EXHIBIT 12
CONFIDENTIAL PORTIONS OF THIS EXHIBIT HAVE BEEN OMITTED PURSUANT TO REGULATION
240.25B-2B OF THE SECURITIES EXCHANGE ACT OF 1934. [*] INDICATES OMITTED
MATERIAL THAT IS THE SUBJECT OF A CONFIDENTIAL TREATMENT REQUEST AND IS FILED
SEPARATELY WITH THE COMMISSION.
THIS AGREEMENT is made this day of January 2000 between:
(1) AVECIA LIMITED acting through its LifeScience Molecules business whose
registered office is at Xxxxxxx Xxxxx, Xxxxxxxx, Xxxxxxxxxx, X0 0XX,
Xxxxxxx ("AVECIA");
(2) RIBOZYME PHARMACEUTICALS INCORPORATED of 0000 Xxxxxxxxxx Xxxxx, Xxxxxxx,
Xxxxxxxx 00000, XXX ("RPI").
WHEREAS
(A) AVECIA has experience and knowledge with regard to the manufacture of
oligonucleotides and intermediates for preparation of oligonucleotides,
process scale-up and GMP (as defined below).
(B) RPI is carrying out research and development work in relation to certain
ribozymes.
(C) It is intended that AVECIA will carry out a development programme upon and
subject to the terms and conditions of this Agreement with a view to
scaling up the process for production of such ribozymes and carrying out
initial production of such ribozymes as set out in Part II of this
Agreement and carrying out such production on behalf of RPI as set out in
Part III of this Agreement.
NOW IT IS HEREBY AGREED AS FOLLOWS:
PART I - DEFINITIONS AND INTERPRETATION
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1. Headings and Definitions
------------------------
1.1 In this Agreement, the following terms and expressions shall have the
following meanings:
Angiozyme means RPI's proprietary anti-angiogenesis ribozyme
compound being jointly developed with Chiron
Corporation. Angiozyme is also designated as
Angiozyme.(TM)
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Anti-HCV means RPI's proprietary anti-hepatitis c virus Ribozyme
ribozyme compound being jointly developed with Xxx
Lilly & Company. Anti-HCV Ribozyme is also designated
as Heptazyme.
Collaborator means any of Chiron Corporation, Xxx Xxxxx & Company or
other corporate partner of RPI who is collaborating
with RPI to develop and commercialise a Product
manufactured under this Agreement, or any licensee of
RPI who is developing and commercialising a Product
manufactured under this Agreement. "Collaborators"
shall mean more than one of them.
Confidential means any information disclosed by RPI to AVECIA
Information pursuant to the Technology Transfer, and any technical
and commercial information relating to the Programme
and any other information of a confidential nature
disclosed (whether disclosed in writing, verbally, by
way of sample or by any other means and whether
directly or indirectly) by either party ("the
Disclosing Party") to the other ("the Receiving
Party"), including and without limitation any
information relating to the Disclosing Party's business
affairs.
GMP means current good manufacturing practices (as provided
for, respectively, in the Rules governing Medicinal
Products in the European Community Volume 4 (Guide to
Good Manufacturing Practice for Medicinal Products) and
by the US Food and Drug Administration as set out in
21CFR210 and 21CFR211, as amended from time to time)
the responsibilities of each party in respect of which
for each Product shall be agreed and defined in the
Quality Agreement, and shall be consistent with the
interpretation for Active Pharmaceutical Intermediates
in guidance documents provided by the Federal Drug
Administration and the International Conference on
Harmonisation.
Effective Date means 13/th/ December 1999.
Intellectual means all know-how, inventions, discoveries, Property
devices, data, patents, designs, copyrights, or other
industrial or intellectual property in all applications
therefor.
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JRC means the joint review committee provided for in Clause
4 and Schedule 2.
Nominated means a contract manufacturer nominated by RPI to
Manufacturer carry out manufacture of the Product(s) on RPI's behalf
and which has agreed to enter into confidentiality
undertakings with AVECIA pursuant to Clause 12.4 below.
Process means the process for production of the Product(s) as
developed during the Programme.
Product means, unless stated specifically, Angiozyme, Anti-HCV
Ribozyme or such other Ribozyme product agreed by the
parties. "Products" shall be a reference to such
Ribozymes taken together.
Product means the specification designated by RPI for each of
Specification the Product(s) and as set out and
determined by the analytical test methods in the
Quality Agreement.
Programme means the programme for development of the Process
(including the Technology Transfer) referred to in
Clause 2 and more specifically detailed in Schedule 1.
Quality means the agreement made between AVECIA and
Agreement RPI in respect of each Product, the terms of which
shall be agreed by the JRC prior to commencement of
manufacture and supply of each Product on a case by
case basis. A draft of the Quality Agreement is
attached as Schedule 3.
Ribozyme means a ribonucleic acid-based molecule able to cause
catalytic cleavage of itself or another molecule
independent of protein.
Technical means the agreement made between AVECIA and
Agreement RPI, the terms of which shall be agreed by the JRC,
detailing the process information and analytical
methods to be communicated to AVECIA during the
Technology Transfer. A draft of the Technical Agreement
is attached as Schedule 4.
Technology means the communication by RPI of technical
Transfer information, including processes and analytical
methods, relating to the Products to AVECIA as may be
required
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by AVECIA to carry out the Programme and as
further set forth in the Technical Agreement.
1.2 The headings of the several sections of this Agreement are intended
for convenience of reference only and are not intended to be a part of
or to affect the meaning or interpretation of this Agreement.
1.3 References to recitals, clauses, paragraphs and Schedules are to
recitals, clauses and paragraphs of and Schedules to this Agreement.
