Exhibit 10.2
Confidential Materials omitted and filed separately with the
Securities and Exchange Commission. Asterisks denote omissions.
PATHEON PROPOSAL # : CTI- FCO1-1100-0604-R1
1. PARTIES: PATHEON PHARMACEUTICALS INC. CRITICAL THERAPEUTICS INC.
("PATHEON")
2110 East Galbraith Road 60 Westview St.
Cincinnati, Ohio 45237-1625 Lexington, MA 02421
USA USA
2. PRODUCT: Zyflo Coated Tablets (600 mg)
3. INDICATION: Asthma
4. CONTRACT: This Proposal (including the Project Scope, Budget
Summary, Standard Terms and Conditions for
Pharmaceutical Development Services ("Terms and
Conditions") when accepted by Client shall become
a contract binding on the parties ("Contract").
5. DESCRIPTION OF SERVICE: See Project Scope (Part A).
6. PAYMENT AND CURRENCY: See Budget Summary (Part B).
7. LEGAL TERMS: See Terms and Conditions (Part C).
8. EFFECTIVE DATE: July-19-2004
9. TERM: From the Effective Date until completion by
Patheon of the pharmaceutical development services
("Services").
10. CONFIDENTIALITY: The Confidentiality Agreement entered into between
the parties shall apply to all confidential
information about the parties and the Services to
be conducted under this Contract and such
Confidentiality Agreement is deemed to be
incorporated herein by reference. If the
Confidentiality Agreement expires or terminates
prior to the expiration or termination of this
Contract, then the terms of the Confidentiality
Agreement shall nonetheless continue to govern the
parties' obligations of confidentiality for the
term of this Contract and for 5 years thereafter.
PATHEON INC. CRITICAL THERAPEUTICS INC.
By: /s/ Ronald B. Mitchell By: /s/ Trevor Phillips
------------------------------- --------------------------
Name: Ronald B. Mitchell Name: Trevor Phillips
Title: Title: COO
-----------------------------
Date: August 12, 2004 Date: 8/4/04
CONFIDENTIAL
Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
PART A:
FOR
CRITICAL THERAPEUTICS INC.
PROPOSAL NO.: CTI- FCO1-1100-0604-R1
DATED: JULY-19-2004
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
TABLE OF CONTENTS
1. PROJECT SCOPE................................................................................. 4
2. ENVIRONMENTAL, HEALTH AND SAFETY.............................................................. 4
3. ANALYTICAL DEVELOPMENT........................................................................ 4
3.1. Cleaning Residuals Assay (Method Evaluation and Validation)................................. 5
3.2. Drug Substance Potency by HPLC (Method Transfer)............................................ 6
3.3. Drug Substance Related Substances Assay by HPLC (Method Transfer).......................... 6
3.4. Drug Substance Residual Solvents Assay (Method Transfer).................................... 6
3.5. Drug Product Potency Assay (Method Validation).............................................. 6
3.6. Drug Product Related Substances and Impurities Assay by HPLC (Method Validation)............ 7
3.7. Drug Product Dissolution Assay by UV (Method Validation).................................... 7
4. MICROBIOLOGY.................................................................................. 7
5. FEASIBILITY MANUFACTURING..................................................................... 8
6. SCALE - UP / CONFIRMATION MANUFACTURING....................................................... 8
8. STABILITY-REGISTRATION BATCHES................................................................ 9
9. VALIDATION.................................................................................... 10
10. STABILITY - VALIDATION BATCHES................................................................ 11
12. PROJECT MANAGEMENT............................................................................ 12
HIGH LEVEL TIMELINE................................................................................. 13
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
1 PROJECT SCOPE
Patheon will perform manufacturing and analytical services in order to transfer
for Client. Analytical methods will be assessed to support the Technical
Transfer Program.
The Budget Summary for this Project Scope is presented in Part B.
Patheon will commence the Services described in this Project Scope following the
execution of the Contract by both parties.
2. ENVIRONMENTAL, HEALTH AND SAFETY
Prior to the commencement of analytical method development and manufacturing
activities, a thorough review by Patheon of the Environmental, Health and Safety
(EH&S) requirements for Zileuton will be completed. The Budget Summary for this
Project Scope assumes that the EH&S review will determine that Zileuton can be
safely handled at Patheon. A summary report of the evaluation will be provided
to the Client.
If it is determined by Patheon's Environmental Health and Safety personnel that
any of the active ingredients are a Category III or Category IV compound (an
occupational exposure level) then an air sampling method will be required at
Client's expense prior to commercialization. Patheon reserves the right, in its
sole and absolute discretion, to conduct an air sampling method on Category I
and II compounds, at such price and upon such terms as may be mutually agreed to
between the parties prior to commercialization.
Patheon will not receive any active pharmaceutical ingredients (API) from the
Client until a MSDS has been received, Patheon has completed the categorization
of the API and that the Client has completed and returned the EH&S Survey to
Patheon.
3. ANALYTICAL DEVELOPMENT
Patheon will perform the method evaluation and method validation work required
supporting the manufacture of the Zyflo Coated Tablets (600 mg). Analytical
protocols will be drafted by Patheon for validation activities only and
submitted to the Client for approval prior to execution with the exception of
the Cleaning
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
Residuals Assay, which will be approved internally by Patheon. Upon completion
of the method evaluation activities, a summary of the data will be provided to
the Client. The analytical methods have been based upon HPLC unless otherwise
stated.
