Exhibit
10.6


 


CONFIDENTIAL
TREATMENT


 


AMENDMENT
NO. 2


to the


MANUFACTURING AND SUPPLY
AGREEMENT


entered into as of
September 30, 2001


by and between


ACS Dobfar, SpA and
Cubist Pharmaceuticals, Inc.


 


This AMENDMENT NO. 2 (“Amendment
No.  2”), to that certain Manufacturing and Supply Agreement (the
“Agreement”) entered into as of September 30, 2001, is made this 12th
day of February, 2003, by and between ACS Dobfar, SpA, an Italian corporation
(“ACSD”) and Cubist Pharmaceuticals, Inc., a Delaware corporation (“Cubist”).
Unless otherwise defined herein, capitalized terms used but not defined herein
shall have the meaning set forth in the Agreement, and the Agreement shall be
amended to incorporate any additional definitions provided for in this
Amendment No. 1, including definitions in the preamble and recitals hereto.


 


WHEREAS, Cubist
and ACSD desire to amend the Agreement as set forth in this Amendment No. 1;


 


NOW, THEREFORE,
in consideration of the foregoing and the mutual promises made herein, and for
other good and valuable consideration, the receipt and sufficiency of which are
hereby acknowledged, the parties hereto agree to amend the Agreement as
follows:


 


1.                                       Amendment of Section 2.1.  The Agreement is hereby amended by deleting
Section 2.1 thereof in its entirety and replacing it with the following Section
2.1:


 


2.1                               Facility
Construction and Timetable


 


(a) By [*] (the Facility Completion Target Date), ACSD will construct,
equip, test and qualify (IQ/OQ/PQ) and make operational the Facility in
accordance with current Good Manufacturing Practices. ACSD’s obligations
hereunder include, but are not limited to:


 


(i)                                     construction
of building(s) necessary to perform the Process in a dedicated Facility;


 


(ii)                                  provision
of [*] for production of commercial batches of Product;


 


(iii)                               the
[*] of all required [*] for the manufacturing and warehousing of Product and
validation of Process: and


 


(iv)                              [*]
to manufacture Product.


 


Subject to adjustment in accordance with Section 2.2,
ACSD will complete all activities and to meet all dates set forth in this
Agreement. ACSD agrees that the following events (the “Targets”) shall occur by
[*]: (i)  ACSD shall produce [*] full
commercial consistency batches for FDA registration of the Facility;  (ii) all data and reports related thereto
shall be completed and ready for submission to the FDA; (iii) ACSD shall
commence validation processes; and (iv) ACSD will be prepared in all respects
for a site inspection by the FDA.  The
target date for FDA approval of the NDA Manufacturing Supplement for the ACSD
facility (the Facility Approval Target Date) is
[*]. In addition, ACSD shall (i) complete IQ/OQ/PQ and validation of the
fermentation process by [*]; and (ii) complete


 










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theconsistency batches, the IQ/OQ/PQ, and the [*]
validation batches for the purification process by [*].   ACSD agrees that time is of the essence in
completing the tasks set forth in this Section 2.1 in order to comply with ACSD’s
obligation to supply Product in [*].  In
connection with ACSD completing all activities required to meet the
aforementioned dates, Cubist shall remit to ACSD [*]of [*] on each of (i) the
date of execution by both parties of this Amendment No. 2 (the “February
Payment”);  (ii)May 1, 2003 (the “May
Payment”); and (iii) August 1, 2003 (the “August Payment”).


 


(b) By March 1, 2003,
ACSD and Cubist shall mutually agree upon a schedule for all tasks required to
meet the Targets set forth in section 2.1(a) above (the “Schedule”). In the
event that, in Cubist’s sole discretion, Cubist determines that the Schedule
will not enable [*], the May and August Payments shall not be payable to ACSD
and ACSD shall promptly refund to Cubist the February Payment.


 


2.                                       Amendment of Section 3.2.  The Agreement is hereby amended by deleting
Section 3.2 thereof in its entirety and replacing it with the following Section
3.2:


 


3.2                               Process
Validation


 


ACSD will develop and complete a validation process at
the Facility in accordance with Exhibit D herein, and at ACSD
expense. [*] and limits for the process must span the [*]and limits developed
and documented during the manufacture of consistency batches at [*]. No Process
changes will be made during the period beginning on [*] and ending on the [*].
All post-validation process changes must be approved by Cubist in writing.
Cubist will provide [*] and [*]as such reports become available. ACSD will
provide Cubist with a [*]for the Facility and Process.


 


3.                                       Amendment of Section 3.3.  The Agreement is hereby amended by deleting
Section 3.3 thereof in its entirety and replacing it with the following Section
3.3:


 


3.3                               Process
Improvements


 


Following the [*] of the date of the Facility
Approval, ACSD may continue operating [*] Process improvements with the prior
written approval of Cubist. No Process improvements will be made during the
period beginning on [*] and ending on the [*]. 
[*]for the purpose of improving ACSD’s margins will be entirely at ACSD’s
expense. ACSD will reimburse Cubist for any additional Cubist expenses [*]. All
[*] related to the [*] will be implemented only after [*]. The authorization
will be obtained in writing following a successful and complete cGMP change
control process outlined in the approved standard operating procedures (SOPs)
of both ACSD and Cubist.