The Schedules and any attachments form part of this Agreement and
shall have the same force and effect as if expressly set out in the
body of the Agreement and any reference to the Agreement shall include
the Schedules and any attachments.
PART II - THE PROGRAMME
-----------------------
2. Performance of the Programme
----------------------------
2.1 The Technology Transfer shall be deemed to have commenced on the
Effective Date. During the Technology Transfer, RPI shall give all
appropriate technical assistance reasonably requested by AVECIA in
relation to the Technology Transfer.
2.2 AVECIA will carry out the work as detailed in the Programme (as may be
amended from time to time in writing by the JRC).
2.3 Subject to Clause 4.2 below, the Programme has four stages as set out
below and as more specifically detailed in Schedule 1 ("Stage(s)"),
provided that AVECIA shall, at all times during any Stage, have the
flexibility to carry out the requirements of the Programme in such
manner and at such times as AVECIA shall see fit and at its sole
discretion and subject to the overall supervision of the JRC and the
provisions of Clause 4.
Stages in Programme
Stage Description
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1 Technology Transfer of process and analytical methods
2 Process development - deprotection and purification scale-up
of the Products as determined by the JRC
3 preparation of GMP manufacturing documentation
4 Process scale up - GMP manufacture of 1kg of a mutually
agreed Product
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2.4 The process information and analytical methods to be communicated to
AVECIA during the Technology Transfer shall be agreed and detailed in
the Technical Agreement. Stage 2 of the Programme shall commence when
the JRC confirms that the Technology Transfer is complete according to
the verification protocol (set forth in the Quality Agreement) to
ensure such information has been received and correctly interpreted.
2.5 Stage 3 of the Programme shall not commence until:
(a) the identity of the first Product to be produced during Stage 4
using the Process is confirmed;
(b) the analytical methods for the Products have been transferred
from RPI to AVECIA; and
(c) the JRC confirms AVECIA's ability to manufacture the Product to
be produced during Stage 4 using the Process.
2.6 For the avoidance of doubt, any time periods specified in Schedule 1
shall be indicative only unless provided for specifically in this
Clause 2.
2.7 AVECIA shall be responsible for obtaining all raw materials and
reagents in order to produce the Product, including solvents, gases,
amidites and other laboratory consumables and the solid support, to be
utilised in conjunction with synthesis of a Product during the
Programme.
2.8 For the avoidance of doubt, it shall not be considered a breach of
this Agreement by AVECIA if an objective of the Programme is not
achieved:
(a) so long as AVECIA uses reasonable commercial and technical
diligence and makes good faith efforts to perform its obligations
to the fullest extent, and any failure to meet an objective of
the Programme shall not relieve RPI of its obligations to make
payment in accordance with Clause 3; or
(b) due to delay caused or contributed to by RPI.
3. Payment for the Programme and First Kilogram of Product
-------------------------------------------------------
Subject to Clauses 4.2 and 13 below, RPI shall pay to AVECIA the following
sums at the time stated:
(a) on signature of this Agreement by both parties: [ * ]; and
(b) upon receipt of Product by RPI but subject to Clause 4.5 below: [ * ]
per gram of Product manufactured to the Product Specification during
Stage 4 of the
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Programme and available for delivery to RPI by AVECIA (subject to a
maximum of [ * ]for up to one kilogram of the Product manufactured
during stage 4 of the Programme unless otherwise agreed under Clause
5.3 below).
For the avoidance of doubt, a gram of Product shall mean a gram of nucleic
acid material which meets the Product Specification, net of any
accompanying salts, water or other residual solvents.
4. Reporting, Variation and Completion of the Programme
----------------------------------------------------
4.1 The Programme and the progress by AVECIA under the Programme shall be
supervised by the JRC which shall be established within the period of
30 days following the date of this Agreement. Such supervision by the
JRC shall take place in accordance with the provisions set out in
Schedule 2.
4.2 The parties may agree to alter the Programme either to extend the
projected duration of any of the Stages or to change any of the work
contained in any of the Stages provided that the parties shall first
agree in writing the terms of such extension and alteration of the
Programme including any amended payment terms.
4.3 The parties shall conduct regular information exchange on at least two
(2) weekly intervals by telephone or in a manner to be agreed by the
JRC, provided that where AVECIA considers that, for the purposes of
optimising or improving the Process, revisions or changes in methods
should be undertaken by AVECIA during the performance of the
Programme, AVECIA shall notify the JRC without delay of the reasons
therefor and the actions which it proposes to take.
4.4 Completion of the Programme will be deemed to have occurred when the
quantity of Product specified in Stage 4 has been manufactured in
accordance with the Product Specification and has been made available
for delivery to RPI pursuant to Clause 5 below.
4.5 RPI shall pay to AVECIA within thirty (30) days of the completion of
the Programme any sums required to be paid pursuant to Clause 3 above
which may remain outstanding at the completion of the Programme.
Notwithstanding the foregoing, and subject to Clause 13, in respect of
the Product held by AVECIA pursuant to Clause 5.1(a), RPI shall not be
obligated to make any payments to AVECIA pursuant to Clause 3(b) prior
to 1/st/ January 2001, unless RPI requests delivery of the Product
prior to 1/st/ January 2001, in which case RPI shall make payments to
AVECIA for the quantity of Product requested by RPI within 30 days of
the date of the invoice for the Product.
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5. Delivery of First Kilogram of Product under Stage 4
---------------------------------------------------
5.1(a) Manufacture of the one kilogram (1kg) of the Product specified in
Stage 4 shall take place on the date(s) agreed by the parties.