An analytical report will be provided to the Client once the method validation
is complete. If method validation is not specified in the title of an analytical
method under this Project Scope, then the validation of such analytical method
is not included in this Project Scope and the additional method validation costs
will be quoted separately by Patheon.
The Client shall provide Patheon with accurate, appropriate, sufficient and the
most current reference standards (the "Reference Standards") for the drug
substances and related substances to complete the scope of work outlined herein.
If the requisite Reference Standards such as USP, NF, BP, EP, and JP can be
readily obtained, then Patheon may purchase these Reference Standards on behalf
of the Client and the Client shall reimburse Patheon for such costs. If the
Client requires Patheon to obtain Reference Standards from sources other then
the ones listed in the preceding sentence, then the Client shall reimburse
Patheon for such cost [**]. However, under no circumstances shall Patheon be
liable for the Reference Standards, including without limitation, for their
accuracy, appropriateness, discrepancies, sufficiency or use.
3.1. CLEANING RESIDUALS ASSAY (METHOD EVALUATION AND VALIDATION)
Patheon will evaluate and validate the test method required for testing cleaning
residuals in order to support the manufacturing program. The evaluation and
validation will challenge the following parameters:
- - System Suitability
- - Linearity
- - Quantitation Limit
- - Detection Limit
- - Accuracy
- - Range
- - Precision
- - Robustness
- - Specificity
- - Solution Stability
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
3.2. DRUG SUBSTANCE POTENCY BY HPLC (METHOD TRANSFER)
Patheon will transfer the test method required for drug Substance potency assay
in order to support the Technical Transfer Program. The method transfer will
challenge the following parameters:
- - System Suitability
- - Linearity
- - Solution Stability
- - Repeatability
- - Quantitation Limit
- - Detection Limit
3.3. DRUG SUBSTANCE RELATED SUBSTANCES ASSAY BY HPLC (METHOD TRANSFER)
Patheon will transfer the test method required for drug product related
substances assay in order to support the Techical Transfer Program. The method
transfer will challenge the following parameters:
- - System Suitability
- - Linearity
- - Solution Stability
- - Repeatability
- - Quantitation Limit
- - Detection Limit
3.4. DRUG SUBSTANCE RESIDUAL SOLVENTS ASSAY (METHOD TRANSFER)
Patheon will transfer the test method required for drug product residual solvent
assay in order to support the Techical Transfer Program. The method transfer
will challenge the following parameters:
- - System Suitability
- - Linearity
- - Solution Stability
- - Repeatability
- - Quantitation Limit
- - Detection Limit
3.5. DRUG PRODUCT POTENCY ASSAY (METHOD VALIDATION)
Patheon will transfer and validate the test method required for drug product
Potency assay in order to support the Techical Transfer Program. The method
transfer and validation will challenge the following parameters:
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
- - System Suitability
- - Linearity
- - Specificity
- - Range
- - Accuracy
- - Precision
- - Robustness
- - Quantitation Limit
- - Detection Limit
- - Content Uniformity by HPLC
- - ID retention time
3.6. DRUG PRODUCT RELATED SUBSTANCES AND IMPURITIES ASSAY BY HPLC (METHOD
VALIDATION)
Patheon will transfer and validate the test method required for drug product
Related Substances assay in order to support the Techical Transfer Program. The
method transfer and validation will challenge the following parameters:
- - System Suitability
- - Linearity
- - Specificity
- - Range
- - Accuracy
- - Precision
- - Robustness
- - Quantitation Limit
- - Detection Limit
- - Content Uniformity by HPLC
- - ID retention time
3.7. DRUG PRODUCT DISSOLUTION ASSAY BY UV (METHOD VALIDATION)
Patheon will transfer and validate the test method required for drug product
dissolution assay in order to support the Techical Transfer Program. The method
transfer and validation will challenge the following parameters:
- - System Suitability
- - Linearity
- - Specificity
- - Range
- - Accuracy
- - Precision
- - Robustness
- - Moisture by KF
4. MICROBIOLOGY
Patheon will validate the test methods required for Microbial Limit Tests (MLT)
in order to support the Techical Transfer Program.
The cost allocated to this Service in the Budget Summary of Part B is the per
sample price and will vary depending on the number of samples required for
method validation. If a worst case scenario approach were taken, the cost would
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
be based upon testing MLT at two dilutions and/or the usage of the largest
volume of diluent(s) based on specification. Testing will be done in compliance
with USP/NF. Client will be billed based on the actual number of samples
required in order to successfully validate Zyflo Coated Tablets (600 mg).
5. FEASIBILITY MANUFACTURING
Patheon will manufacture [**] feasibility batches [**] of Zyflo Coated Tablets
(600 mg). These batches will undergo complete analytical release testing in
compliance with USP/NF requirements. Patheon will prepare a master batch record,
which will be provided to the Client for approval prior to manufacturing, that
specifies manufacturing procedures and acceptance criteria. These batches will
not undergo a full QA review and will be packaged as a trial run into blisters.
Feasibility Manufacturing Process Train [**]:
- - [**]
The following in-process and finished product testing is based upon one set of
analysis for each of the described tests. If additional sample testing is
required these will be considered as additional activities for which a separate
costing will be provided to the Client.
