
deliverables, but ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ acknowledges that such separate transmission
shall be made at or about the time of the shipment of other Program Deliverables
as set forth in this section.
2.10 QUALITY CONTROL. Before authorizing shipment of any batch of
the Product, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall conduct and complete quality control testing
of the Intermediate and Product as set forth in Exhibit 1 and 2 hereto and
ensure that the Batches: (i) were manufactured and tested in accordance with the
Master Batch Production and Control Records, Master Quality Control analytical
testing methods and All Applicable Laws and Regulations and (ii) meet applicable
Specifications. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall immediately notify Client of: (i) any
known deviation and/or errors by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ personnel from procedures set
forth in the Master Manufacturing Batch Production and Control Records ("Process
Deviation"), equipment, procedures, QC analytical testing methods and
procedures, utilities, facility or other systems, or other breach of
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ obligations and of (ii) any "Out-of-Specification" test data
or results pertaining to any testing carried out in relation to the performance
of the CTM Program, operation of the CTM Program Facilities involved in the
manufacturing of the Intermediate and/or Product or completion of the CTM
Program Deliverables. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall obtain Client's written approval
prior to implementing any further manufacturing, retesting or resampling in
connection with such deviation, error or Out-of-Specification test data or
result for the Intermediate and Product, except for such further manufacturing,
retesting or resampling procedures specifically authorized under Client approved
procedures in effect prior to the occurrence of the deviation, error or the
Out-of-Specification test data or result. Except as
Page 9
provided in a written manufacturing procedure approved in writing by Client,
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ acknowledges and agrees that it shall not rework or reprocess
any non-conforming raw or in-process materials, Intermediate or Product.
Deviations undertaken by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, unless expressly approved in advance
by Client, remain the responsibility of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. Any failure of any
aseptic validation Batches or Batches of Intermediate and Product resulting from
such deviations and/or errors by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ personnel shall be the
responsibility of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, at its total expense, will
be responsible for replacing a batch of product that is rejected because of such
deviations and/or errors by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ personnel. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ is
responsible for formally investigating and documenting any failures to follow or
deviations from the Master Manufacturing Batch Production and Control Records or
QC analytical testing methods or procedures, any test or in-process test which
fails to meet Specifications and any failures of the equipment, utilities,
facility or other systems used to manufacture the Intermediate and Product, in
accordance with ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ procedures and cGMP Regulations.
2.11 NON-CONFORMING INTERMEDIATE OR PRODUCT. (i) Client from time
to time may conduct verification testing of Batches of Intermediate or Product
in accordance with the Specifications ("Conformance Verification Testing"). Such
Conformance Verification Testing shall be initiated promptly upon receipt of any
Batches and shall be completed within thirty (30) days. Client shall have the
right to reject, and to revoke any acceptances for, any shipment or batch (and
all Batches made from such batch) of Intermediate or Product that fails to meet
the applicable Specifications (including stability where a stability
specification is established and failed because of a manufacturing deficiency)
and other requirements under this Agreement (including Intermediate and Product
determined not to have been manufactured in accordance with this Agreement.)
(ii) All claims of non-conformance arising from the
Conformance Verification Testing, except for good cause, shall be deemed waived
unless made by the Client in writing and received by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ within
forty-five (45) days of Client's receipt of the documentation specified in
Section 2.9.
(iii) If, after its own analysis of the Intermediate or
Product batch(es), or other information, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ confirms the
non-conformity, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall manufacture and ship a replacement batch
or Batches for the non-conforming batch or shipment at its expense. If, after
its own analysis, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ does not confirm the non-conformity, the
Parties shall in good faith agree to retest the shipment or batch or otherwise
in good faith attempt to agree on a resolution of the issue. In the event that
the Parties cannot resolve the issue, the Parties shall submit the disputed
shipment or batch to a mutually agreed independent testing laboratory or other
expert for testing and review. That laboratory's or expert's finding shall be
binding on the Parties, absent manifest error.
(iv) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall bear such expense of the
independent laboratory testing and other expert review if testing or expert
review confirms the non-conformity of the shipment or batch with applicable
Specifications, and Client shall bear such expenses otherwise. In the
Page 10
event that any shipment or batch is ultimately agreed or determined to not meet
the Specifications, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall at Client's election (a) use its best
efforts to promptly (but no longer than within sixty (60) days from the date of
such agreement or determination) manufacture and ship a replacement batch or
Batches for the non-conforming batch or shipment at its expense. Client shall
return, or cause its designee to return, any rejected or revoked shipment or
batch to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ if so instructed by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, at
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ expense. In the event that any shipment or batch is ultimately
agreed or found to meet the Specifications and other applicable requirements,
Client shall accept and pay for the shipment or batch.
2.12 MODIFICATION. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and Client may from time to time
in good faith negotiate amendments to the Attachments and Exhibits hereof in the
event that (i) Client's requirements change and, as a result, Client determines
that any requirements stated in these Exhibits are no longer required, (ii)
Client requires additional services, (iii) the standards or requirements with
respect to any described activities need to be changed, or (iv) either Party
determines that a modification is desirable. Any modification shall be effective
only when approved in writing by the Parties.
2.13 REPORTING/TRANSFER OF RESULTS. (i) Upon completion of the CTM
Program, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will provide Client with a written report of the
results, which have been developed, compiled or learned during the course of the
CTM Program, including other relevant manufacturing documentation such as the
stability data package, all as more particularly described in Exhibit 1 of this
Agreement hereto. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall also (a) provide monthly written
reports, the content and format of said reports to be mutually agreed upon in
writing, detailing the status of the CTM Program, (b) respond timely to Client's
inquiries regarding the status of the CTM Program on an ongoing basis, and (c)
keep Client reasonably informed of interim results on an informal basis,
including if requested, periodic meetings at ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ facility to
discuss the CTM Program results and progress. (ii) In addition to the foregoing,
the parties shall appoint a Project Steering Committee consisting of four
persons, two appointed by each party. The ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ representatives to the
Project Steering Committee shall consist of one member of senior management and
the individual directly responsible for managing the CTM Program for
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. The Client and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ representatives responsible for
managing the CTM Program will confer regarding the status of the CTM Program by
telephone at minimum every two (2) weeks. The Project Steering Committee will
meet in person at least once per quarter during the term of the CTM Program, if
determined necessary by the Parties. The Project Steering Committee will be
responsible for overseeing the execution of the CTM Program and for approving
any changes related to the Program.
2.14 ACCESS. Client at its discretion may have its representatives
observe any performance of the CTM Program, including any equipment, facility,
qualification, analytical, manufacturing, inspection and bulk packaging
activities to provide appropriate technical support and to ensure compliance
with All Applicable Laws and Regulations. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, at its cost, shall
provide Client's representatives carrying out such observations with reasonable
office space and telephone access.
Page 11
2.15 OWNERSHIP OF TANGIBLE MATERIALS Subject to Sections 2.16 and
2.17, Client shall retain ownership of all information, documents and materials
which Client provides to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in connection with the performance of
the CTM Program hereunder, and Client shall have full possession of, and all
rights to use, all reports, documents and other tangible materials which
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ provides to Client as part of the results of the CTM Program.
Information, documents and materials provided by the Client, and any copies
thereof, shall be returned to the Client by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ at the conclusion of
the CTM Program.
2.16 (a) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ PROPERTY. Client acknowledges that
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ possesses certain inventions, processes, know-how, trade
secrets, improvements, other intellectual properties and other assets, including
but not limited to procedures and techniques, computer technical expertise,
software, and certain technical expertise and conceptual expertise in the area
of drug processing and manufacturing, which have been independently developed by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ or its Affiliates without the benefit of any information
provided by Client (collectively "▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ PROPERTY"). Client and
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ agree that any ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Property or improvements thereto
which are used, improved, modified or developed by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ under or
during the term of this Agreement are the product of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ technical
expertise possessed and developed by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ or its Affiliates prior to
or during the performance of this Agreement and are the sole and exclusive
property of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ or its Affiliates, as the case may be.
(b) ACUSPHERE PROPERTY. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ acknowledges that
Client possesses certain inventions, processes, know-how, trade secrets,
improvements, other intellectual properties and other assets, including but not
limited to procedures and techniques, computer technical expertise, software,
and certain technical expertise and conceptual expertise relating to the
Intermediate and Product, which have been independently developed by Client or
its Affiliates without the benefit of any information provided by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ (collectively "CLIENT PROPERTY"). Client and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
agree that any Client Property or improvements thereto which are used, improved,
modified or developed by Client under or during the term of this Agreement are
the product of Client's technical expertise possessed and developed by Client or
its Affiliates prior to or during the performance of this Agreement and are the
sole and exclusive property of Client or its Affiliates, as the case may be.
2.17 OWNERSHIP AND RIGHTS TO INVENTIONS AND TECHNOLOGY. All
inventions, technology and information, whether patentable or not (other than
those described in Section 2.16(a), which shall be owned by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
pursuant to Section 2.16(a)), conceived, reduced to practice or created by
either party and/or its agents during the performance of this Agreement
("Program Technology"), shall be owned by the Client; provided, however, to the
extent that any such invention relates to production processes not related to
the manufacture of Product, the Client shall grant and hereby grants to
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ a royalty-free, non-exclusive, world-wide, irrevocable license
to practice such Program Technology in facilities owned, operated, licensed,
rented or otherwise controlled by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. Client shall be responsible
for the costs of filing, prosecution and maintenance for patents and patent
applications on Program Technology
Page 12
and shall have full control over such filing, provided that the decision to
proceed with any such filing shall be solely at the discretion of the Client.