AVECIA shall hold such manufactured Product in stock at its
facilities and at its expense under the terms of the Quality
Agreement, including the storage and stability instructions
provided by RPI to AVECIA. Any Product so held by AVECIA shall be
deemed to have been delivered and any risk shall immediately pass
to RPI, except insofar as any damage occurs to the Product as a
result of the negligence of AVECIA.
(b) Avecia shall use its best endeavours to deliver one kilogram
(1kg) of Product as specified in Stage 4. However, if AVECIA
shall manufacture at least [ * ] and up to [ * ], RPI shall be
obliged to purchase all such Product from AVECIA during 2000
subject to Clause 5.3 below. Subject to the foregoing, during
2000 AVECIA shall deliver quantities of Product at RPI's request
from time to time, such request not to be for less than 250 grams
of Product.
5.2 In the event that only a portion of the Product produced during
Stage 4 is delivered to RPI, RPI shall be responsible only to pay
for the quantity of the Product delivered.. If the quantity of
the Product supplied by AVECIA is less than [ * ], then AVECIA
agrees to synthesise sufficient Product in order to supply the
shortfall quantity of Product to RPI, and the price for such
shortfall quantity shall be no more than that paid by RPI for the
initial delivered quantity. In the event that AVECIA then
produces more than the 1 kilogram (1kg) of Product specified in
Stage 4, the provisions of Clause 5.3 shall apply.
5.3 In the event that AVECIA produces more than the 1 kilogram (1kg)
of Product specified in Xxxxx 0, XXX agrees to purchase such
additional quantity up to a maximum of [ * ] at a price to be
negotiated in good faith by the parties. Such agreed price shall
be less than [ * ] per gram and shall be determined according to
the yield and price matrix attached as Schedule 5 hereto. In the
event that AVECIA produces more than [ * ] of the Product, RPI
shall have an option, but not an obligation, to purchase such
additional quantity of the Product at its sole discretion at a
price per gram which does not exceed the price per gram paid for
the additional [ * ] of the Product.
5.4 Avecia will arrange for shipment and insurance of the Product
produced during Stage 4 of the Programme to RPI as directed by
RPI at RPI's cost and expense. The Products will be shipped and
packaged by Avecia in accordance with RPI's shipping and
packaging instructions as may be agreed from time to time.
Deliveries will be made FOB Avecia's Grangemouth facility
(Incoterms 2000) and will be shipped to RPI's address as set
forth in this Agreement, or as otherwise directed by RPI in
writing. Risk and title in respect of all Product
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supplied to RPI under this Agreement shall pass on delivery at
AVECIA's Grangemouth facility.
6. Intellectual Property arising during the term of this Agreement
---------------------------------------------------------------
6.1 Pre-Existing and Independently Developed Intellectual Property.
--------------------------------------------------------------
Subject to the obligations of confidentiality contained in Clause 12
below and subject to Clause 6.2 below, each party shall be entitled to
apply for registrations of its Intellectual Property provided that
nothing in this Agreement shall affect the ownership by either party
of any Intellectual Property owned or in the possession of that party
at the date of this Agreement, or Intellectual Property developed
independently of this Agreement by any employee of that party without
reference to any of the Confidential Information disclosed by the
other party.
6.2 Ownership.
---------
(a) All rights in patents, inventions, processes, discoveries,
biological samples and other research materials and any other
novel or valuable information reflected in any medium which
arises or is created during the course of this Agreement shall be
the property of the creating party. The Parties shall promptly
report to each other any inventions, discoveries, biological
samples or other research materials made to the Process or to the
Products under the Agreement.
(b) Intellectual Property, whether or not patentable, which may arise
under this Agreement and made solely by an employee or agent of
RPI shall be owned by RPI ("RPI Inventions").
(c) Intellectual Property, whether or not patentable, made jointly by
an employee or agent of RPI and AVECIA shall be jointly owned
("Joint Inventions").
(d) Intellectual Property, whether or not patentable, which may arise
under this Agreement and made solely by an employee or agent of
AVECIA shall be owned by AVECIA ("AVECIA Inventions").
(e) Inventorship will be determined according to applicable patent
law.
(f) AVECIA and RPI shall promptly disclose to each other in writing
each invention and discovery conceived and/or reduced to practice
under this Agreement.
(g) Intellectual Property arising from this Agreement and in the
possession of a party shall be treated as having been disclosed
to that party by the
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party owning such Intellectual Property pursuant to this Clause
6.2, and the expressions "Disclosing Party" and "Receiving Party"
defined and used in connection with the obligations of
confidentiality contained in Clause 12 shall be construed
accordingly.
(h) In the event of a Joint Invention, RPI and AVECIA, and any wholly
owned group company of either, shall each be entitled to work
under such joint invention, but otherwise no sub-licensing shall
be permitted without the written consent of the joint inventor,
such consent not to be unreasonably withheld or delayed.
6.3 Limited Licence to carry out the activities under this Agreement.
-----------------------------------------------------------------
Each party grants to the other a limited, non-exclusive, royalty-free
licence to do all things necessary in order to carry out the
obligations and responsibilities under this Agreement under its
Intellectual Property (whether pre-existing Intellectual Property
under Clause 6.1 above or Intellectual Property arising as a result of
the Agreement under Clause 6.2(b) or (d) above). Such licence shall
expire at the completion of the Agreement and shall not be
transferable or sub-licensable.
6.4 Maintenance of Patents.
----------------------
(a) Subject to Clauses 6.1 and 6.4(e), RPI shall be responsible for
filing, prosecuting and maintaining patent applications and
resulting patents, if any, on RPI Inventions and on any Joint
Inventions insofar as they do not relate to synthesis or
manufacture of oligonucleotides other than Ribozymes.