Blend Analysis: Tablet Analysis:
[**] - [**]
6. SCALE - UP / CONFIRMATION MANUFACTURING
Patheon will manufacture [**] Scale - up & [**] confirmation batch [**] of Zyflo
Coated Tablets (600 mg). These batches will undergo complete analytical release
testing in compliance with USP/NF requirements. Patheon will prepare a master
batch record, which will be provided to the Client for approval prior to
manufacturing, that specifies manufacturing procedures and acceptance criteria.
[**]:
- - [**]
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
The following in-process and finished product testing is based upon one set of
analysis for each of the described tests. If additional sample testing is
required these will be considered as additional activities for which a separate
costing will be provided to the Client.
Blend Analysis: Tablet Analysis:
[**] - [**]
7. REGISTRATION MANUFACTURING
Patheon will manufacture three registration batches [**] of Zyflo Coated Tablets
(600 mg). These batches will undergo complete analytical release testing in
compliance with USP/NF requirements. Patheon will prepare a master batch record,
which will be provided to the Client for approval prior to manufacturing, that
specifies manufacturing procedures and acceptance criteria.
Registration Manufacturing Process Train [**]
- - [**]
The following in-process and finished product testing is based upon one set of
analysis for each of the described tests. If additional sample testing is
required these will be considered as additional activities for which a separate
costing will be provided to the Client.
Blend Analysis: Tablet Analysis:
[**] - [**]
8. STABILITY-REGISTRATION BATCHES
Patheon shall design a stability program to monitor [**] packaged lots of Zyflo
Coated Tablets (600 mg) under ICH conditions.; i.e., [**].
Additional samples will be stored as contingency samples if required to generate
data for long-term stability of the product.
The following storage conditions and test-points are suggested for testing:
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
- - [**]
[**]
The analytical data used for the release of each lot manufactured at Patheon
will be considered as [**].
Cost efficiencies for analytical testing have been built into the stability
program based upon the [**] in a given month. The cost for this stability
program assumes that all lots will be placed on stability at the same time. If
these lots are not placed on stability at the same time, the cost will be
adjusted accordingly through Change of Scope Agreement.
[**] [**] [**] [**] [**] [**] [**] [**] [**]
[**] [**] [**] [**] [**] [**] [**] [**] [**]
Therefore, the stability sample breakdown is:
- - [**]
The following standard tests are usually performed as part of the Stability
Program:
- - Potency & Related Substances
- - Physical Appearance and Moisture
- - MLT (annually)
- - Dissolution (Profile)
9. VALIDATION
Patheon shall complete validation activities on [**] validation batches of Zyflo
Coated Tablets (600 mg). Patheon will prepare protocols for the Master
Validation plan, processing validation, packaging validation and cleaning
validation and bulk hold time study. These protocols will be supplied to and
approved by the Client before execution.
The scope and the degree of the validation will be discussed and approved by the
Client before proceeding. Since the final validation approach has not been
defined, a typical costing has been given below for review. A final budget cost
will be proposed to the Client once a validation protocol has been agreed upon.
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
The validation costs listed in this proposal are for the validation of [**]
commercial batches; manufacturing costs for the registration / validation
batches are additional and will be based on commercial rates.
10. STABILITY - VALIDATION BATCHES
Patheon shall design a stability program to monitor [**] packaged lots of Zyflo
Coated Tablets (600 mg) under ICH conditions.; i.e., [**].
Additional samples will be stored as contingency samples if required to generate
data for long-term stability of the product.
The following storage conditions and test-points are suggested for testing:
- - [**]
[**]
The analytical data used for the release of each lot manufactured at Patheon
will be considered as [**].
Cost efficiencies for analytical testing have been built into the stability
program based upon the [**] in a given month. The cost for this stability
program assumes that all lots will be placed on stability at the same time. If
these lots are not placed on stability at the same time, the cost will be
adjusted accordingly through Change of Scope Agreement.
[**] [**] [**] [**] [**] [**] [**] [**] [**]
[**] [**] [**] [**] [**] [**] [**] [**] [**]
Therefore, the stability sample breakdown is:
- - [**]
The following standard tests are usually performed as part of the Stability
Program:
- - Potency & Related Substances
- - Physical Appearance and Moisture
- - MLT (annually)
- - Dissolution (Profile)
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
12. PROJECT MANAGEMENT
Patheon will provide project management support to monitor the progress of the
project against established timelines and will provide the Client with frequent
updates. The project manager will coordinate regular biweekly teleconference
meetings and quarterly face-to-face meetings. The fee for project management is
[**] in the Budget Summary.
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
HIGH LEVEL TIMELINE
The attached High Level Timeline is presented at this stage as a projected
estimate of the duration and achievable milestones, based upon Patheon's
experience and history. The High Level Timeline should not be taken as part of
an agreed legal deliverable of this proposal.
Once the project has been awarded to Patheon and the relevant legal
documentation is in place, a revised Timeline detailing set milestones and
duration of deliverables will be agreed upon between Patheon and the Client. The
revised Timeline would likely have a similar duration and would be based upon
resources and the availability of manufacturing time at the initiation of the
project.