ARTICLE 3
RIGHT OF NEGOTIATION TO MANUFACTURE
3.1 Subject to rights which may be granted by Client to third
parties in connection with collaborative development and marketing arrangements,
prior to commencing negotiations with any third party regarding the commercial
manufacture of the Product, Client shall commence good faith negotiations
regarding the same with ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
ARTICLE 4
CONFIDENTIALITY
4.1 DEFINITION. In carrying out the CTM Program it is recognized
by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and Client that each may have to disclose to the other
information of a business or technical nature which is proprietary and
confidential to the disclosing Party (hereinafter ("Information")). Since both
Parties wish to assume that the Information is properly protected they hereby
agree as follows:
4.2 FORM OF DISCLOSURE. Information may be disclosed in either
oral, written or electronic form. For any Information to be deemed confidential
by the disclosing party, it will either be supplied in writing or electronically
and marked "CONFIDENTIAL" or, if supplied, orally (or electronically and not
clearly marked as "CONFIDENTIAL"), summarized in writing within thirty (30) days
of disclosure and marked "CONFIDENTIAL".
4.3 OBLIGATIONS. The receiving Party agrees to hold Information in
strict confidence for a period of five (5) years from receipt and to use it only
for the purposes under this Agreement. The receiving Party agrees not to
disclose the Information to any Third Party unless prior written authorization
has been obtained from the disclosing Party. These obligations shall not apply
to:
(a) Information which, at the time of disclosure, is in
the public domain.
(b) Information which, after disclosure, becomes a part
of the public domain by publication or otherwise, except by breach of this CTM
Agreement by the receiving Party.
(c) Information which the receiving Party can demonstrate
by its written records was in the receiving Party's possession at the time of
such disclosure, and which was not acquired, directly or indirectly, from the
disclosing Party.
Page 13
(d) Information which is lawfully disclosed to the
receiving Party on a non-confidential basis by a Third Party who is not
obligated to the disclosing Party or any other Third Party to retain such
Information in confidence.
(e) Information which results from research and
development by the receiving Party independent of such disclosure as shown by
competent evidence.
(f) Information which is required to be disclosed by
legal process; provided, in each case the Party so disclosing Information timely
informs the other Party and uses its best efforts to limit the disclosure and
maintain confidentiality to the extent possible and permits the other Party to
attempt by appropriate legal means to limit such disclosure.
ARTICLE 5
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ REPRESENTATIONS,
WARRANTIES AND COVENANTS
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ represents, warrants and covenants to Client as
follows:
5.1 COMMERCIALLY REASONABLE BEST EFFORTS. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall
use its best efforts to perform the services contemplated hereunder in
accordance with the CTM Program and the CTM Program schedule, it being
recognized, however, that since the services are of a developmental or research
nature, there can be no guarantee that the CTM Program will be successfully
completed, or successfully completed within the contemplated time frame, despite
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ commercially reasonable best efforts to do so. However,
following the successful completion of the required media fill Batches,
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will be responsible for manufacturing the Intermediate and
Product to Specifications agreed upon by the Parties in writing. If
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ is, for any reason, unable to meet any contemplated time frames
in the CTM Program, it shall immediately notify Client of same, as provided in
Section 2.1 hereof.
5.2 ADHERENCE TO SPECIFICATIONS. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall, subject to
Section 5.1 hereof, produce the Product in accordance with the Specifications
for the Product.
5.3 QUALIFIED PERSONNEL. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall engage and employ,
train and supervise professionally qualified personnel to safely and lawfully
perform the services contemplated hereunder.
5.4 GENERAL. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall exercise all due and reasonable
care with regard to all raw materials, components, equipment, Intermediate and
Drug Product in its custody relating to the CTM Program. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
warrants that it has the capacity, facilities, equipment, personnel, skill,
know-how, permits, approvals and licenses to perform the CTM Program.
Page 14
5.5 Debarment. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ represents and warrants to Client
that it has neither been debarred nor subject to debarment and that it does not
and will not use in any capacity in connection with the CTM Program any person
who has been debarred pursuant to Section 306 of the Act or who is the subject
of a conviction (or an investigation or prosecution for an offense) described in
this section. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ agrees to inform Client immediately in writing if
it or any person who is performing the CTM Program hereunder on behalf of
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ is debarred or is the subject of a conviction described in
Section 306 of the Act or if any action, suit, claim, investigation or
proceeding is pending or, to the knowledge of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, threatened
relating to debarment of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ or of any person performing the CTM
Program on behalf of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ hereunder.
5.6 DISCLAIMER. THE FORGOING EXPRESS WARRANTIES, TOGETHER WITH
THOSE SET FORTH IN ARTICLE 6, ARE IN LIEU OF ALL OTHER WARRANTIES, EXPRESS OR
IMPLIED, INCLUDING WITHOUT LIMITATION, ANY WARRANTY OF MERCHANTABILITY, FITNESS
FOR A PARTICULAR PURPOSE, OR AGAINST INFRINGEMENTS, AND ALL OTHER WARRANTIES ARE
HEREBY DISCLAIMED AND EXCLUDED BY ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
ARTICLE 6
GENERAL REPRESENTATION AND WARRANTIES
Each Party represents, warrants and covenants to the other as follows:
6.1 POWER AND AUTHORIZATION. It has all requisite power and
authority (corporate and otherwise) to enter into this Agreement and has duly
authorized by all necessary action the execution and delivery hereof by the
officer or individual whose name is signed on its behalf below.
6.2 NO CONFLICT. Its execution and delivery of this Agreement and
the performance of its obligations hereunder do not and will not conflict with
or result in a breach of or a default under its organizational instruments or
any other agreement, instrument, order, law or regulation applicable to it or by
which it may be bound.
6.3 ENFORCEABILITY. This Agreement has been duly and validly
executed and delivered by it and constitutes its valid and legally binding
obligation, enforceable in accordance with its terms, except as enforcement may
be limited by bankruptcy, insolvency or other laws of general application
relating to or affecting the enforcement of creditors' rights and except as
enforcement is subject to general equitable principles.
Page 15
6.4 COMPLIANCE WITH APPLICABLE LAWS. Each Party shall comply with
All Applicable Laws and Regulations in connection with the performance of this
Agreement. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ acknowledges and agrees that, upon the written
request of Client, it shall comply with the laws and regulations of any foreign
governmental authorities as set forth in such written request.
6.5 Financial Condition. It has delivered to the other Party
financial statements containing a balance sheet as of June 30, 2001 and related
statements of operation and cash flows for the six-month period then ended. Such
financial statements have been prepared in accordance with generally accepted
accounting principles (except that such statements do not contain footnotes and
are subject to year-end adjustments on audit which shall not in the aggregate be
material) and fairly present the financial condition of such Party as of such
date. In addition, it has disclosed to the other Party all facts relating to its
financial conditions and prospects that are material to an understanding of its
financial condition and prospects.
6.6 NOTIFICATION OF POTENTIAL LIABILITY. Each Party shall notify
the other in writing as soon as reasonably possible following any event,
including the receipt of any notice, warning, citation, finding, report or
service of process or the occurrence of any release, spill, upset or discharge
of hazardous wastes or substances, related to the CTM Program that could
reasonably be expected to give rise to liability on the part of the other Party
under any law, rule or regulation prescribed by a public authority or otherwise.
6.7 INTELLECTUAL PROPERTY. Each Party represents and warrants to
the other that it owns and/or has full legal rights to use its respective
Property as described in Section 2.16 hereof in conjunction with and to the
extent required to perform all work required under this Agreement.
ARTICLE 7
INDEMNIFICATION
7.1 INDEMNIFICATION BY CLIENT. Client shall indemnify, defend and
hold ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, its Affiliates and their respective directors, officers,
employees, agents, successors and assigns harmless from and against any damages,
judgments, claims, suits, actions, liabilities, costs and expenses (including,
but not limited to, reasonable attorneys' fees) resulting from any Third Party
claims or suits arising solely out of (a) the use, handling, distribution,
marketing or sale of the Product (except to the extent caused solely by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ negligent acts or omissions or willful misconduct in its
performance of the CTM Program or the manufacture or bulk packaging of the
Product), (b) Client's uncured material breach of any of its warranties or
representations hereunder, or (c) Client's grossly negligent acts or omissions
or willful misconduct.
7.2 INDEMNIFICATION BY ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. Except as otherwise
provided in Section 7.1 above, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall indemnify, defend and hold
Client, its Affiliates and their respective directors, officers, employees,
agents, successors and assigns harmless from and against any damages, judgments,
claims, suits, actions, liabilities, costs and expenses (including, but not
Page 16
limited to, reasonable attorneys' fees) resulting from any Third Party claims or
suits arising solely out of (a) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ material breach of any of its
warranties or representations hereunder or (b) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ grossly
negligent acts or omissions or willful misconduct in its performance of the CTM
Program or the manufacture or bulk packaging of the Product.
7.3 INDEMNIFICATION PROCEDURES.
(a) Any party hereto seaking indemnification hereunder
(in this context, the "indemnified party") shall notify the other party (in this
context, the "indemnifying party") in writing reasonably promptly after the
assertion against the indemnified party any Claim by a Third Party (a
"Third-Party Claim") in respect of which the indemnified party intends to base a
Claim for indemnification hereunder.
(b) (i) The indemnifying party shall have the right, upon
written notice given to the indemnified party within 30 days after receipt of
the notice from the indemnified party of any Third Party Claim, to assume the
defense and handling of such Third Party Claim, at the indemnifying party's sole
expense, in which case the provisions of Section 7.3(b) (ii) below shall govern.