 


4.                                       Amendment of Section 3. The
Agreement is hereby amended by adding the following Section 3.5 immediately
following the end of Section 3.4 of the Agreement


 










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3.5                               Q.A.
Director


 


In order to ensure and maintain consistent quality
assurance with respect to the Product and the process, on or before April 1,
2003 ACSD shall have hired, with the
approval of Cubist (which approval shall not be unreasonably withheld), a
full-time Quality Assurance Director and shall engage an independent validation
consultant, each with significant experience in the process of manufacturing
and supply of pharmaceutical products.


 


5.                                       Amendment of Section 5.1.  The Agreement is hereby amended by deleting
Section 5.1 thereof in its entirety and replacing it with the following Section
5.1:


 


5.1                               Purchase
Commitment


 


Contingent upon the receipt of the necessary Product
and Facility Approvals, Cubist will purchase a [*] kilograms of Product during
the term of this Agreement, [*] and further subject to the [*]. In the event
that the [*], or the [*], Cubist shall not be required to purchase [*] kg of
Product [*] or in any other year during the term of the Agreement.
Notwithstanding anything to the contrary herein, ACSD will [*] to be delivered
in the year [*] and, if longer, the [*], in accordance with the commercial
Process specified in the Exhibits B-1, C-1 and D herein which may be modified
in writing by Cubist from time to time. To the extent that there is any
conflict between the specifications set forth in Exhibit C-1 and those set
forth in Exhibit B-1, the specifications set forth in Exhibit C-1 shall
supersede in all respects. During the period prior to the receipt of Product
Approvals, Cubist [*] in accordance with Exhibits B-1, C-1,
and D herein. Any such Product purchases shall count toward the [*]
kilograms of Product that Cubist is required to purchase. Subject to the
conditions of this Agreement, Cubist agrees to make the following yearly
purchases:


 


	
  Year

  	
   

  	
  Purchase Minimum(kg)

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2004

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2005

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2006

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2007

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2008

  	
   

  	
  [*]*

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2009

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2010

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  [*]

  	
   

  



 


The above schedule will be extended for any delays
caused by ACSD.


 


6.                                       Amendment of Section 5.6.  The Agreement is hereby amended by deleting
Section 5.6(a) in its entirety and replacing it with the following Section
5.6(a)


 










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5.6                               Obligation
to Supply


 


(a)          ACSD shall accept and
fill each order for Product submitted by Cubist [*], provided that such request
is delivered to ACSD at least [*] days prior to the beginning of the
corresponding quarter. ACSD shall not be in breach of this Section 5.6 if
[*].  Delivery dates will be set
independently from Product release and invoice dates as described in Section
5.7;


 


7.                                       Amendment of Section 6.1.  The Agreement is hereby amended by deleting
Section 6.1 thereof in its entirety and replacing it with the following Section
6.1:


 


6.1                               Product
Price


 


(a)                                  Subject
to the provisions of Sections 5, 6 and 7, Cubist will [*], including the
additional [*] kg required to be purchased by Cubist in [*], at a price of [*]
per kilogram (USD [*]/kg);


 


8.                                       Amendment of Section 6.2.  The Agreement is hereby amended by deleting
Section 6.2 thereof in its entirety and replacing it with the following Section
6.2:


 


6.2                               Product
Price [*]


 


Cubist will pay ACSD [*] per kilogram (USD [*]) on the
[*] purchased over the life of the contract other than the [*] kgs of Product
[*] in [*] until cumulative [*] payments equal [*] (USD [*]). Once the
cumulative [*] payments have accrued to [*] (USD [*]), Cubist will immediately
stop paying the [*] and will pay [*] per kilogram (USD [*]/kg) of Product, as
provided in Section 6.1 herein.


 


	
  Year

  	
   

  	
  Purchase

  Minimum

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2005

  	
   

  	
  [*]

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2006

  	
   

  	
  [*]

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2007

  	
   

  	
  [*]

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2008

  	
   

  	
  [*]

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2009

  	
   

  	
  [*]

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2010

  	
   

  	
  [*]

  	
   

  	
  [*]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
  [*]

  	
   

  



 










* CONFIDENTIAL TREATMENT REQUESTED: MATERIAL HAS BEEN OMITTED AND FILED
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The above schedule will be extended for any delays
caused by ACSD. In the event that Cubist [*] as provided in Section 5.1, Cubist
will pay [*] corresponding to the original minimum purchase commitment in the
year specified in this Section 6.2. Any delays [*] (including, but not limited,
to [*]) will extend [*].