(b) Subject to Clauses 6.1 and 6.4(e), AVECIA shall be responsible
for filing, prosecuting and maintaining patent applications and
resulting patents, if any, on AVECIA Inventions or on any Joint
Inventions relating to synthesis or manufacture of
oligonucleotides other than Ribozymes.
(c) Reasonable patent expenses for any Joint Invention will be shared
equally by the Parties, and reimbursed promptly upon presentation
of an invoice by the filing party.
(d) The non-filing party shall have the right to review and comment
in a timely manner on any such patent filings (applications and
response to office actions) prior to submission to the relevant
patent offices. Each party shall be solely responsible for
filing, prosecuting and maintaining patent applications and
resulting patents on any invention owned solely by it.
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(e) Each of AVECIA and RPI shall solely own its respective technology
and any technology or other technology developed solely by it and
each shall be responsible for filing, prosecuting and monitoring
patent applications and resulting patents, if any, related
thereto.
6.5 Reservation of All Other Rights. Except as expressly set forth in
-------------------------------
this Agreement, nothing contained herein shall be construed as to
create any right to:
(a) AVECIA in any Intellectual Property of RPI or any other
proprietary technology (whether pre-existing Intellectual
Property under Clause 6.1 above or Intellectual Property arising
as a result of this Agreement under Clause 6.2(b)) of RPI
including, without limitation, any of RPI's patent rights
relating to the design, synthesis, delivery, development,
testing, use and sale of Ribozymes; or
(b) RPI in AVECIA Intellectual Property or any other proprietary
technology (whether pre-existing Intellectual Property under
Clause 6.1 above or Intellectual Property arising as a result of
this Agreement under Clause 6.2(d))of AVECIA.
PART III - SUBSEQUENT MANUFACTURE OF THE PRODUCT
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7. Sale and Purchase
-----------------
7.1 Minimum Order. Unless this Agreement has been terminated under
-------------
Clauses 13 or 21 below, RPI agrees that, following completion of the
Programme, it shall purchase a minimum of [ * ] of the Products in
aggregate ("the Product Minimum") from AVECIA during the calendar
years 2000 to 2002, pursuant to the pricing and delivery provisions
contained in Clauses 7.2 and 7.3 below.
7.2 Price for Product. The parties shall negotiate in good faith the
-----------------
pricing schedule for the Products, on a per gram basis, to be
manufactured by AVECIA following completion of the Programme prior to
the manufacture of each order of Product. An example of the pricing
schedule is attached as Schedule 5 hereto. The price for quantities of
Products manufactured by Avecia following completion of the Programme
shall be based on:
(a) yields achieved dependent upon usage of raw materials; and on
(b) order volume, provided that for individual orders of less than
500 grams of Product the price per gram for such Product shall
not exceed [ * ] of the per gram price for Product(s) ordered
for delivery in multiples of 500 grams or more.
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7.3 Delivery Schedule. The parties shall agree on a schedule for
-----------------
delivery of Products by AVECIA to RPI ("the Delivery Schedule"). The
minimum order shall be 500 grams of Product except as otherwise
agreed subject to the pricing provisions of Clause 7.2 above.
7.4 Delivery. AVECIA will arrange for shipment and insurance of the
--------
Products ordered for delivery to RPI at RPI's direction and at RPI's
cost and expense. The Products will be shipped and packaged by
AVECIA in accordance with RPI's shipping and packaging instructions
as may be agreed from time to time. Deliveries will be made FOB
Avecia's Grangemouth facility (Incoterms 2000) and will be shipped
to RPI's address as set forth in this Agreement, or as otherwise
directed by RPI in writing. Risk and title in respect of all Product
supplied to RPI under this Agreement shall pass on delivery at
AVECIA's Grangemouth facility
7.5 Delivery Quantities
-------------------
(a) In the event that AVECIA delivers less than [ * ]of the amount of
Product required to be delivered pursuant to the delivery schedule
agreed under Clause 7.3 above, RPI shall, subject to Clause 8, pay
AVECIA for the actual amount of Product delivered. Avecia shall
synthesise sufficient Product to complete the order and will supply
this to RPI and the price for such completion quantity shall be no
more, on a per gram basis, than that paid by RPI for the initial
delivered quantity under that order. For the avoidance of doubt, if
AVECIA delivers [ * ] of the amount of Product, RPI shall, subject
to Clause 8, be obligated to pay AVECIA only for the [ * ] of the
Product delivered.
(b) In the event that Avecia manufactures Product in quantities
exceeding the amount ordered for delivery under the delivery
schedule, RPI agrees to purchase upto [ * ] of the order volume at a
price to be negotiated in good faith by the parties in respect of
the additional [ * ], according to the yield and price matrix
attached as Schedule 5, but such amount shall not cost more per gram
than for the said amount ordered In the event AVECIA produces more
than [ * ] of the Product, RPI shall have an option, but no
obligation, to purchase such additional quantity of the Product at
its sole discretion at a price per gram not to exceed the price per
gram paid for the additional quantity of the Product.