(ii) The indemnifying party shall select counsel reasonably acceptable to the
indemnified party in connection with conducting the defense and handling of such
Third Party Claim, and the indemnifying party shall defend or handle the same in
consultation with the indemnified party, and shall keep the indemnified party
timely appraised of the status of the Third Party Claim. The indemnifying party
shall not, without the prior written consent of the indemnified party, which
consent shall not be unreasonably withheld, agree to a settlement of any Third
Party Claim that could directly or indirectly lead to liability or create any
financial or other obligation on the part of the indemnified party for which the
indemnified party is not entitled to indemnification hereunder. The indemnified
party shall cooperate with the indemnifying party and shall be entitled to
participate in the defense or handling of such Third Party Claim with its own
counsel and at its own expense.
(c) (i) If the indemnifying party does not give written
notice to the indemnified party, within 30 days after receipt of the notice from
the indemnified party of any Third Party Claim, of the indemnifying party's
election to assume the defense or handling of such Third Party Claim, the
provisions of Section 7.3(c)(ii) below shall govern. (ii) The indemnified party
may, at the indemnifying party's expense, select counsel in connection with
conducting the defense or handling of such Third Party Claim and defend or
handle such Third Party Claim in such manner as it may deem appropriate,
provided, however, that the indemnified party shall keep the indemnifying party
timely appraised of the status of such Third Party Claim and shall not settle
such Third Party Claim without prior written consent of the indemnifying party,
which consent shall not be unreasonably withheld. If the indemnified party
defends or handles such Third Party Claim, the indemnifying party shall
cooperate with the indemnified party and shall be entitled to participate in the
defense or handling of such Third Party Claim with its own counsel and at its
own expense.
Page 17
(d) If the indemnified party intends to seek
indemnification hereunder, other than for a Third Party Claim, then it shall
notify the indemnifying party in writing within three months after its discovery
of facts upon which it intends to base its Claim for indemnification hereunder;
provided, however, the failure to timely give such notice shall limit the
indemnifying party's liability for indemnification only to the extent the
indemnifying party's defense of such matter has been prejudiced.
(e) Except with regard to fraud, the indemnification
remedies in this Article 7, enforced in accordance with Section 9.3, shall
constitute the sole and exclusive remedies of the parties with respect to any
matters arising under or relating to this CTM Agreement.
7.4 SURVIVAL OF INDEMNIFICATION OBLIGATIONS. The provisions of
this Article 7 shall survive the expiration or termination of this Agreement for
a period of five (5) years.
7.5 LIMITATION OF LIABILITY AND CLAIMS. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall not
be liable to Client for indirect, incidental, special, punitive or consequential
damages of any kind, including without limitation lost profits or loss of good
will or otherwise. Neither Party's liability to the other under this Agreement
shall exceed [CONFIDENTIAL TREATMENT REQUESTED] /*/.
7.6 Insurance. Both Client and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall obtain and
maintain, either itself or through one or more of its affiliates, with reputable
carriers, product liability insurance with limits of not less than [CONFIDENTIAL
TREATMENT REQUESTED] /*/per claim/annual aggregate by no later than the
scheduled manufacturing date of the first CTM batch. Each party hereto shall
have its insurance carrier(s) furnish the other party hereto with a certificate
that such insurance is in force. In the event of any proposed cancellation,
non-renewal, or material adverse change in such coverage, the other party hereto
shall be given at least thirty (30) days advance written notice thereof.
ARTICLE 8
TERM AND TERMINATION
8.1 TERM. This Agreement shall remain in full force and effect to
and including June 30, 2005 unless and until terminated in accordance with the
provisions of this Article.
8.2 TERMINATION BY MUTUAL AGREEMENT. This Agreement may be
terminated at any time upon mutual written agreement between the Parties.
8.3 TERMINATION FOR DEFAULT. This Agreement may be terminated by
either Party in the event of the material breach or default by the other Party
of the terms and conditions hereof; provided, however, the other Party shall
first give to the defaulting Party written notice of the proposed termination or
cancellation of this Agreement, specifying the grounds therefor. Upon
Page 18
receipt of such notice, with respect to such defaults as are capable of being
cured, the defaulting Party shall have sixty (60) days to respond by curing such
default (or ten (10) days with respect to a failure by Client to pay any amounts
hereunder when due, with the exception of contested amounts for which Client has
provided notice to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ as provided in Section 2.4 hereof). If the
breaching Party does not so respond or fails so to work diligently and to cure
such breach within the additional time set forth above, then the other Party may
either suspend the Agreement indefinitely or terminate the Agreement.
Termination of this Agreement pursuant to this Section 8.3 shall not affect any
other rights or remedies which may be available to the nondefaulting Party.
8.4 BANKRUPTCY; INSOLVENCY. (i) Either Party may terminate this
Agreement upon the occurrence of any of the following with respect to the other
Party:
(a) The entry of a decree or order for relief by a court
having jurisdiction in the premises in respect of such other Party in an
involuntary case under the Federal Bankruptcy Code, as now constituted or
hereafter amended, or any other applicable federal or state insolvency or other
similar law and the continuance of any such decree or order unstayed and in
effect for a period of sixty (60) consecutive days;
(b) The filing by such other Party of a petition for
relief under the Federal Bankruptcy Code, as now constituted or hereafter
amended, or any other applicable federal or state insolvency or other similar
law; or
(c) The failure of such other Party to pay its debts when
due.
(ii) ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall notify Client of its intent to
file for protection under the Federal Bankruptcy Code as soon as such a
determination is made. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will segregate all Client-related
documentation, including, but not limited to, manufacturing and analytical
equipment protocols, qualifications, procedures, methods, calibrations reports
and/or certificates, Specifications, Manufacturing Batch Production Records,
Intermediate and Product analytical data, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ facility documentation
in support of the CTM Program; all Client provided manufacturing and analytical
testing equipment, including any equipment purchased by Client for
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in conjunction with the CTM Program; all unconsumed raw
materials provided by Client to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in conjunction with the CTM
Program; and all Intermediate and Product Batches, including stability samples,
that were produced in accordance with the CTM Program. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will
provide Client complete and total access to these materials at Client's request.
8.5 TERMINATION WITHOUT CAUSE. Client may terminate this CTM
Agreement without cause on ninety (90) days prior written notice to
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
8.6 RIGHTS AND DUTIES UPON TERMINATION. Upon termination of this
Agreement ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall, as promptly as practicable, (i) cease work on
the CTM Program, and (ii) turn over to Client all results, documentation and
information obtained during the CTM Program
Page 19
(whether in written or electronic form) which are then in ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇
possession and which are the property of Client in accordance with Article 2 of
this Agreement. Upon termination of this Agreement Client shall remain liable
for all fees, expenses and uncancellable obligations incurred hereunder through
the date of such termination, less any costs or expenses incurred by the
termination to move the CTM Program to another facility. If the Agreement is
terminated during the construction phase of the Facility renovations, Client
will be responsible for costs associated with completing the Facility
renovations (i.e., Capital equipment and facility renovations costs) in
accordance with Exhibit 9 of this Agreement. In addition, upon expiration or
termination of this Agreement, whichever is sooner, the Parties shall promptly
agree on a procedure which allows Client to possess any Equipment located at
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ facility that is owned by Client (with Client paying all
reasonable costs to access and remove such equipment, including the cost of
removing special plumbing or electrical connections added in connection with the
original installation of such equipment). Upon termination, all ownership and
rights to inventions and technology shall be as set forth in Section 2.16
hereof. The provisions of Article 2, Section 2.2(i) and Article 4 hereof shall
survive any termination of this Agreement.
ARTICLE 9
FORCE MAJEURE/DISPUTE RESOLUTION
9.1 EFFECT OF FORCE MAJEURE. Neither Party shall be held liable or
responsible for any loss or damages resulting from any failure or delay in its
performance due hereunder (other than the payment of money) caused by force
majeure. As used herein, force majeure shall be deemed to include any condition
beyond the reasonable control of the affected Party including, without
limitation, Acts of God, strikes or other labor disputes, war, riot, earthquake,
tornado, hurricane, fire, civil disorder, explosion, accident, flood, sabotage,
lack of or inability to obtain adequate fuel, power, materials, labor,
containers, transportation, supplies or equipment; compliance with governmental
requests, laws, rules, regulations, orders or actions; inability despite good
faith efforts to renew operating permits or licenses from local, state or
federal governmental authorities; breakage or failure of machinery or apparatus;
national defense requirements; or supplier strike, lockout or injunction.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall notify Client of any foreseeable force majeure events,
including, but not limited to foreseeable strikes and other labor disputes,
shipping interruptions or problems, and inability to procure supplies necessary
for ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to perform any of its obligations under this CTM Agreement.
9.2 NOTICE OF FORCE MAJEURE. In the event either Party is delayed
or rendered unable to perform due to force majeure, the affected Party shall
give notice of the same and its expected duration to the other Party promptly
after the occurrence of the cause relied upon, and upon the giving of such
notice the obligations of the Party giving the notice will be suspended during
the continuance of the force majeure; provided, however, such Party shall take
commercially reasonable steps to remedy the force majeure with all reasonable
dispatch. The requirement that force majeure be remedied with all reasonable
dispatch shall not require the settlement of strikes or labor controversies by
acceding to the demands of the opposing party.