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
REF
NUM TASK % Dur. Start Finish Dates
- ------ ---------------------------------------------- ---- ---- ----- ------ -----
1 CRITICAL THERAPEUTICS - ZYFLO COATED TABLET [**] [**] [**] [**] [**]
2 Proposal Approval [**] [**] [**] [**] [**]
3 ENVIRONMENTAL, HEALTH AND SAFETY ASSESSMENT [**] [**] [**] [**] [**]
4 EH&S Assessment [**] [**] [**] [**] [**]
5 Explosivity Testing [**] [**] [**] [**] [**]
6 CLEANING RESIDUALS ASSAY [**] [**] [**] [**] [**]
7 Protocol Generation/Approval [**] [**] [**] [**] [**]
8 Benchwork [**] [**] [**] [**] [**]
9 Method Generation/Approval [**] [**] [**] [**] [**]
10 Report Generation/Approval [**] [**] [**] [**] [**]
11 Cleaning Residual Assay - Total Budget [**] [**] [**] [**] [**]
12 DRUG SUBSTANCES POTENCY ASSAY [**] [**] [**] [**] [**]
13 Protocol Generation/Approval [**] [**] [**] [**] [**]
14 Benchwork [**] [**] [**] [**] [**]
15 Method Generation/Approval [**] [**] [**] [**] [**]
16 Report Generation/Approval [**] [**] [**] [**] [**]
17 Drug Substances Potency Assay - Total [**] [**] [**] [**] [**]
18 DRUG SUBSTANCES RELATED SUBSTANCES ASSAY [**] [**] [**] [**] [**]
19 Protocol Generation/Approval [**] [**] [**] [**] [**]
20 Benchwork [**] [**] [**] [**] [**]
21 Method Generation/Approval [**] [**] [**] [**] [**]
22 Report Generation/Approval [**] [**] [**] [**] [**]
23 Drug Substances Related Substances [**] [**] [**] [**] [**]
24 DRUG SUBSTANCES RESIDUAL SOLVENTS ASSAY [**] [**] [**] [**] [**]
25 Protocol Generation/Approval [**] [**] [**] [**] [**]
26 Benchwork [**] [**] [**] [**] [**]
27 Method Generation/Approval [**] [**] [**] [**] [**]
28 Report Generation/Approval [**] [**] [**] [**] [**]
29 Drug Substances Related Substances [**] [**] [**] [**] [**]
30 DRUG PRODUCT POTENCY ASSAY [**] [**] [**] [**] [**]
31 Protocol Generation/Approval [**] [**] [**] [**] [**]
32 Benchwork [**] [**] [**] [**] [**]
33 Method Generation/Approval [**] [**] [**] [**] [**]
34 Report Generation/Approval [**] [**] [**] [**] [**]
35 Drug Product Potency and Related Substances [**] [**] [**] [**] [**]
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
36 DRUG PRODUCT RELATED SUBSTANCES ASSAY [**] [**] [**] [**] [**]
37 Protocol Generation/Approval [**] [**] [**] [**] [**]
38 Benchwork [**] [**] [**] [**] [**]
39 Method Generation/Approval [**] [**] [**] [**] [**]
40 Report Generation/Approval [**] [**] [**] [**] [**]
41 Drug Product Related Substances Assay [**] [**] [**] [**] [**]
42 DRUG PRODUCT DISSOLUTION ASSAY [**] [**] [**] [**] [**]
43 Protocol Generation/Approval [**] [**] [**] [**] [**]
44 Benchwork [**] [**] [**] [**] [**]
45 Method Generation/Approval [**] [**] [**] [**] [**]
46 Report Generation/Approval [**] [**] [**] [**] [**]
47 Drug Product Dissolution Assay - Total [**] [**] [**] [**] [**]
48 MICROBIOLOGY [**] [**] [**] [**] [**]
49 Micro Validation (Per Product/Raw Material) [**] [**] [**] [**] [**]
50 FEASIBILITY MANUFACTURING [**] [**] [**] [**] [**]
51 Batch Record Generation [**] [**] [**] [**] [**]
52 Manufacturing [**] [**] [**] [**] [**]
53 Analytical Support and QA Review [**] [**] [**] [**] [**]
54 Feasibility Manufacturing - Total Budget [**] [**] [**] [**] [**]
55 SCALE UP/CONFIRMATION MANUFACTURING [**] [**] [**] [**] [**]
56 Batch Record Generation [**] [**] [**] [**] [**]
57 Manufacturing [**] [**] [**] [**] [**]
58 Bulk Packaging [**] [**] [**] [**] [**]
59 Analytical Support and QA Review [**] [**] [**] [**] [**]
60 Feasibility Manufacturing - Total Budget [**] [**] [**] [**] [**]
61 REGISTRATION MANUFACTURING [**] [**] [**] [**] [**]
62 Batch Record Generation [**] [**] [**] [**] [**]
63 Manufacturing [**] [**] [**] [**] [**]
64 Packaging [**] [**] [**] [**] [**]
65 Analytical Support and QA Review [**] [**] [**] [**] [**]
66 Registration Manufacturing - Total Budget [**] [**] [**] [**] [**]