7.6 Delay in Delivery. In the event that the AVECIA delivers any
-----------------
Product later than four weeks from the date of delivery set out in
the Delivery Schedule other than as a result of Force Majeure as set
out in Xxxxxx 00, XXX shall be entitled to a five per cent reduction
in the price of the Product delivered one month late and to an
additional ten per cent reduction in price for each of the next two
complete month's delay thereafter. In the event AVECIA is unable to
deliver the Product within three months from the date set out in the
Delivery Schedule, then RPI shall have the option to either
terminate the Agreement pursuant to
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Clause 13.3(b) or to manufacture or have manufactured by a Nominated
Manufacturer the Product. In the event RPI chooses the latter
option, then in order to satisfy RPI's requirement for that quantity
of the Product ordered, AVECIA, subject to Clause 12, agrees (i) to
make a good faith effort to provide, at no cost to RPI or to a
Nominated Manufacturer, the technical information necessary for such
manufacture of the Product; and (ii) to grant to RPI or a Nominated
Manufacturer a personal, royalty free licence under AVECIA's
relevant Intellectual Property to enable RPI or such Nominated
Manufacturer to undertake the manufacture of the Product7.7 Invoices
--------
and Payment Terms. AVECIA shall issue an invoice at the price agreed
-----------------
under Clause 7.2, as adjusted pursuant to Clause 7.6 if relevant,
above in respect of each shipment of the Product to RPI on despatch
by AVECIA of the Product for delivery to RPI. RPI shall pay all such
invoices in full within thirty days from the date of invoice,
provided that RPI shall not have rejected such delivery of Product
under Clause 8.1. In the event that payment is made by RPI before
any Product is examined by RPI pursuant to Clause 8.2, AVECIA will
reimburse RPI for the price of such Product if it is found that the
Product does not meet the Product Specification.
7.8 Responsibility for Raw Materials. AVECIA shall be responsible for
--------------------------------
obtaining all raw materials and reagents in order to produce the
Product, including solvents, gases, amidites and other laboratory
consumables and the solid support, to be utilised in conjunction
with synthesis of a Product.
7.9 Third Party Price Notice. After a period of [ * ] from signature
------------------------
of this Agreement, RPI shall be entitled to give AVECIA written
notice if a third party under a supply agreement with RPI of at
least three years duration is able to supply identical products in
identical volumes to RPI at a price which is at least ten per cent
lower than the price for the Products agreed under Clause 7.2 above
("Third Party Price Notice"). RPI and AVECIA shall meet to discuss
the position and if agreement on price is not reached within 30 days
of receipt of such Third Party Notice, then RPI may purchase the
quantity so offered from the third party and the amounts of such
Products purchased shall be construed as falling within the amounts
of Products to be delivered according to the Product Minimum
referred to in Clause 7.1. RPI shall not be obliged to divulge the
identity of such third party, but at the request of AVECIA shall in
lieu provide satisfactory evidence, signed by an independent notary
public certifying the genuineness of the competitive offer.
7.10 Non-use of RPI's Intellectual Property. Other than as provided in
--------------------------------------
this Agreement, AVECIA agrees that it will not use for its internal
purpose or for third parties any Intellectual Property of RPI
(whether pre-existing Intellectual Property under Clause 6.1 above
or Intellectual Property arising as a result of this Agreement under
Clause 6.2(b) above) or Confidential Information acquired under this
Agreement.
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8. Quality of the Product
----------------------
8.1 The Product manufactured and delivered by AVECIA to RPI under Clause 7
above shall conform to the Product Specification for such Product.
8.2 RPI shall examine all Product delivered to it pursuant to this
Agreement in accordance with the methods of analysis set out in the
Quality Agreement for such Product. RPI shall notify AVECIA of any
failure of the Product to meet the Product Specification within [ * ]
days of receipt of the relevant Product. RPI shall be entitled to
reject any Product which does not meet the Product Specification
("Rejected Product")
8.3 (a) RPI will return any Rejected Product to AVECIA and, if AVECIA
agrees with RPI's notification of failure, AVECIA shall replace
the Rejected Product at no additional cost to RPI within [ * ]
days of receiving notice from RPI under Clause 8.2 or on a new
delivery date as mutually agreed to in writing by the Parties.
(b) In the event AVECIA is unable to replace the Rejected Product
within such time, RPI shall be entitled to exercise its Standby
Rights (as set out in Clause 9.1 below) to enable RPI or a
Nominated Manufacturer to manufacture sufficient Product to
replace the Rejected Product, and AVECIA, subject to Clause 12,
agrees to make a good faith effort to provide, at no cost to RPI
or to a Nominated Manufacturer, the technical information
necessary for such manufacture of the Product. In addition,
AVECIA will reimburse to RPI that element of the reasonable cost
of the Product manufactured by the Nominated Manufacturer which
is in excess of the price which RPI would have had to pay to
AVECIA. The amounts of such Products manufactured by the
Nominated Manufacturer shall be construed as falling within the
amounts of Product to be purchased by RPI in accordance with the
Product Minimum in Clause 7.1 above.
(c) If AVECIA disagrees with RPI's notification of failure the JRC
shall consider the matter and in the event no agreement is then
reached, the parties shall jointly appoint an expert to determine
whether the Product is a Rejected Product, and the costs and fees
of the expert shall be borne by the losing party. During the
period of dispute resolution under this Clause 8.3(c):-
(i) If RPI requests AVECIA to resynthesise the quantity of the
Rejected Product, AVECIA shall in good faith resynthesise
the
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Product and deliver it to RPI within [ * ] of receiving
such a request from RPI. Subject to Xxxxxx 0, XXX will
make payment for the resynthesised quantity within [ * ]
of delivery. If the dispute is resolved in favour of
AVECIA, RPI agrees to purchase from AVECIA both batches of
the Product, and such additional quantity of the Product
resynthesised by AVECIA shall not count towards the
Product Minimum. If the dispute is resolved in favour of
RPI, RPI will make payment only for the resynthesised
Product.