Page 20
9.3 DISPUTE RESOLUTION. The parties hereto hereby agree to perform
the terms of this CTM Agreement in good faith, and to attempt to resolve any
controversy, claim a dispute arising hereunder in good faith. Any dispute
regarding the validity, construction, interpretation or performance of this CTM
Agreement (other than any provisions, hereof relating to any intellectual
property, rights, or the confidentiality obligations contained in Article 4
hereof) shall be (i) first attempted to be resolved between the CEO/President of
each Party and failing that (ii) submitted to binding arbitration in Boston,
Massachusetts, U.S.A. to be conducted in accordance with the Arbitration Rules
of the American Arbitration Association ("AAA"); provided however, that nothing
in this Section 9.3 shall be construed to preclude either party from seeking
provisional remedies, including, but not limited to, temporary restraining
orders and preliminary injunctions, from any court of competent jurisdiction, in
order to protect its rights pending arbitration, but such preliminary relief
shall not be sought as a means of avoiding arbitration. Any arbitration
hereunder shall be submitted to an arbitration tribunal made up of three (3)
members, one of whom shall be selected by Client, one of whom shall be selected
by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, and one of whom shall be selected by the other two
arbitrators. All arbitration proceedings shall be conducted in English. The
order or award of the arbitrators shall be final and may be enforced in any
court of competent jurisdiction. The prevailing party in any legal or
arbitration action brought by one party against the other shall be entitled, in
addition to any other rights and remedies it may have, to reimbursement for its
expenses incurred thereby, including court costs and reasonable attorneys' fees.
The parties shall have the right of limited prehearing discovery, including (i)
exchange of witness lists, (ii) exchange of documentary evidence and reasonably
related documents, (iii) written interrogatories, and (iv) subject to the
reasonable discretion of the arbitrators and upon good cause shown depositions
under oath of any witnesses who are to be called to testify at the arbitration
hearing. As soon as the discovery is concluded, the arbitrators shall hold a
hearing in accordance with the aforesaid shall hold a hearing in accordance with
the aforesaid AAA rules.
ARTICLE 10
NOTICES
10.1 All notices provided for herein shall be in writing and shall
be deemed to be delivered when deposited in the United States mail, postage
prepaid, or hand-delivered to an authorized representative of the Party to whom
notice is directed, or sent by telex, facsimile, telegram or cable, charges
prepaid, to the address of the other Party designated below:
Client: ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇:
Acusphere, Inc. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC
▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇▇ 3525 North Regal Street
Page 21
▇▇▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
Attention: ▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇ III Attention: ▇▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇▇▇▇
FAX: ▇▇▇-▇▇▇-▇▇▇▇ FAX: (▇▇▇) ▇▇▇-▇▇▇▇
The address and person provided above may be charged by either Party by
providing the other Party with written notice of such change.
ARTICLE 11
MISCELLANEOUS
11.1 ENTIRE AGREEMENT. This Agreement and attachments contain the
entire understanding between the Parties with respect to the subject matter
hereof, and may be modified, only by a written instrument duly executed by each
Party's authorized representative.
11.2 INDEPENDENT CONTRACTOR. Client will not have the right to
direct or control the activities of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ performing the service
provided herein, and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall perform services hereunder only as an
independent contractor, and nothing herein shall be construed to be inconsistent
with relationship or status. Under no circumstances shall ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ be
considered to be an employee or agent of Client, nor shall Client be liable in
any way for employment activities or employees of ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
11.3 PUBLICITY. Any press release, publicity or other form of
public written disclosure related to this Agreement prepared by one Party shall
be submitted to the other Party prior to release for approval, which approval
shall not be unreasonably withheld or delayed by such other Party.
11.4 USE OF PARTY'S NAME. Except as expressly provided or
contemplated hereunder and except as otherwise required by applicable law, no
right is granted pursuant to this CTM Agreement to either Party to use in any
manner the trademarks or name of the other Party, or any other trade name,
service ▇▇▇▇, or trademark owned by or licensed to the other Party in connection
with the performance of the CTM Agreement. Notwithstanding the above, the
Parties shall be permitted to use the other Party's name and marks in connection
with general advertising and promotional activities and, to the extent required
by applicable law, the parties shall be permitted to use the other Party's name
and disclose the existence and terms of this Agreement in connection with
required public regulatory filings, public securities filings and private
placement memoranda and documentation, using reasonable commercial efforts to
protect the confidentiality of the terms of this Agreement.
11.5 SEVERABILITY. Each Party hereby expressly agrees that it has
no intention to violate any public policy, statutory or common laws, rules,
regulations, treaty or decision of any government agency or executive body
thereof of any country or community or association of
Page 22
countries; that if any word, sentence, paragraph, clause or combination thereof
in this Agreement is found by a court or executive body with judicial powers
having jurisdiction over this Agreement or either Party hereto, in a final
unappealed order, to be in violation of any such provisions in any country or
community or association of countries, such words, sentences, paragraphs,
clauses or combination shall be inoperative in such country or community or
association of countries and the remainder of this CTM Agreement shall remain
binding upon the Parties, so long as enforcement of the remainder does not
violate the Parties' overall intentions in this transaction.
11.6 ASSIGNMENT; SUBCONTRACTORS. This Agreement may not be assigned
or otherwise transferred by either Party without the prior written consent of
the other Party; provided, however, either Party may, without such consent,
assign this Agreement (a) in connection with the transfer or sale of all or
substantially all of the assets of such Party or the line of business of which
this Agreement forms a part, (b) in the event of the merger or consolidation of
a Party hereto with another company, or (c) to any Affiliate of the assigning
Party fully capable of performing hereunder. Any purported assignment in
violation of the preceding sentence shall be void. Any permitted assignee shall
assume all obligations of its assignor under this Agreement. No assignment shall
relieve either Party of responsibility for the performance of any obligation
which accrued prior to the effective date of such assignment.
11.7 GOVERNING LAW. This Agreement shall be governed by and
construed in accordance with the laws of the state of Washington, irrespective
of any conflicts of law rule which may direct or refer such determination of
applicable law to any other state; and if this Agreement were performed wholly
within the state of Washington.
11.8 HEADINGS. Paragraph headings and captions used herein are for
convenience of reference only and shall not be used in the construction or
interpretation of this Agreement.
11.9 CONTINUING OBLIGATIONS. Termination, assignment or expiration
of this Agreement shall not relieve either Party from full performance of any
obligations incurred prior thereto.
11.10 WAIVER. Neither Party's waiver of any breach or failure to
enforce any of the terms and conditions of this CTM Agreement, at any time,
shall in any way affect, limit or waive such Party's right thereafter to enforce
and compel strict compliance with every term and condition of this CTM
Agreement.
11.11 CONSTRUCTION. This Agreement has been jointly prepared on the
basis of the mutual understanding of the Parties and shall not be construed
against either Party by reason of such Party's being the drafter hereof or
thereof.
11.12 EXHIBITS, SCHEDULES AND ATTACHMENTS. Any and all exhibits,
schedules and attachments referred to herein form an integral part of this
Agreement and are incorporated into this Agreement by such reference.
Page 23
11.13 NON-COMPETITION. During the term of this Agreement and for two
(2) years thereafter, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ agrees that it shall not manufacture or
agree to manufacture any material using microsphere technology for use as or in
connection with an ultrasound contrast agent that competes with the Product.
Further, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ shall not use any inventions, processes, know-how,
trade secrets, improvements, other intellectual properties and other assets,
including but not limited to procedures and techniques, computer technical
expertise, software, and certain technical expertise and conceptual expertise
relating to the Intermediate and Product which have been independently developed
by Client or its Affiliates to assist any third party in connection with an
ultrasound contrast agent that competes with the Product.
IN WITNESS WHEREOF, this Agreement has been executed by the Parties
hereto as of the day and year first written above.
ACUSPHERE, INC. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ LABORATORIES LLC
/s/ ▇▇▇▇▇▇ ▇. ▇▇▇▇▇ /s/ A. Bonanzino
------------------------------ --------------------------------
Signature Signature
▇▇▇▇▇▇. ▇. ▇▇▇▇▇ A. Bonanzino
------------------------------ --------------------------------
Name Name
President and C.E.O. President and CEO
------------------------------ --------------------------------
Title Title
Page 24
Exhibit 1
(See Attachment)
Page 25
EXHIBIT 1
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC ("Hollister") and Acusphere, Inc.
("Client") have identified in this Exhibit 1 certain manufacturing activities to
be provided by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, and various assumptions associated with the
project.
I. MANUFACTURING ACTIVITIES
CATEGORY DESCRIPTION
-------- -----------
Analytical Draft analytical testing method transfer for Client
approval, execute analytical methods and equipment
transfer, including confirmation of Client methods
and procedures; draft analytical methods transfer
report for Client approval; draft equipment transfer
protocol for Client approval; draft equipment
procedure documents using Client supplied analytical
method and equipment protocols and procedures for
Client approval; conduct raw material release
testing, conduct Intermediate and Product batch and
stability testing; generate Intermediate and Product
batch testing result reports for Client approval and
release; draft release Specifications for raw
material, Intermediate and Product testing using
Client supplied raw material, Intermediate and
Product Specifications for Client approval.
Process Development MSDS/Safety training; confirm Client's
lyophilization cycle on ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇
lyophilizer.
Batch Precursor Confirm performance of Client's vial, stopper and
Work seal on ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ production equipment;
calibrate Client supplied equipment; execute I/OQ
protocols of Client supplied equipment using Client
supplied I/OQ protocols; draft equipment procedure
documents using Client supplied protocols and
procedures for Client approval; execute appropriate
qualification or validation protocols on
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ production equipment (i.e., autoclave
load patterns) for use with Client supplied equipment
and components; draft Steam-in-place (SIP) protocols
for Client supplied equipment for Client
1 of 8
approval; execute Steam-in-place (SIP) protocols for
Client supplied equipment; draft Steam-in-place (SIP)
reports for Client approval, confirm Client supplied
equipment cleaning procedures; execute minimum number
of simulation, demonstration and development batches
prior to aseptic validation batches; execute Process
Simulation (Intermediate) and Media Fill (Product)
batches (aseptic validation); create/update
environmental monitoring procedures for Intermediate
and Product manufacturing; confirm shipping container
for bulk shipment of Product to Client designated
location, using appropriate temperature monitoring
device(s).