67 STABILITY - REGISTRATION [**] [**] [**] [**] [**]
68 T = Initial [**] [**] [**] [**] [**]
69 T = 1 Month [**] [**] [**] [**] [**]
70 VALIDATION [**] [**] [**] [**] [**]
71 Master Validation Plan [**] [**] [**] [**] [**]
72 Processing Validation [**] [**] [**] [**] [**]
73 Packaging Validation [**] [**] [**] [**] [**]
74 Cleaning Validation [**] [**] [**] [**] [**]
75 Bulk Hold Time Study [**] [**] [**] [**] [**]
76 Validation - Total Budget [**] [**] [**] [**] [**]
77 STABILITY - VALIDATION [**] [**] [**] [**] [**]
78 T = Initial [**] [**] [**] [**] [**]
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Patheon Proposal # CTI- FCO1-1100-0604-R1
July-19-2004
79 T = 1 Month [**] [**] [**] [**] [**]
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Patheon Proposal # CTI-FCO1-1100-0604-R1
REF
NUM TASK DATE
- ------ ---------------------------------------------- ----
1 CRITICAL THERAPEUTICS - ZYFLO COATED TABLET [**]
2 Proposal Approval [**]
3 ENVIRONMENTAL, HEALTH AND SAFETY ASSESSMENT [**]
4 EH&S Assessment [**]
5 Explosivity Testing [**]
6 CLEANING RESIDUALS ASSAY [**]
7 Protocol Generation/Approval [**]
8 Benchwork [**]
9 Method Generation/Approval [**]
10 Report Generation/Approval [**]
11 Cleaning Residual Assay - Total Budget [**]
12 DRUG SUBSTANCES POTENCY ASSAY [**]
13 Protocol Generation/Approval [**]
14 Benchwork [**]
15 Method Generation/Approval [**]
16 Report Generation/Approval [**]
17 Drug Substances Potency Assay - Total [**]
18 DRUG SUBSTANCES RELATED SUBSTANCES ASSAY [**]
19 Protocol Generation/Approval [**]
20 Benchwork [**]
21 Method Generation/Approval [**]
22 Report Generation/Approval [**]
23 Drug Substances Related Substances [**]
24 DRUG SUBSTANCES RESIDUAL SOLVENTS ASSAY [**]
25 Protocol Generation/Approval [**]
26 Benchwork [**]
27 Method Generation/Approval [**]
28 Report Generation/Approval [**]
29 Drug Substances Related Substances [**]
30 DRUG PRODUCT POTENCY ASSAY [**]
31 Protocol Generation/Approval [**]
32 Benchwork [**]
33 Method Generation/Approval [**]
34 Report Generation/Approval [**]
35 Drug Product Potency and Related Substances [**]
36 DRUG PRODUCT RELATED SUBSTANCES ASSAY [**]
37 Protocol Generation/Approval [**]
38 Benchwork [**]
39 Method Generation/Approval [**]
40 Report Generation/Approval [**]
41 Drug Product Related Substances Assay [**]
42 DRUG PRODUCT DISSOLUTION ASSAY [**]
43 Protocol Generation/Approval [**]
44 Benchwork [**]
45 Method Generation/Approval [**]
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Patheon Proposal # CTI-FCO1-1100-0604-R1
46 Report Generation/Approval [**]
47 Drug Product Dissolution Assay - Total [**]
48 MICROBIOLOGY [**]
49 Micro Validation (Per Product/Raw Material) [**]
50 FEASIBILITY MANUFACTURING [**]
51 Batch Record Generation [**]
52 Manufacturing [**]
53 Analytical Support and QA Review [**]
54 Feasibility Manufacturing - Total Budget [**]
55 SCALE UP/CONFIRMATION MANUFACTURING [**]
56 Batch Record Generation [**]
57 Manufacturing [**]
58 Bulk Packaging [**]
59 Analytical Support and QA Review [**]
60 Feasibility Manufacturing - Total Budget [**]
61 REGISTRATION MANUFACTURING [**]
62 Batch Record Generation [**]
63 Manufacturing [**]
64 Packaging [**]
65 Analytical Support and QA Review [**]
66 Registration Manufacturing - Total Budget [**]
67 STABILITY - REGISTRATION [**]
68 T = Initial [**]
69 T = 1 Month [**]
70 VALIDATION [**]
71 Master Validation Plan [**]
72 Processing Validation [**]
73 Packaging Validation [**]
74 Cleaning Validation [**]
75 Bulk Hold Time Study [**]
76 Validation - Total Budget [**]
77 STABILITY - VALIDATION [**]
78 T = Initial [**]
79 T = 1 Month [**]
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Patheon Proposal # CTI-FCO1-1100-0604-R1
PART B: BUDGET SUMMARY
THE FOLLOWING COSTS ARE ALL QUOTED IN: USD
ALL AMOUNTS QUOTED ARE VALID FOR SIXTY (60) DAYS FROM THE DATE OF THIS PROPOSAL.