(ii) In the event AVECIA is unable to replace the Rejected
Product within the time stated in Clause 8.3(c)(i) above,
RPI shall be entitled to exercise its Standby Rights (as
set out in Clause 9.1 below) to enable RPI or a Nominated
Manufacturer to manufacture sufficient Product to replace
the Rejected Product, and AVECIA, subject to Clause 12,
agrees (i) to make a good faith effort to provide to RPI
or to a Nominated Manufacturer, at RPI's cost, the
technical information necessary for such manufacture of
the Product; and (ii) to grant to RPI or a Nominated
Manufacturer a personal, royalty free licence under
AVECIA's relevant Intellectual Property to enable RPI or
such Nominated Manufacturer to undertake such manufacture.
If the dispute is resolved in favour of AVECIA, RPI agrees
to purchase from AVECIA the entire amount of the Product
in dispute and to make immediate payment, and any
additional quantity of the Product manufactured by RPI or
its Nominated Manufacturer shall not count toward the
Product Minimum. If the dispute is resolved in favour of
RPI, AVECIA will reimburse to RPI that element of the
reasonable cost of the Product manufactured by the
Nominated Manufacturer which is in excess of the price
which RPI would have had to pay to AVECIA, together with
any costs paid by RPI in respect of the transfer of the
technical information by AVECIA, and the originally
ordered quantity of the Product shall be construed as
falling within the amount of Product to be purchased by
RPI in accordance with the Product Minimum.
(iii) If RPI does not request AVECIA to resynthesise the
Rejected Product, then AVECIA shall not be required to
start the resynthesis until the dispute is resolved or
until RPI make such a request, whichever is the sooner.
For the avoidance of doubt, no act or omission of RPI
under this Sub-clause 8.3(c)(iii) shall cause the Product
Minimum to be reduced by the amount of the Rejected
Product.
S-15
8.4 In the absence of notification that the Product does not meet the
Product Specification within the period set out in Clause 8.1 above,
the relevant consignment of the Product shall be deemed to have been
accepted by RPI in full compliance with the Product Specification.
9. Licence under AVECIA Intellectual Property to Manufacture the Product
---------------------------------------------------------------------
9.1 If AVECIA is unable to meet the delivery requirements set out in the
Delivery Schedule agreed under Clause 7.3 above, then subject to
Clause 12, AVECIA shall grant to RPI or a Nominated Manufacturer a
personal licence on reasonable commercial terms under AVECIA's
relevant Intellectual Property to enable RPI or such Nominated
Manufacturer to undertake the manufacture of Products, in order to
satisfy its requirements for Products ("Standby Rights"). In the
event that RPI wishes to exercise its Standby Rights, RPI will provide
Avecia with written notice thereof in advance of such exercise and,
subject to Clause 8, the volume of products manufactured under the
Standby Rights will be subtracted from the Product Minimum.
9.2 Manufacture of Products in excess of Product Minimum. In the event
----------------------------------------------------
that RPI's requirements for delivery of the Product over the period
from 1/st/ January 2000 to 31/st/ December 2002, as set out in the
Delivery Schedule, are in excess of the Product Minimum, then provided
that RPI shall purchase the greater of the Product Minimum or [ * ] of
its total requirements for delivery of the Product from AVECIA, RPI
shall have the ability to exercise its Standby Rights for manufacture
of the balance of the Product required during such period. AVECIA, at
its cost, shall have the right to have an independent third party
certify RPI's delivery requirements each twelve months within the
above said period, subject to Clause 12.
9.3 Any royalty payable under the licence granted as a result of the
exercise of the Standby Rights shall be dependent upon the volume of
Products to be manufactured by AVECIA on behalf of RPI and shall not
exceed [ * ]of the selling price of Products made by such a Nominated
Manufacturer. Neither RPI nor the Nominated Manufacturer, shall be
obligated to make any payments to AVECIA for the exercise of Standby
Rights pursuant to Clause 7.6 or pursuant to Clause 8.3 unless the
dispute is resolved in AVECIA's favour.
9.4 Without prejudice to Clause 13.5, upon the expiry or termination of
this Agreement, RPI may request a licence under AVECIA's Intellectual
Property, and the parties will negotiate in good faith the commercial
terms of such royalty bearing licence.
PART IV - GENERAL TERMS
-----------------------
S-16
10. Quality Agreements
------------------
AVECIA and RPI shall enter into a quality agreement in respect of each
Product on a case by case basis, the terms of which shall be agreed by the
JRC prior to manufacture and supply of each Product.
11. Warranties, Liability and Indemnity
-----------------------------------
11.1 Intellectual Property Warranty and Indemnity
--------------------------------------------
(a) Each party warrants to the other that:
(i) it has the necessary right and authority to enter into this
Agreement and that to the best of its knowledge at the date
of this Agreement it is the rightful owner or licensee of
all of its Intellectual Property; and
(ii) to the best of its knowledge at the date of this Agreement,
the use of Intellectual Property made available by it to the
other party pursuant to this Agreement for the purposes set
out in this Agreement will not infringe the Intellectual
Property of a third party.
(b) Subject to Clause 11.5, each party ("the Indemnifying Party")
will indemnify and hold harmless the other ("the Indemnified
Party") against any and all liability, loss, damages, costs,
legal costs, professional and other expenses whatsoever incurred
or suffered by Indemnified Party in respect of any claim or
action that the use of the Indemnifying Party's Intellectual
Property by the Indemnified Party in its performance of this
Agreement infringes the Intellectual Property of any third party
(an "Intellectual Property Infringement") provided that the
Indemnified Party:
(i) gives notice to the Indemnifying Party of any Intellectual
Property Infringement forthwith on becoming aware of the
same;
(ii) gives the Indemnifying Party the sole conduct of the defence
to any claim or action in respect of Intellectual Property
Infringement and does not at any time admit liability or
otherwise settle or compromise or attempt to settle or
compromise the said claim or action except upon the express
instructions of the Indemnifying Party; and
S-17
(iii) acts in accordance with the reasonable instructions of the
Indemnifying Party and gives the Indemnifying Party such
assistance as it shall reasonably require in respect of
the conduct of such defence.