Batch Activities Draft Master Batch Production and Control records,
including aseptic validation Batch Production and
Control records, using Client supplied manufacturing
and aseptic validation batch records for Client
approval. (Labor associated with the manufacturing,
inspection and packing of the (Intermediate) and
Product is included in the batch cost).
Post-Batch Activities Preparation of CTM Program Summary Report
following completion of contract, The content of the
CTM Program Summary Report will be mutually agreed
upon in writing by the Parties before execution.
Stability Draft Product stability testing protocol and
Program stability report format for Client approval; store
stability batches and conduct testing of all
CTM/stability batches of the Product in upright and
inverted orientations at accelerated and standard
controlled storage conditions according to ICH
guidelines and verified analytical methods; generate
stability testing result reports to Client at
appropriate frequency.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will submit invoices in accordance with
Section 2.4 of the CTM Agreement. The format of the invoice will be
approved by the Client. The invoice will be submitted to Client by no
later than thirty (30) days from the completion of an applicable
milestone.
The anticipated number of batches and batch costs are stated
below. The number of Development (Simulation) batches is an estimate.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and
2 of 8
Client shall cooperate in efforts to attempt to minimize the required
number of these batches; and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will invoice Client only
for batches actually produced.
Number Batch Type Batch Description/Purpose Price/Batch (1) Total Price
------ ---------- ------------------------- ------------ -----------
1* Water Batch Test process recipes/activities [CONFIDENTIAL TREATMENT [CONFIDENTIAL TREATMENT
REQUESTED] /*/ REQUESTED] /*/
1-2* Development Simulation - [CONFIDENTIAL [CONFIDENTIAL TREATMENT [CONFIDENTIAL TREATMENT
TREATMENT REQUESTED] /*/ REQUESTED] /*/ REQUESTED] /*/
3* Media Fills Validate batch processing [CONFIDENTIAL TREATMENT [CONFIDENTIAL TREATMENT
REQUESTED] /*/ REQUESTED] /*/
1*** CTM Clinical trial/stability [CONFIDENTIAL TREATMENT [CONFIDENTIAL TREATMENT
batches REQUESTED] /*/ REQUESTED] /*/
2-6*** CTM Clinical trial/stability [CONFIDENTIAL TREATMENT [CONFIDENTIAL TREATMENT
batches REQUESTED] /*/ REQUESTED] /*/
----------------------------
Total Batch Cost [CONFIDENTIAL TREATMENT
REQUESTED] /*/
* Includes costs for all raw materials and components.
** Includes costs for all raw materials and components, with the
exception of the perfluorocarbon gas, phospholipid and polymer raw
materials which will be supplied by Client .
*** The CTM batch cost also includes inspection and bulk packaging.
All Development (Simulation), Media Fill (including Process Simulation
batches for the Intermediate) and CTM batches are comprised of one (1)
Intermediate batch and one (1) Product batch.
C. CAPITAL COSTS.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ anticipates that the following capital costs
will be incurred in connection with this project. Renovations to the
CTM Program Facilities are required to provide Client with CTM and
commercial scale-up capability for manufacturing the Intermediate. The
renovations will create a manufacturing area dedicated to Client.
Excess capacity of this dedicated manufacturing area not utilized by
Client may be used by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ upon written approval from
Client. Such approval will not be unreasonably withheld. Client's
manufacturing equipment may not be used by other ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
clients.
DESCRIPTION PRICE
----------- -----
Facility Renovations [CONFIDENTIAL TREATMENT REQUESTED] /*/
Capital Equipment [CONFIDENTIAL TREATMENT REQUESTED] /*/
Total Capital Cost [CONFIDENTIAL TREATMENT REQUESTED] /*/
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will invoice Client for such capital costs in
accordance with Section 2.4 of the CTM Agreement. Client will review
and approve the layout and installation of its equipment within the CTM
Program Facilities.
3 of 8
II. TECHNOLOGY TRANSFER ACTIVITIES
The parties have identified a series of technology transfer activities
required to prepare for Intermediate and Product batch production by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. The Technology Transfer Project activities listed in Section
II.A. of this Exhibit will be completed prior to the manufacture of CTM batches
of the Intermediate and Product.
A. TECHNOLOGY TRANSFER PROJECT ACTIVITIES.
The following activities, at a minimum, must be completed to
enable ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to manufacture the Intermediate and the Product.
The activities assume success at each stage; no contingency activities
have been included as part of the project work or in estimates of
price, modification of which will require mutual agreement of the
parties.
- Cleaning Methodology - verify the Intermediate and the Product
can be removed from ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ supplied manufacturing
equipment and CTM Program Facilities, as applicable.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will confirm that procedures are in-place to
remove product residues other than the Intermediate and Product
from ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ supplied equipment and the CTM Program
Facilities.
- [CONFIDENTIAL TREATMENT REQUESTED] /*/
- Biological Methods Development/Transfer - Sterility, LAL.
- Qualification/Validation Activities - execute as set forth in
Section I(A) Batch Precursor Work of this Exhibit.
- Water Batch - One (1) full scale water batch/line test to verify
the Intermediate and Product manufacturing processes: focal
points include the Intermediate manufacturing process flow
(includes homogenization), the Product manufacturing process,
including fill accuracy, [CONFIDENTIAL TREATMENT REQUESTED] /*/,
freeze drying, capping, loading and unloading. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇
and Client acknowledge that water cannot simulate certain
processing steps within the Intermediate and Product
manufacturing processes.
- Development (Simulation) Batches - One (1) to two (2) batches to
simulate the Intermediate and Product manufacturing process using
[CONFIDENTIAL TREATMENT REQUESTED] /*/ rather than active
formulation and does not include the perfluorocarbon gas.
- Process Simulation/Media Fills - a minimum of three (3)
consecutive, successful Process Simulation/Media Fill batches to
qualify the aseptic manufacturing of the Intermediate and the
Product, and container closure integrity.
- Clinical Trial Material Batches - Three (3) to six (6) batches
using the active formulation and perfluorocarbon gas.
4 of 8
- ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ agrees to work with Client to attempt to minimize
the number of Development batches required and will ▇▇▇▇ only for
batches actually performed.
B. ASSUMPTIONS.
Manufacturing Assumptions
1. Project may require completion of MSDS, Safety Assessment,
Environmental Assessment, and Waste Disposal procedures as
appropriate for this project. Costs associated with these
assessments will be borne by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. The parties
shall in good faith identify capital expenditures needed to
achieve compliance with safety and environmental issues and to
the relative responsibility of each party to pay for any such
expenditures.
2. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will furnish all raw materials and
components for all activities, with the exception of the
polymer, phospholipid and perfluorocarbon gas which will be
provided by Client. Sampling and release testing
[CONFIDENTIAL TREATMENT REQUESTED] /*/ will be performed at
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ on all raw materials and components supplied
by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and including all raw materials supplied
by Client; additional release testing will be performed by an
outside laboratory as stated in Item #23 of the Analytical
Assumptions Section.
3. Client will be responsible for [CONFIDENTIAL TREATMENT
REQUESTED] /*/ disposal costs. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to identify
appropriate disposal company and disposal cost/55 gallon drum.
4. Development of procedures for recovery of unused
perfluorocarbon gas is not included in this proposal.
5. Client will (in good faith) approve master batch
documentation using ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ documentation approval
procedures prior to change implementation. The Master Batch
Documentation includes: Master Formulas (a.k.a. Manufacturing
Work Orders), Filling Work Orders (Fwos), equivalent
documents for Process Simulation/Media Fill Batches, Bills of
Materials for Filling & Packaging Operations and SOPs for
dedicated Client supplied equipment. Client will approve all
protocols for proposed Validation work for the Client's
Intermediate and Product specific equipment, processes and
systems. Client reserves the right to approve additional
documents as they are defined.
6. All cleaning procedures will be verified by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will develop suitable
residue methods, if required. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will verify
that the Intermediate and the Product can be removed from
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ supplied manufacturing equipment and CTM
Program
5 of 8
Facilities, as applicable. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will confirm that
procedures are in-place to remove product residuals other than
the Intermediate and Product from ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ supplied
equipment and the CTM Program Facilities.
7. The batch size is estimated at [CONFIDENTIAL TREATMENT
REQUESTED] /*/ of the Intermediate, and [CONFIDENTIAL
TREATMENT REQUESTED] /*/ of the Product, with an estimated
yield of [CONFIDENTIAL TREATMENT REQUESTED] /*/ vials of
Product.
8. Primary packaging consists of
▇▇▇▇▇▇-▇▇▇▇ 20-mL type 1 tubing vials - West Catalog No.:
68000321 Daikyo 20mm Flurotech stoppers - West Catalog No.:
V10-F451W SVLYO West 20mm flip-off seals - West Catalog No.:
5420-2054
9. [CONFIDENTIAL TREATMENT REQUESTED] /*/
10. [CONFIDENTIAL TREATMENT REQUESTED] /*/
11. Metrology schedules for manufacturing equipment will be
jointly agreed upon by Client and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
12. Manufacturing facility temperature and humidity
requirements for the Intermediate and Product are as follows:
temperature < 23(Degree)C; humidity < 55% RH. - -
13. The Product will be 100% manually inspected following
capping. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and Client will jointly determine
inspection criteria for acceptability.
14. A minimum of three (3) consecutive, successful Process
Simulation/Media Fill batches is required for the aseptic
processing qualification and container/closure integrity
testing. The cost of additional Process Simulation/Media Fill
batches is outside of the scope of this proposal.