2.0 ENVIRONMENTAL HEALTH AND SAFETY USD
ACTIVITY PRICE
EH&S Assessment $ [**]
Explosivity Testing $ [**]
3.0 ANALYTICAL DEVELOPMENT USD
ACTIVITY HOURS PRICE HOURS PRICE
3.1 CLEANING RESIDUALS ASSAY (METHOD EVALUATION AND VALIDATION) [**] [**] [**] [**]
Protocol/benchwork
Final Report
3.2 DRUG SUBSTANCE POTENCY ASSAY BY HPLC (METHOD TRANSFER) [**] [**] [**] [**]
Protocol/benchwork
Final Report
3.3 DRUG SUBSTANCE RELATED SUBSTANCES ASSAY BY HPLC (METHOD TRANSFER) [**] [**] [**] [**]
Protocol/benchwork
Final Report
3.4 DRUG SUBSTANCE RESIDUAL SOLVENT ASSAY BY HPLC (METHOD TRANSFER) [**] [**] [**] [**]
Protocol/benchwork
Final Report
3.5 DRUG PRODUCT POTENCY ASSAY (METHOD VALIDATION) [**] [**] [**] [**]
Protocol/benchwork
Final Report
3.6 DRUG PRODUCT RELATED SUBSTANCES ASSAY (METHOD TRANSFER) [**] [**] [**] [**]
Protocol/benchwork
Final Report
3.7 DRUG PRODUCT DISSOLUTION ASSAY BY UV (METHOD VALIDATION) [**] [**] [**] [**]
Protocol/benchwork
Final Report
TOTAL (ANALYTICAL DEVELOPMENT) [**] [**]
4.0 MICROBIOLOGY DEVELOPMENT AND VALIDATION USD
ACTIVITY HOURS PRICE HOURS PRICE
PREPARATION [**] [**]
[**] [**] [**]
TOTAL (MICRO DEVELOPMENT AND VALIDATION) - NUMBER OF TRIALS ASSUMED = [**] [**] [**] [**]
[**]
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Patheon Proposal # CTI-FCO1-1100-0604-R1
5.0 FEASIBILITY MANUFACTURING USD
ACTIVITY SHIFTS HOURS PRICE SHIFTS HOURS PRICE
PER BATCH: Manufacturing [**] [**] [**]
Packaging Trial run
Analytical Support
Project Support
TOTAL ([**] BATCHES - FEASIBILITY MANUFACTURING) [**] [**] [**]
6.0 SCALE-UP/CONFIRMATION MANUFACTURING USD
ACTIVITY SHIFTS HOURS PRICE SHIFTS HOURS PRICE
PER BATCH: Manufacturing [**] [**] [**]
Bulk Packaging
Analytical Support
Project Support
TOTAL ([**] SCALE-UP & [**] CONFIRMATION BATCH - MANUFACTURING) [**] [**] [**]
7.0 REGISTRATION MANUFACTURING USD
ACTIVITY SHIFTS HOURS PRICE SHIFTS SHIFTS PRICE
PER BATCH: Manufacturing [**] [**] [**]
Packaging
Analytical Support
Project Support
[**] [**] [**] [**]
TOTAL (REGISTRATION MANUFACTURING) [**] [**] [**]
8.0 STABILITY - REGISTRATION USD
ACTIVITY HOURS PRICE HOURS PRICE
Number of Lots [**] [**]
Total Samples
[**] [**] [**] [**]
TOTAL (STABILITY) [**] [**]
9.0 VALIDATION USD
ACTIVITY HOURS PRICE HOURS PRICE
Master Validation Plan [**] [**]
Processing Validation
Packaging Validation
Cleaning validation
Bulk Hold Time Study
Air Sampling Monitoring
Equipment IQ/OQ/PQ
TOTAL (VALIDATION) [**] [**]
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Patheon Proposal # CTI-FCO1-1100-0604-R1
10.0 STABILITY - VALIDATION USD
ACTIVITY HOURS PRICE HOURS PRICE
Number of Lots [**] [**]
Total Samples
[**]
TOTAL (STABILITY - VALIDATION) [**] [**]
BUDGET TOTAL (LOW POTENCY, CAT. 1 & 2) USD [**]
DEPOSIT [**]
*The manufacturing cost given in this proposal is based upon the assumption that
the drug substance is classified as a Category 1 or 2 material in accordance
with Patheon's Categorization System. If it is determined through Patheon's
Environmental Health and Safety Review that the drug substance is not
categorized as a Category 3, the manufacturing cost will be revised through a
Change of Scope to reflect handling charges for a Category 1, 2 or 4 product.
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Patheon Proposal # CTI-FCO1-1100-0604-R1
PART C:
STANDARD TERMS AND CONDITIONS
FOR PHARMACEUTICAL DEVELOPMENT SERVICES
1. SERVICES:
(a) Patheon agrees to perform the pharmaceutical development services
described in the Project Scope (as described in Part A)
("Services").
(b) Parties must agree on changes, deletions or additions to the
Services ("Changes").
(c) Minor Changes shall be confirmed by electronic mail, facsimile or
other written document. Significant Changes (such as a request by
the Client to change the Project Scope) shall be confirmed by a
Change of Scope Agreement.
(d) The Services shall be performed in accordance with the [**] and
according to the [**] as of the signing of this Agreement.
2. PAYMENT:
A. PAYMENT
(a) Client shall pay Patheon for the Services as outlined in this
Contract and for any Changes which shall be invoiced
separately at Patheon's then prevailing hourly rates.
(b) The costs of all third party suppliers' fees and the purchase
of project specific items (such as special equipment, change
parts, laboratory columns and reagents and tooling) ("Project
Specific Items") necessary for Patheon to perform the Services
shall be charged separately to Client, [**] and the [**].
(c) If Client causes any delay to Patheon's provision of Services
for reason within its control (such as a delay in responding
to a Patheon inquiry or a delay in the delivery of the active
pharmaceutical ingredient ("API")), then Patheon shall be
entitled to charge the Client for any reasonable additional
costs incurred in the provision of the Services as a result of
the delay.
(d) Each Patheon invoice shall be due and payable within 30 days
of the date of such invoice.
3. SUPPLY OF API AND MATERIALS:
(a) Client shall, at its expense, supply Patheon with sufficient
quantities of the API for Patheon's use in performing the Services.
(b) Other than Project Specific Items, all other materials (such as
excipients, packaging and raw materials) required to perform the
Services shall be purchased by Patheon and charged to Client [**].
(c) If applicable, Patheon and the Client will cooperate and provide
such assistance to each other as may be reasonably necessary to
permit the import of the API and other materials into the country
where the Services will be performed.