11.2 Liability for the Products. Liability in respect of any Product
--------------------------
delivered to RPI and not rejected by RPI within the period set out in
Clause 8.2 above (including, without limitation, the use to which it
is put) following delivery to RPI of such Product shall rest solely
on RPI and RPI shall indemnify AVECIA against any liability, loss,
damages, costs, legal costs, professional and other expenses
whatsoever incurred or suffered by AVECIA arising out of or in
respect of such Product following its delivery to RPI including,
without limitation, RPI's use of the Product following delivery.
11.3 Liability for Manufacture of the Products. Liability in respect of
-----------------------------------------
manufacture of the Products, whether by use or operation of the
Process (or any part of the Process) or otherwise, by RPI or by a
Nominated manufacturer on behalf of RPI shall rest solely on RPI. RPI
shall indemnify AVECIA against any liability, loss, damages, costs,
legal costs, professional and other expenses whatsoever incurred or
suffered by AVECIA arising out of or in respect of manufacture of the
Products, whether use or operation of the Process (or any part of the
Process) or otherwise by RPI or by a Nominated Manufacturer on behalf
of RPI.
11.4 Limit on AVECIA's Liability. Subject to the unlimited liability
---------------------------
provisions of Clause 11.1, AVECIA's total liability (whether for
breach of contract, negligence, breach of statutory duty and/or other
tort, or otherwise):
(a) in connection with or as a result of the work carried out during
the Programme shall be limited to the aggregate amount received
by AVECIA from RPI under this Agreement at the time such
liability arises; or
(b) in connection with the manufacture of the Product pursuant to
Part III of this Agreement shall in no event exceed the purchase
price paid by RPI for the ordered quantity of Product in respect
of which the claim is made or liability has arisen.
11.5 No liability for consequential loss. Neither party shall be liable to
-----------------------------------
the other for any indirect, consequential or special loss, loss of
profits or damage howsoever arising.
11.6 No exclusion of liability for personal injury. Nothing in this
---------------------------------------------
Agreement shall remove or limit the liability of either party in
respect of death or personal
S-18
injury arising out of the negligence or wilful default of that party
its servants or agents.
12. Confidentiality
---------------
12.1 In consideration of the Disclosing Party disclosing the Confidential
Information to the Receiving Party, the Receiving Party hereby
undertakes to maintain confidential all such Confidential Information
and it will accordingly not directly or indirectly disclose any of
the Confidential Information in whole or in part, other than under
Clause 12.4 below. For the purposes of this Clause 12, Intellectual
Property arising from the Programme and in the possession of a party
shall be treated as having been disclosed to that party by the party
owning such Intellectual Property pursuant to Clause 6.2 above, and
the expressions "Disclosing Party" and "Receiving Party" shall be
construed accordingly.
12.2 The foregoing restrictions on the Receiving Party shall not apply to
any Confidential Information which:
(a) the Receiving Party can prove was already in its possession and
at its free disposal before the disclosure hereunder to it;
(b) is hereafter disclosed to, purchased or otherwise legally
acquired by the Receiving Party by or from a third party who has
not derived it directly or indirectly from the Disclosing Party;
(c) is or becomes available to the public whether in printed
publications or otherwise through no act or default on the part
of the Receiving Party or its agents or employees; or
(d) the Receiving Party can prove to the reasonable satisfaction of
the Disclosing Party has been developed independently of the
Programme by any employee of the Receiving Party without
reference to any of the Confidential Information disclosed by
the Disclosing Party.
12.3 In order to secure the obligations set out in this Clause 12 the
Receiving Party agrees to exercise every reasonable precaution to
prevent and restrain the unauthorised disclosure and use of
information subject to confidentiality, including restricting access
to such information to such of its employees as are bound to keep
such information confidential and need to have such access for the
purpose of this Agreement.
12.4 The Receiving Party may disclose Confidential Information: (i) in the
case of AVECIA to Avecia Inc., 0000 Xxxxx Xxxx, XX Xxx 00000,
Xxxxxxxxxx, XX 00000-0000 and to Boston Biosystems Inc. of 00X
Xxxxxxx Xxxxxx, Xxxxxxx,
X-00
Xxxxxxxxxxxxx; and (ii) in the case of RPI to its Nominated
Manufacturer(s) (each a "Permitted Recipient"), provided that the
Receiving Party shall procure that prior to such disclosure each
Permitted Recipient to which Confidential Information is to be
disclosed is made aware of the obligations contained in this
Agreement and enters into confidentiality obligations in
substantially the same terms as those contained in this Agreement
directly with the Disclosing Party.
12.5 The provisions of this Clause 12 shall survive termination or expiry
of this Agreement and shall continue for a period of 10 years from
the date of that termination or expiry.
12.6 The parties shall remain bound by the obligations in the Mutual
Confidentiality Agreement signed by them and dated 23/rd/ December
1998, but in the event of any conflict between the terms of that
Mutual Confidentiality Agreement and the terms of this Agreement, the
latter shall prevail.
13. Duration and Termination
------------------------
13.1 Duration. This Agreement and the Programme shall be deemed to have
--------
commenced on the Effective Date and shall continue (unless terminated
in accordance with the provisions of Clauses 13.2, 13.3, 13.4 or 21)
until the expiry of the period of three years from the date of
commencement of manufacture of the Product pursuant to Part III of
this Agreement following completion of the Programme.