15. CTM batches will be bulk packaged unlabeled.
Analytical Assumptions
16. The project requires Analytical Methods Transfer and assay
verification for pertinent analytical testing. Client will
approve the Analytical Standards (Raw Materials and
Intermediate and Product Specifications, Test Methods and
Addenda) prior to change implementation. Client will receive
and approve all Master Analytical Method Transfer Protocols
and Reports, all Master Analytical Standards Documents (Raw
Materials,
6 of 8
Intermediate and Product Specifications, Testing and Agenda
and Standard Operating Procedures (SOPs)) for Client supplied
equipment. Client reserves the right to approve additional
documents as they are defined.
17. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will perform release testing of liquid
nitrogen used in the manufacturing processes for the
Intermediate and Product.
18. Transfer of the Intermediate and Product ID, in-process
and release methods, and transfer of the Sterility, and LAL
methods, will consist of closely adapting Client's validated
methods and confirming their validity.
19. Analytical methods and specifications must be generated by
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and approved by Client for raw materials, the
Intermediate and Product. Analytical methods and
specifications are critical documents and review and approval
is required per assumption #16.
20. The project assumes that the scope of analytical testing
at ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ includes: [CONFIDENTIAL TREATMENT
REQUESTED]/*/. These tests will be performed as in-process
or release tests once finalized by Client. Closure integrity
testing will be required for stability.
21. In order for ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ to perform certain release
testing for the Product, it may be necessary to purchase
additional capital equipment for the laboratory.
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will notify Client prior to the purchase of
additional equipment, if required. Client will provide this
additional equipment to ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇, as appropriate.
22. Stability sample controlled storage and testing of the
Product will be performed by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇.
23. (1)HNMR testing will be performed by a contract
laboratory.
24. The first three (3) QA released CTM batches will be
placed on stability.
7 of 8
General Assumptions
25. Client will compensate ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ for travel and
other expenses associated with a technical transfer discussion
at the current site of manufacture, if required.
26. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Regulatory Affairs will provide, at a
minimum, in-house regulatory support, necessary documentation
to support regulatory submissions, including raw data, and
regulatory consulting activities. Regulatory consulting will
be billed on a per-hour basis[CONFIDENTIAL TREATMENT
REQUESTED] /*/.
27. Following successful completion of the required Process
Simulation/Media fill batches, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will be
responsible for manufacturing the Intermediate and Product to
agreed specifications.
28. The project assumes that ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ does not have to
purchase new equipment for the manufacture of the Intermediate
and Product. Purchases not agreed by the parties are outside
the scope of the project.
29. Shipping of Product will be at Client's expense, with
delivery FOB Spokane, WA.
30. The Intermediate and Product will be manufactured
according to USP, EP, and applicable cGMP requirements.
31. Client personnel will be available on site to serve on the
Project Team. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will provide an appropriate
office space for Client personnel (2 individuals) as set forth
in Section 2.14 of the CTM Agreement.
32. Client will conduct a formal cGMP audit of the appropriate
manufacturing and analytical areas associated with this
project. The audit date will be mutually agreed upon by both
parties, but must occur before August 31, 2001. Prior to
initiating the CTM Program, ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will promptly
remedy to Client's satisfaction any reasonable issues or
concerns noted during Client's formal cGMP audit.
8 of 8
Exhibit 2
Intermediate and Product Specifications
Page 26
Exhibit 3
Schedule
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Page 27
Exhibit 4
Documentation
ANALYTICAL DOCUMENTATION
1. Method Transfer Protocols
2. Method Transfer Final Report
3. Equipment SOP's (for Acusphere provided equipment)
RAW MATERIAL/MANUFACTURING COMPONENT/PRODUCT DOCUMENTATION
1. Raw Material and Manufacturing Component Specification Sheets
2. PLGA Microspheres for AI-700 Specification
3. AI-700 Specification
4. Raw Material and Manufacturing Component Release Reports
5. PLGA Microspheres for AI-700 Certificate of Analysis
6. PLGA Microspheres for AI-700 Certificate of Compliance
7. AI-700 Certificate of Analysis
8. AI-700 Certificate of Compliance
9. Bulk Shipping Label Format
MANUFACTURING DOCUMENTATION
1. Equipment I/OQ Protocols (for Acusphere provided equipment)
2. Equipment SIP Protocols (for Acusphere provided equipment)
3. Equipment SOP's (for Acusphere provided equipment)
4. Qualification or Validation protocols on ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ equipment used in conjunction with
Acusphere equipment or processes (e.g., autoclave - load patterns)
5. Aseptic manufacturing batch records (Process Simulation & Media Fills)
6. PLGA Microspheres for AI-700 manufacturing batch records
7. AI-700 manufacturing batch records
8. Equipment Cleaning & Use Log Books for all manufacturing equipment (Acusphere or
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇) used in this project
9. Certificates of Calibration for Acusphere-supplied equipment
10. Preventative maintenance or maintenance work orders preformed on Acusphere-supplied equipment
11. Environmental Monitoring Data/batch
12. WFI Data/batch
13. Deviations/Incidents
14. Investigations
15. Change Control documents
16. Bulk Package/Shipping Records
STABILITY DOCUMENTATION
1. Stability Protocol
2. Stability Reports
Page 28
Exhibit 5
Analytical and Manufacturing Equipment
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Page 29
Exhibit 5 (cont'd)
Analytical and Manufacturing Equipment
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Page 30
Exhibit 6
Intermediate and Product Master Batch Production and Control Records
Page 31
Exhibit 7
Intermediate and Product Master Quality Control Analytical
Testing Methods and Procedures
Page 32
Exhibit 8
Analytical Testing Method Transfer Protocols
Page 33
Exhibit 9
H-S CTM Manufacturing Proposal
(See Attachment)
Page 34
August 16, 2001
▇▇. ▇▇▇▇▇▇ ▇. ▇▇▇▇▇▇ III
Senior Director, Manufacturing and Process Development
Acusphere, Inc.
University Park at M.I.T.
▇▇ ▇▇▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇▇
Dear ▇▇. ▇▇▇▇▇▇:
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC (H-S) is pleased to provide the following
quotation for the aseptic manufacturing of PLGA Microspheres and AI-700 for
clinical trials. The scope of this quote includes production of CTM batches and
the stability program associated with those batches. Commercial production of
the product is not included in this proposal.
Project Assumptions
1. Manufacturing Assumptions
1.1 Projected AI-700 Lot Size: [CONFIDENTIAL TREATMENT REQUESTED]
/*/ vials maximum (approximately [CONFIDENTIAL TREATMENT
REQUESTED] /*/).
1.2 One (1) batch of PLGA Microspheres will produce one (1) batch
of AI-700.
1.3 All manufacturing process equipment to be provided by
Acusphere.
1.4 ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will purchase the following excipient
ingredients as specified by Acusphere: D-Mannitol (Powder),
Polysorbate 80, (certified Kosher) [CONFIDENTIAL TREATMENT
REQUESTED] /*/. All of the raw materials listed above can be
stored at room temperature.
1.5 The following raw materials will be provided by Acusphere for
all development and CTM batches: Polymer (2-8(degrees)C
storage), Phospholipid (less than -20(degrees)C storage), and
Perfluorocarbon Gas (room temperature storage). Acusphere will
be responsible for the cost and coordination of the shipment
for these bulk raw materials.
1.6 Acusphere will provide the Lyophilization cycle.
Page 1 of 12
1.7 Acusphere will provide insulated packaging for the shipment of
finished product. Temperature monitoring methods and
instrumentation used during shipment will be provided by
Acusphere. Acusphere will provide any hardware and software
required to run, download, or program their devices.
1.8 Product will be shipped F.O.B. Spokane to a single location
designated by Acusphere at Acusphere's expense and liability.
1.9 Finished product will be stored at H-S between 2-8(Degree)C.
1.10 The cost of the [CONFIDENTIAL TREATMENT REQUESTED] /*/ are
included in the batch production cost.
1.11 The minimum shelf temperature that can be reliably attained on
the ▇▇▇▇▇▇▇ Lyophilizer is -45(Degree)C.
1.12 At this time H-S is assuming that employee health screening
will not be required for the use of [CONFIDENTIAL TREATMENT
REQUESTED] /*/. Acusphere has provided H-S with a health
screening history of their employees.
1.13 [CONFIDENTIAL TREATMENT REQUESTED] /*/
1.14 Process equipment operation and trouble shooting will be the
responsibility of Acusphere. This responsibility will be
transferred to H-S upon the first CTM batch.
2. Documentation Assumptions
2.1 Revisions to SOPs related to the operation of the process equipment and
batch records will be the responsibility of H-S. [CONFIDENTIAL
TREATMENT REQUESTED] /*/
2.2 The SOP for the integrity testing of solution filters will be the
responsibility of H-S.
2.3 H-S will perform equipment I/OQs that will be provided electronically
by Acusphere. A very brief protocol supplement will be written by H-S
to document the performance of Acusphere's I/OQ and any additional
qualification steps required. The supplement will be issued an H-S
protocol number and will follow the H-S standard protocol filing
procedure. Both H-S and Acusphere will approve the protocol
supplements.
Page 2 of 12
3. QA Assumptions
3.1 Acusphere's approval to proceed with this project is
contingent on the successful completion of a cGMP audit. This
cGMP audit is currently being scheduled for the week of August
20th, 2001.
3.2 Product will be produced using ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇'▇ general
quality control program, subject only to product specific
changes.
3.3 Acusphere will provide copies of all relevant test procedures,
method validation reports, and product and component
specifications. These will be converted to H-S format. Both
H-S and Acusphere will approve procedures and method
validation reports. Acusphere will support the technical
transfer of test procedures and method validation.
3.4 Acusphere will provide the polymer, phospholipid, and
perfluorocarbon needed to produce the required product.