4. TERMINATION:
(a) Either party may terminate this Contract if the other party is in
material breach of any provisions of this Contract and the other
party fails to remedy such breach within 30 days of the date of
notice of such breach by the non-breaching party.
(b) Client may terminate this Contract immediately for any reason.
(c) Any re-scheduling resulting in a delay in Patheon's ability to
provide any part of the Services beyond 120 days requested by Client
shall, at Patheon's option, be deemed to be a termination of the
Contract.
(d) If the Client terminates the Contract pursuant to Section 4(b) or if
Patheon terminates the Contract because of: (i) Client's failure to
cure any default within the 30 day notice period; or (ii) Client
rescheduling any part of the Services beyond the 120 days, then
Client shall pay to Patheon:
- any fees and expenses due to Patheon for the Services rendered
up to the date of termination;
- all actual costs incurred by Patheon to complete activities
associated with the termination and close of the Services
rendered up to the date of termination; and
- any additional costs incurred by Patheon in connection with
the Services that are required to fulfill applicable
regulatory and contractual requirements.
(e) Client shall arrange for the pickup from the Patheon site of all
materials and supplies owned by Client within [**] business days
after the earlier of the termination or expiration of this Contract.
Patheon shall charge a [**] storage fee for all materials and
supplies stored at the Patheon site after the [**] business day
following the termination of the Contract.
5. INTELLECTUAL PROPERTY:
(a) The term "Intellectual Property" includes, without limitation,
rights in patents, patent applications, formulae, trade-marks,
trade-mark applications, trade-names, trade secrets, inventions,
copyright, industrial designs and know-how.
(b) For the term of this Contract, Client hereby grants to Patheon, a
non-exclusive, paid-up, royalty-free, non-transferable license of
any of Client's Intellectual Property that Patheon must use in order
to perform the Services.
(c) All Intellectual Property generated or derived by Patheon in the
course of performing the Services, to the extent it is specific to
the development, manufacture, use and/or sale of the Client's
Product that is the subject of the Services shall be the exclusive
property of Client.
(d) All Intellectual Property generated or derived by Patheon in the
course of performing the Services which have general application to
manufacturing processes or formulation development of drug products
or drug delivery systems shall be the exclusive property of Patheon;
provided, however, the [**] Intellectual Property [**].
(e) The parties agree to execute, verify and deliver such documents and
perform such other acts (including appearances as a witness) as the
other party may reasonably request for use in applying for,
obtaining, perfecting, evidencing, sustaining and enforcing such
Intellectual Property rights and the assignment thereof.
6. INDEMNITY:
A. INDEMNIFICATION BY CLIENT
Subject to Sections 6B and 6C(c), Client shall defend, indemnify and hold
Patheon, its affiliates and their respective directors, officers,
employees and agents (collectively, "Patheon Indemnitees") harmless from
and against any and all third-party actions, causes of action, costs
(including reasonable legal fees), claims, damages, liabilities and
expenses (collectively, "Losses") relating to or arising from:
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Patheon Proposal # CTI-FCO1-1100-0604-R1
- any misrepresentation, negligence or willful misconduct by Client or
any of its affiliates and their respective directors, officers,
employees and agents (collectively, "Client Indemnitees");
- the performance of the Services in accordance with the terms of this
Contract
- any breach by the Client of the Client's obligations or warranties
under this Contract; or
- any claim of infringement or alleged infringement of any third
party's intellectual property rights covering the Client's Product.
This indemnity shall not apply to the extent that such Losses are:
- determined to have resulted from the negligence or willful
misconduct of Patheon; or
- for which Patheon is obligated to indemnify the Client Indemnitees
pursuant to Section 6B.
B. INDEMNIFICATION BY PATHEON
Subject to Sections 6A and 6C(c), Patheon shall defend, indemnify and hold
the Client Indemnitees harmless from and against any and all Losses
resulting from, relating to or arising from the breach by Patheon of any
of its obligations or warranties under this Contract except to the extent
that such Losses are:
- determined to have resulted from the negligence or willful
misconduct of Client; or
- for which Client is obligated to indemnify the Patheon Indemnitees
pursuant to Section 6A.
C. LIMITATION OF LIABILITY
(a) If Patheon fails to materially perform any part of the Services in
accordance with the terms of this Contract, then Client's sole
remedy shall be to request Patheon to:
- repeat that part of the Service at Patheon's costs provided
that Client provides the API; or
- reimburse Client for the price for that part of the Service,
excluding the cost of the API.
(b) Under no circumstances whatsoever shall Patheon reimburse Client for
the cost of the API unless the loss or damage to the API is as a
result of Patheon's negligence, provided however that in no case
shall Patheon liability for the loss of API exceed $400 USD/Kilo up
to a maximum liability of $200,000 in aggregate in all circumstances
(c) Under no circumstances whatsoever shall either party be liable to
the other in contract, tort, negligence, breach of statutory duty or
otherwise for any loss of profits, of production, of anticipated
savings, of business or goodwill or for any liabilities, damages,
costs or expenses of any kind incurred by the other party of an
indirect or consequential nature, regardless of any notice of the
possibility of such damages.
D. NO WARRANTY
PATHEON MAKES NO WARRANTY OF ANY KIND, EITHER EXPRESSED OR IMPLIED, BY
FACT OR LAW, OTHER THAN THOSE EXPRESSLY SET FORTH IN THIS CONTRACT.