 


9.                                       Amendment of Section 7.  The Agreement is hereby amended by deleting
Section 7 thereof in its entirety and replacing it with the following Section
7:


 


7.                                      Exclusivity


 


ACSD covenants that it will not promote, sell, deliver
or provide any Product or Daptomycin to any third party without the prior
written consent of Cubist, or produce any product, bulk drug substance or
active pharmaceutical ingredient in the Facility other than the Product.
Notwithstanding the foregoing, ACSD shall be permitted to produce vancomycin
(the “Competing Product”) in the Facility for Eli Lilly & Company, provided
that the following conditions have been and continue to be met at all times:


 


(i)                                     ACSD
has met all of the Targets and as well as the Facility Approval Target Date;


 


(ii)                                  ACSD
fills all Product orders in accordance with the schedules set forth in Cubist’s
Purchase Orders;


 


(iii)                               ACSD,
at its cost, completes all cleaning validation processes in accordance with FDA
requirements; and


 


(iv)                              At
Cubist’s request, ACSD Promptly purchases separate, dedicated additional
columns that will be used solely for the production of the Product.


 


In the event that any of conditions (i) through (iv)
are not met, ACSD shall lose its right to produce the Competing Product and
shall cease production thereof upon receipt of written notice from Cubist.


 


10.                                 Amendment of Section 12.1.  The Agreement is hereby amended by deleting
Section 12.1 thereof in its entirety and replacing it with the following
Section 12.1:


 


12.1                        Term


 


This Agreement shall take effect as of the Effective
Date and shall remain in effect until the seventh anniversary of Facility
Approval or until ACSD has received all payments due under Section 6.2 unless
sooner terminated in accordance with Section 12.2 or extended in accordance
with this Section 12.1. Thereafter, this Agreement shall automatically renew
for additional two-year terms. Not later than the sixth (6h)
anniversary of the Effective Date, Cubist shall notify ACSD in writing whether
Cubist desires to extend the Agreement for an additional two years. All 


 










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applicable terms and conditions of this Agreement
shall remain in effect during such extension term, unless expressly amended in
writing by the parties. Cubist may renew this Agreement for additional two-year
extension terms by providing written renewal notice to ACSD not later than
twelve (12) months prior to the expiration of the then current extension term.


 


11.                               Amendment of Section 12.2.  The Agreement is hereby amended by adding the
following Section 12.2(c) immediately following Section 12.2(b) of the
Agreement:


 


(c)                                In
the event that any current Cubist supplier of Product purchases substantially
all of the stock or assets relating to that portion of ACSD’s business that is
related to the subject of this Agreement, all payments hereunder shall be
promptly returned to Cubist and Cubist shall have the right to modify any
Purchase Requirements set forth herein. Cubist shall also have the right to
pursue an alternative source of supply for the Product.


 


12.                                 Amendment to Exhibits B and C and Addition of New Exhibit F.  The
Agreement is hereby amended by replacing Exhibits B (In-Process Testing
Procedures and Specifications) and C (Product Release Test Methods and
Specifications) with Exhibits B-1 (CMC section of the Cubist U.S. NDA filing)
and C-1 (Master Product Specifications) attached hereto. To the extent that
there is any conflict between the specifications set forth in Exhibit C-1 and
those set forth in Exhibit B-1, the specifications set forth in Exhibit C-1
shall supersede in all respects.


 


13.                                 No Other Amendments.  Except
to the extent amended hereby, all of the definitions, terms, provisions and
conditions set forth in the Agreement are hereby ratified and confirmed and
shall remain in full force and effect. 
The terms and conditions herein and subject matter hereof shall at all
times be considered Confidential Information of Cubist, as defined in the
Agreement. The Agreement and this Amendment No. 2 shall be read and
construed together as a single agreement and the term “Agreement” shall be
deemed a reference to the Agreement as amended by this Amendment No. 2.  This Amendment No. 2 may be signed in any
number of counterparts, each of which shall be deemed to be an original and all
of which together shall constitute but one and the same instrument.  In making proof of this Amendment No. 2 it
shall not be necessary to produce or account for more than one such
counterpart.


 


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IN WITNESS WHEREOF, this
Amendment No. 2 has been executed under seal by the parties hereto as of the
day and year first above written.


	
   

  	
  ACS DOBFAR SpA

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
    /s/ Marco
  Feliciani

  	
   

  
	
   

  
	
   

  	
  Title: 
  President

  
	
   

  
	
   

  	
  Date: 02/20/03

  



 


 


	
   

  	
  CUBIST PHARMACEUTICALS,
  INC.

  
	
   

  
	
   

  	
  By:

  	
    /s/ Michael W. Bonney

  	
   

  
	
   

  	
   

  
	
   

  	
  Title: 
  President/COO

  
	
   

  	
   

  
	
   

  	
  Date: 2/13/03

  



 


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Exhibit B-1


 


CMC Section of US
NDA Filing


 


[*]


 


                CONFIDENTIAL
TREATMENT REQUESTED: MATERIAL HAS BEEN OMITTED AND FILED WITH THE COMMISSION


 


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Exhibit C-1


 


Specifications


 


[*]


 


                CONFIDENTIAL
TREATMENT REQUESTED: MATERIAL HAS BEEN OMITTED AND FILED WITH THE COMMISSION


 


9