[CONFIDENTIAL TREATMENT REQUESTED] /*/
3.5 Acusphere will provide:
3.5.1 [CONFIDENTIAL TREATMENT REQUESTED] /*/
3.5.2 [CONFIDENTIAL TREATMENT REQUESTED] /*/
3.5.3 [CONFIDENTIAL TREATMENT REQUESTED] /*/
3.6 Validated/qualified methods will be provided by Acusphere for
all analytical testing.
3.7 Retention sample storage will be an H-S responsibility and
will satisfy the requirements of Acusphere. Retention sample
storage environmental conditions will be 2-8oC.
3.8 Regulatory support is currently undefined.
3.9 Stability sample incubation and the stability test program
will be the responsibility of H-S. Stability test quantities
and environmental conditions are listed on page 10 of this
proposal.
3.10 H-S will perform endotoxin and sterility testing in-house
using qualified/validated methods transferred from Acusphere
contract laboratories.
3.11 An outside laboratory will perform container/closure integrity
testing by dye leakage. H-S will be responsible for shipment
of vials to the laboratory.
Page 3 of 12
4. Validation Assumptions
4.1 Solution filter validation will be completed by Acusphere by
Q4, 2001.
4.2 [CONFIDENTIAL TREATMENT REQUESTED] /*/
4.3 [CONFIDENTIAL TREATMENT REQUESTED] /*/
4.4 [CONFIDENTIAL TREATMENT REQUESTED] /*/
5. Engineering/Facility Assumptions
5.1 In the new production facility design, H-S will provide floor
space encompassing existing rooms S17, S19, S18A, and portions
of S12 and S8 in the area formerly known as Allpyral. In
addition, H-S will provide a temporary equipment qualification
area known as S28.
5.2 Travel to meet the requirements of this project will be billed
to Acusphere at cost. H-S has identified two pieces of
critical equipment that will require Factory Acceptance
Testing (F.A.T.) and/or design review visits. These pieces of
equipment are the aseptic compounding booth and the facility
Air-Handling Unit (AHU). Travel and expenses will be invoiced
separately (at cost) and no labor will be charged. Any vendor
visits will be discussed with the Acusphere Project Manager
prior to travel, and a visit report/copies of receipts will be
issued to Acusphere with the invoice. Acusphere may wish to
attend these F.A.T. or design review visits, and this is
acceptable to H-S. The total cost of project travel will not
exceed $20,000.
5.3 Disposal of the used [CONFIDENTIAL TREATMENT REQUESTED] /*/ is
included in the batch production cost.
5.4 H-S will provide cleaning and use logs for the process
equipment.
5.5 Factory calibrations required on sophisticated instrumentation
will be provided by Acusphere. All other instrument
calibrations will be provided by H-S.
5.6 Process hoses, filters, filter stands, support equipment, and
equipment spare parts will be provided by Acusphere.
Page 4 of 12
5.7 A floor scale for compounding accountability will be provided
by Acusphere. The floor scale will be provided with an
appropriate printer in order to document the critical steps
during the processing.
5.8 The facility renovation project schedule holds a 3-week
contingency. Delivery time lines from vendors have not been
received for the following: critical equipment, A&E firms,
construction firms or demolition crews. These lead times could
have an impact on the estimated completion date.
ATTACHMENTS TO QUOTE
1. CTM Project Schedule A preliminary project schedule is provided in
Section #1. The scope of this schedule includes the manufacture of the
first batch of CTM material. All other CTM batches will proceed per a
schedule supplied by Acusphere and agreed upon by H-S.
2. CTM Facility Renovation Layout A preliminary facility renovation layout
is provided in Section #2. This preliminary design was the result of a
joint effort between the Acusphere and H-S Engineering groups. The
scope of this design is to provide PLGA Microsphere CTM and commercial
scale up capacity for Acusphere. Facility capacity not used by
Acusphere can be used by H-S for the production of other CTMs.
Acusphere will have pre-notification of the other product types to be
manufactured in the CTM facility.
3. CTM Facility Renovation Schedule A preliminary facility renovation
schedule is provided in Section #3. This renovation schedule is based
on H-S experience, and no timelines have been provided by contractors.
4. CTM Facility Renovation Costs/Equipment Costs A preliminary facility
renovation cost spreadsheet is provided in Section #4. This renovation
schedule is based on H-S experience, and no formal quotes have been
provided by contractors or vendors. Acusphere will retain ownership of
all portable equipment.
5. CTM Facility Documentation Costs A variety of costs related to
validation and documentation are referenced in Section #5. All prices
are estimates, subject to change as the project is more clearly
defined.
6. Product Release Testing and Stability Program Testing A spreadsheet is
attached in Section #6 which delineates all analytical testing required
for product release and for the stability program.
Page 5 of 12
7. Detailed Costs for the Stability Study Program. A document is reflected
in Section #7, which delineates details on the costs associated with
the stability study program.
8. Copies of Presentation Section #8 includes copies of the PowerPoint
Presentation provided in Cambridge, MA on August 7, 2001.
PROJECT COSTS
1. One Time Technology Transfer Costs
1.1 Various costs related to validation and documentation. These costs are
detailed in Section #5. [CONFIDENTIAL TREATMENT REQUESTED] /*/
1.2 Project Management
Project Leader: 6 months [CONFIDENTIAL TREATMENT REQUESTED] /*/
- Primary project interface at H-S, track the project schedule,
organize and chair the team meetings, budget tracking, meeting
minutes, project book management, control of project scope.
Facility Engineer: 6 months [CONFIDENTIAL TREATMENT REQUESTED] /*/
- Primary responsibility for facility design, utility design,
demolition, renovation, equipment purchase, contractor
supervision, documentation, commissioning, qualification, etc.
Equipment Engineer: 6 months [CONFIDENTIAL TREATMENT REQUESTED] /*/
- Specification and purchase of the aseptic compounding booth,
the chemical fume hood, the -20(degrees)C freezer, components
for SIP of the control piping and drying coil of the spray
dryer and five (5) tanks, permit management, electrical
installation and supervision, set up of process development
area, Building Automation System, drawing support, etc.
Analytical Scientist: 6 months total [CONFIDENTIAL TREATMENT REQUESTED]
/*/
- Familiarization/Preparation for Tech Transfer: 3 months
- Review analytical package.
- Ensure H-S equipment/reagents/supplies are available
and in-place.
- Set-up, training with [CONFIDENTIAL TREATMENT
REQUESTED] /*/ representative.
- Training time with Acusphere analyst.
- Establish assay parameters with "training" supplies.
- Tech Transfer: 3 months
- Provide written draft of protocol with Acusphere
procedures and input for acceptance criteria, to
encompass all analytical methodologies to be
transferred, edited, with final approval by both
sites.
- Complete the studies upon approval of the protocol.
Page 6 of 12
- Investigation of unexpected results and resolution of
any problems.
- Provide final acceptance report for approval at both
sites.
- Convert procedures to H-S format and receive approval
from H-S and Acusphere.
- Unplanned analytical support for process work.
Validation Support - Sterilization Process: 3 months[CONFIDENTIAL
TREATMENT REQUESTED] /*/
- Develop and validate the autoclave sterilization loads for all
aseptic assembly parts and all SIP validation support. This
includes full validation on two 75L processing tanks and the
spray dryer skid.
Production: 6 months [CONFIDENTIAL TREATMENT REQUESTED] /*/
- Development of 4 batch records to include ▇▇▇▇ ▇▇▇▇▇▇▇▇▇▇▇▇,
▇▇-▇▇▇, Process Simulation [CONFIDENTIAL TREATMENT REQUESTED]
/*/ and media fill batch records, manufacturing and PIC
coordination, SOP writing, development of filling/freezing
process, and lyophilizer cycle development and test runs.
Dedicated Process Specialist: 6 months[CONFIDENTIAL TREATMENT
REQUESTED] /*/
- This will include one validation person who will be
responsible for performance of equipment I/OQ,
writing/modifying SOPs, learning the process and operation of
the equipment, commissioning of equipment, and I/OQ
supplements.
Regulatory Support: 1 month TBD
- FDA notification for major utility modifications, CBE30 for
SLM area. These activities are not yet defined and will be
billed for actual hours worked @[CONFIDENTIAL TREATMENT
REQUESTED] /*/.
TOTAL: PROJECT MANAGEMENT ONE TIME COST
[CONFIDENTIAL TREATMENT REQUESTED] /*/
NOTE: If this project extends for greater than 6 months (up to the
point of the first development batch) additional time will be charged
at the standard [CONFIDENTIAL TREATMENT REQUESTED] /*/.
1.3 New Capital Equipment Costs -
(see details in Section #4) [CONFIDENTIAL TREATMENT REQUESTED] /*/
1.4 Facility Renovation Costs - (see details in Section #4)
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Page 7 of 12
1.5 Process Development and Commissioning Area. In order to expedite the
project schedule, H-S is recommending immediate receipt of the process
equipment for development work. A dedicated commissioning area for the
receipt and testing of this equipment has been identified. The area is
rich in utilities such as electrical, compressed air and nitrogen in
order to start up and commission equipment. Modifications will be
required to the existing electrical in this area, and a short clean
steam run will need to be installed. Relocation of the existing
racking, equipment and spare parts located in the area will be
required. SIP development for the processing vessels will be of prime
importance in this area. [CONFIDENTIAL TREATMENT REQUESTED] /*/
TOTAL ONE TIME COST FOR ANALYTICAL METHODS TRANSFER, VALIDATION, SOPS, FOUR
BATCH RECORDS, MISCELLANEOUS DOCUMENTATION, PROJECT MANPOWER, NEW CAPITAL
EQUIPMENT, FACILITY RENOVATION, AND THE RENOVATION OF ROOM S28 =[CONFIDENTIAL
TREATMENT REQUESTED] /*/
2. PAYMENT SECTION
PAYMENT SCHEDULE FOR TECHNOLOGY TRANSFER ONE TIME COSTS
2.1 Payment #1, [CONFIDENTIAL TREATMENT REQUESTED] /*/ for down
payment on long lead-time equipment and the initiation of
contracted design for the facility renovation. Long lead-time
equipment includes AHU, aseptic compounding booth, heat
exchangers, HEPA filters and housings, S.S. doors and frames,
etc. Receipt of [CONFIDENTIAL TREATMENT REQUESTED] /*/ and
approval of the quotation will initiate the project and the
purchase of long lead-time equipment.