PATHEON MAKES NO WARRANTY OF FITNESS FOR A PARTICULAR PURPOSE OR WARRANTY
OF MERCHANTABILITY IN RESPECT OF THE CLIENT'S PRODUCT.
7. FDA FILINGS:
(a) Client shall have the sole responsibility for filing of all
documents with the United States Food and Drug Administration
("FDA"), and to take any other actions that may be required for the
receipt of FDA Approval from the commercial manufacture of the
Product; provided, however, [**] shall be [**] the information
needed for [**] and shall be [**]. In general, [**] to obtain FDA
Approval for the commercial manufacture of all Products as quickly
as reasonably possible.
(b) At least [**] business days prior to filing any documents with the
FDA that incorporate data generated by Patheon, Client shall provide
Patheon with a copy of the documents incorporating such data so as
to give Patheon the opportunity to verify the accuracy and
regulatory validity of such documents as they relate to the
Patheon-generated data.
(c) At least [**] business days prior to filing with the FDA the
Chemistry and Manufacturing Controls ("CMC") of the initial
regulatory filing for any Product, the Client shall provide Patheon
with a copy of the portion of the CMC submission describing
Patheon's activities as well as references to all supporting
documents which have been relied upon to prepare such portion of the
CMC submission so as to permit Patheon to verify that such portion
of the CMC accurately describes the work that Patheon has performed
and the manufacturing processes that Patheon will perform pursuant
to this Contract. At the Client's request, Patheon shall also review
any subsequent regulatory filing relating to the portion of the CMC
describing Patheon's activities. At such time, the Client shall
provide Patheon with a copy of the portion of the CMC submission
describing Patheon's activities as well as references to all
supporting documents which have been relied upon to prepare such
portion of the CMC submission so as to permit Patheon to verify that
such portion of the CMC submission accurately describes the work
that Patheon has performed and the manufacturing processes that
Patheon will perform pursuant to this Contract.
(d) If in Patheon's sole discretion, acting reasonably, Patheon
determines that any of the information provided by the Client in
accordance with paragraphs (b) and (c) above are inaccurate or
deficient in any manner whatsoever (the "Deficiencies"), Patheon
shall notify the Client in writing of such Deficiencies. Until such
Deficiencies have been resolved or agreement has been reached with
the Client, Patheon reserves the right not to participate in the
Regulatory Authority inspection which is, or is equivalent to the
FDA's pre-approval inspection ("PAI"). In such event, Patheon's
non-participation in the PAI shall not be construed as a breach of
any of its obligations under this Contract.
(e) For clarity, the parties agree that in reviewing the documents
referred to in paragraphs (b) and (c) above, Patheon's role [**]
Patheon. As such, Patheon shall [**], as the case may be. The [**].
8. SHIPPING (IF APPLICABLE):
Shipments (if applicable) of Client's Product shall be made [**] (as defined in
INCOTERMS 2000) Patheon's shipping point unless otherwise mutually agreed. Risk
of loss or of damage to such Product shall transfer to the Client when the
Product is loaded onto the carrier's vehicle by Patheon for shipment [**]. The
Product shall be transported in accordance with the Client's instructions.
9. MISCELLANEOUS:
A. ASSIGNMENT
Neither this Contract, nor any of either party's rights hereunder,
may be assigned or otherwise transferred by either party without the
prior written consent of the other party, which consent shall not be
unreasonably withheld.
B. FORCE MAJEURE
Except for payment obligations, neither party will be responsible
for delay or failure in performance resulting from acts beyond the
reasonable control and without the fault or negligence of such
party, including, but not limited to, strikes or other labour
disturbances, lockouts, quarantines, communicable disease outbreaks,
riots, wars, acts of terrorism, fires, floods, storms, lack of or
inability to obtain fuel or power or compliance with any order or
regulation of any government entity.
C. SURVIVAL
Any termination or expiration of this Contract shall not affect any
outstanding obligations or payments due hereunder prior to such
termination or expiration, nor shall it prejudice any other remedies
that the parties may have
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under this Contract. The Confidentiality Agreement and sections 4,
5, and 6 of the Contract shall survive the expiration or termination
of this Contract.
D. INDEPENDENT CONTRACTORS
The parties are independent contractors and this Contract shall not
be construed to create between Patheon and the Client any other
relationship such as, by way of example only, that of
employer-employee, principal, agent, joint-venturer, co-partners or
any similar relationship.
E. OTHER TERMS
No terms, provisions or conditions of any purchase order or other
business form or written authorization used by Client or Patheon
will have any effect on the rights, duties or obligations of the
parties, or otherwise modify, this Contract, regardless of any
failure of Client or Patheon to object to such terms, provisions, or
conditions unless such document specifically refers to this Contract
and is signed by both parties.
F. INSURANCE
Each party shall maintain during the term of this Contract general
liability and product liability insurance. Either party may request
evidence of such insurance.
G. ENTIRE AGREEMENT
This Contract constitutes the complete agreement between the parties
with respect to this subject matter and supersedes all other prior
agreements and understandings, whether written or oral. Any
modifications, amendment or supplement to this Contract must be in
writing and signed by authorized representatives of both parties.
H. FACSIMILE
This Contract may be signed in counterparts and by facsimile.
I. CHOICE OF LAW
This Contract is governed by the laws of the State of New York
without regard to any conflicts-of-law principle that directs the
application to another jurisdiction's law.
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