2.2 Payment #2, [CONFIDENTIAL TREATMENT REQUESTED] /*/ of the
total one time technology transfer cost [CONFIDENTIAL
TREATMENT REQUESTED] /*/ to be paid approximately 30 days from
the initiation of the project. It is the goal of H-S and
Acusphere to have a signed contract by payment #2.
2.3 Payment #3, [CONFIDENTIAL TREATMENT REQUESTED] /*/ of the
total one time technology transfer cost [CONFIDENTIAL
TREATMENT REQUESTED] /*/ to be paid upon achieving the
facility renovation project schedule midpoint (milestone
payment is referenced on project schedule). Two credits will
be provided on this payment.
2.3.1 The down payment of [CONFIDENTIAL TREATMENT
REQUESTED] /*/ will be credited on this payment.
2.3.2 At this early stage in the facility renovation
design, H-S Engineering is confident of a NTE
facility renovation cost including a [CONFIDENTIAL
TREATMENT REQUESTED] /*/ contingency. Upon completing
the A&E design, H-S Engineering will have developed a
facility renovation cost plus a [CONFIDENTIAL
TREATMENT REQUESTED] /*/ contingency. The
[CONFIDENTIAL TREATMENT REQUESTED] /*/ contingency
amount is scheduled to be available by 10-6-01. The
cost of the facility renovation with a [CONFIDENTIAL
TREATMENT REQUESTED] /*/ contingency is expected to
be less than the current facility
Page 8 of 12
renovation estimate detailed on this proposal. If the
[CONFIDENTIAL TREATMENT REQUESTED] /*/ contingency
cost is less than the current estimate, the
difference will be credited to Acusphere.
2.4 Payment #4, [CONFIDENTIAL TREATMENT REQUESTED] /*/ of the
total one time technology transfer cost [CONFIDENTIAL
TREATMENT REQUESTED] /*/ to be paid upon performance of the
first development batch.
3. Qualification Run Charges
3.1 Development Batch (1) [CONFIDENTIAL TREATMENT REQUESTED] /*/
3.2 Process Simulation/Media Fill [CONFIDENTIAL TREATMENT
REQUESTED] /*/ [CONFIDENTIAL TREATMENT REQUESTED] /*/
3.3 Qualification run billing schedule: Upon producing the
development batch, an invoice will be submitted to Acusphere
with NET 30 payment terms. Upon completing the 14-day
incubation period for media fills and performing the media
inspection, an invoice will be submitted to Acusphere with NET
30 payment terms.
4. Routine Production Costs - Routine production costs are based on H-S
providing the following services:
4.1 Purchasing and releasing of excipient raw materials and
components including vials, stoppers, and seals as specified
by Acusphere.
4.2 Aseptic processing of PLGA Microspheres and aseptic processing
of AI-700.
4.3 Individual product vials will not be labeled or ink jetted.
The finished product vials will be placed into Acusphere's
insulated package and bulk labeled by H-S. H-S will not
provide any packaging design support. Acusphere will supply
H-S a letter requesting the vials to be shipped without labels
or ink jetting.
4.4 Cosmetic inspection for vial defects, missing stoppers,
stopper defects, seal defects, cake cosmetics and color, and
gross particulate.
4.5 Required product release testing (see Section #6 for specific
testing to be performed) and retention sample storage.
4.6 AI-700 batch size will be limited to the maximum capacity of
the ▇▇▇▇▇▇▇ Lyophilizer, which is [CONFIDENTIAL TREATMENT
REQUESTED] /*/ vials.
4.7 H-S will provide copies to Acusphere of requested
manufacturing, analytical and environmental documentation
associated with each CTM batch produced.
Page 9 of 12
4.8 Price per batch of CTM material produced. The current estimate
is [CONFIDENTIAL TREATMENT REQUESTED] /*/ in Q1/Q2 of 2002.
[CONFIDENTIAL TREATMENT REQUESTED] /*/
NOTE: Upon completing batch record documentation for each CTM
batch, an invoice will be submitted to Acusphere with NET 30
payment terms.
5. Stability Program Costs (detailed breakdown of costs are provided in
Section #7).
5.1 [CONFIDENTIAL TREATMENT REQUESTED] /*/
5.2 [CONFIDENTIAL TREATMENT REQUESTED] /*/
5.3 Container/closure Integrity test at [CONFIDENTIAL TREATMENT
REQUESTED] /*/ time points: [CONFIDENTIAL TREATMENT REQUESTED]
/*/ upright vials and [CONFIDENTIAL TREATMENT REQUESTED] /*/
inverted vials. [CONFIDENTIAL TREATMENT REQUESTED] /*/ vials
from each CTM batch will be tested for closure integrity.
Closure integrity testing will be performed at an outside
laboratory, and H-S will be responsible for the shipment and
documentation of the results of the testing.
Total stability program cost/lot is [CONFIDENTIAL TREATMENT
REQUESTED] /*/ =[CONFIDENTIAL TREATMENT REQUESTED] /*/
PROJECT COST SUMMARY
One Time Technology Transfer Costs..........................................................[CONFIDENTIAL TREATMENT REQUESTED] /*/
One Development Batch.......................................................................[CONFIDENTIAL TREATMENT REQUESTED] /*/
Process Simulation/Media Fill [CONFIDENTIAL TREATMENT REQUESTED]/*/.........................[CONFIDENTIAL TREATMENT REQUESTED] /*/
CTM Batches [CONFIDENTIAL TREATMENT REQUESTED] /*/..........................................[CONFIDENTIAL TREATMENT REQUESTED] /*/
Stability Program Costs.....................................................................[CONFIDENTIAL TREATMENT REQUESTED] /*/
TOTAL PROJECT COST [CONFIDENTIAL TREATMENT REQUESTED] /*/
REGULATORY STATUS
CBER (Team Biologics) inspected ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in September of 2000. This
inspection was a general inspection of the entire facility including SVP. The
FDA Form 483 issued at the conclusion of the inspection contained 13
observations, all of which were addressed by January 2000. CBER categorized the
inspection as Voluntary Action Indicated (VAI). ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ also received a
PAI and Establishment Inspection by CDER in September 1999. This inspection
resulted in approval of the SVP Department, and no FDA Form 483 was issued.
Page 10 of 12
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ is very excited about the opportunity to work with Acusphere on
the PLGA and AI-700 project, and we are confident of our ability to meet your
requirements. Since Acusphere's project timeline is critical, we suggest that
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ and Acusphere sign a Letter of Intent indicating both parties'
willingness to reach agreement on a contract for clinical lot production. Such a
letter will be accompanied by a payment of [CONFIDENTIAL TREATMENT REQUESTED]
/*/. Signature of both parties below will constitute a Letter of Intent between
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC and Acusphere, Inc. ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will
initiate this project and begin the purchase of long lead-time equipment upon a
signed copy of this letter and payment of [CONFIDENTIAL TREATMENT REQUESTED]
/*/.
RIDER A (ATTACHED)
Sincerely,
/s/ ▇▇▇▇▇▇▇ ▇▇▇▇▇
----------------------------------------------------
▇▇▇▇▇▇▇ ▇▇▇▇▇
Director, Contract Manufacturing
By signing this letter, both parties acknowledge a Letter of Intent between
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC and Acusphere, Inc. to fill Phase III AI-700 at
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC in Spokane, WA.
/s/ ▇▇▇▇▇▇▇ ▇▇▇▇▇ 8-16-10
---------------------------------------------------- -----------
▇▇▇▇▇▇▇ ▇▇▇▇▇ Date
Director, Contract Manufacturing
▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ Laboratories LLC
/s/ ▇▇▇▇▇▇ ▇▇▇▇▇▇▇▇▇ 08-20-01
---------------------------------------------------- -----------
Designee Date
Acusphere, Inc.
Page 11 of 12
RIDER A
For the avoidance of doubt, the parties hereto acknowledge and agree that,
other than with respect to the provisions contained herein concerning the
[CONFIDENTIAL TREATMENT REQUESTED] /*/ down payment to be made by Acusphere
upon execution hereof (the "Down Payment"), this is a non-binding Letter of
Intent, is entered into in anticipation of entering into a binding CTM
manufacturing arrangement concerning the topics contained herein (a
"Manufacturing Agreement") and no legally binding obligations will be created,
implied or inferred hereby. The parties further acknowledge and agree that the
Down Payment shall be credited against future payments owed ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ in
connection with any such Manufacturing Agreement, and if no such Manufacturing
Agreement shall exist as of September 10, 2001, the Down Payment shall be
promptly returned to Acusphere in full and ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ will cease all
Acusphere project activity (subject to deduction for actual, documented
expenses including ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ labor, contracted labor, facility
modifications, purchased materials and any applicable restock charges incurred
by ▇▇▇▇▇▇▇▇▇-▇▇▇▇▇ prior to September 10, 2001 in anticipation of entering into
a Manufacturing Agreement).
Page 12 of 12
Section #1
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #2
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #3
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #4
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #5
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #6
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #7
[CONFIDENTIAL TREATMENT REQUESTED] /*/
Section #8
[CONFIDENTIAL TREATMENT REQUESTED] /*/