13.2 (A) Termination by mutual agreement. Subject to Clause 13.5 below,
-------------------------------
this Agreement may be terminated by mutual agreement at any time
prior to completion of the Programme in the event that both
parties agree that the Programme is not technically feasible.
(B) Termination for technical non-feasibility. Subject to Clause 13.5
below, this Agreement may be terminated by either party on or
after 1 January 2001 if it has not been agreed that the Programme
is technically feasible in respect of the Product Specification,
quantity and timeframe.
13.3 Termination by RPI. Subject to Clause 13.5 below, RPI may terminate
------------------
this Agreement in the following ways:
(a) by [ * ] written notice to AVECIA if RPI is unable to, or
elects not to, pursue development of any of the Products;
(b) forthwith upon written notice if Avecia has been unable to
deliver the Product within [ * ] of the date for delivery
of such Product specified in the Delivery Schedule or, in
respect of the kilogramme of the Product
S-20
ordered under the Programme, on or before [ * ] for reasons
not relating to technical feasibility as referred to in
Clauses 13.2(A) and 13.2(B)
(c) forthwith if AVECIA is in breach of this Agreement (other
than under Clause 13.3(b) above) and AVECIA does not
rectify such breach within [ * ] of receipt of written
notice from RPI requiring rectification of the breach,
provided that it is intended that the parties will discuss
any alleged breach and its remediation as soon as it is
known; or
(d) forthwith upon written notice if AVECIA has a liquidator,
receiver, manager receiver or administrator appointed, or
ceases to continue trading or is unable to pay debts as
defined in Section 227 of the Insolvency Xxx 0000 (England
and Wales).
13.4 Termination by AVECIA. Subject to Clause 13.5 below, AVECIA may
---------------------
terminate this Agreement in the following ways:
(a) forthwith if RPI is in breach of this Agreement (other than
under Clause 13.3(b) above) and RPI does not rectify such
breach within [ * ] of receipt of written notice from
AVECIA requiring rectification of the breach, provided that
it is intended that the parties will discuss any alleged
breach and its remediation as soon as it is known; or
(b) forthwith upon written notice if RPI has a liquidator,
receiver, manager receiver or administrator appointed, or
ceases to continue trading or is unable to pay debts as
defined in Section 227 of the Insolvency Act 1986 (England
and Wales), or equivalent occurs in the USA or any other
jurisdiction in which RPI is incorporated or resident.
13.5 Consequences of Termination. Termination under Clauses 13.2 -
---------------------------
13.4 above shall have one or more of the following consequences
according to the table set out below:
A RPI shall pay to AVECIA all sums payable up to the date of
termination but not yet paid, together with all reasonable
costs already incurred by AVECIA at the date of termination
or costs incurred by AVECIA after termination which could
not reasonably be avoided.
B The parties shall agree upon a sum payable by RPI in
respect of work done by AVECIA under the Programme for
which monies have not yet become payable under Clause 3
above and in the absence of agreement upon such sum the
provisions of Clause 26 shall apply.
S-21
C Any moneys paid by RPI to AVECIA up to the date of
termination shall be non-refundable, subject to D below
where applicable.
D Termination of this Agreement prior to the commencement of
Stage 3 of the Programme can only take place if agreed by
the JRC. In such event, AVECIA shall reimburse to RPI
within 30 days of the date of termination, a proportion of
the [ * ]received from RPI under Clause 3(a) as follows:
(i) termination prior to completion of Stage 1 - [ * ]
(ii) termination between Stages 1 and 2 - [ * ]; or
(iii) termination between Stages 2 and 3 - [ * ]
E AVECIA shall grant to RPI or a Nominated Manufacturer (at
RPI's option), a royalty-free, non-exclusive world-wide
licence under AVECIA's Intellectual Property including any
AVECIA Invention arising under Clause 6.2(d) above
necessary for RPI or a Nominated Manufacturer (at RPI's
option) to manufacture Products identified for manufacture
under this Agreement Any such licence granted under this
Clause 13.5(E) shall expire at such time asa quantity of
Product is manufactured which fulfills the Product Minimum
requirement in Clause 7.1, plus any amount ordered by RPI
and accepted by AVECIA, and in this respect RPI will
provide, or procure its Nominated Manufacturer to provide,
all necessary manufacturing information and records to
Avecia:
F Any licence granted under Clauses 6.3, 9.1 or 9.2 shall
terminate.
G RPI shall purchase all quantities of Product ordered by RPI
and manufactured by AVECIA but not yet delivered to RPI,
including any quantity of Product held by AVECIA pursuant
to Clause 5.1(a), at the price agreed under Clause 7.2
above.
Termination Clauses and Consequences
Clause Consequences
------ ------------
Clause 13.2 A [ * ]
Clause 13.2B [ * ]
Clause 13.3 (a) [ * ]
Clause 13.3 (b) [ * ]
Clause 13.3 (c) [ * ]
Clause 13.3 (d) [ * ]
Clause 13.4 (a) [ * ]
Clause 13.4 (b) [ * ]
* In the event of termination under Clause 13.2 , the amount to
be paid to AVECIA shall not exceed [ * ]
S-22
** In the event of termination under Clause 13.2 only, the
amount to be repaid by AVECIA to RPI shall be limited to
[ * ] of the [ * ] received from RPI under Clause 3(a)
irrespective of the Stage in the Programme at which
termination takes effect.
*** In the event of termination under Clause 13.3(a) only, the
amount payable by RPI to AVECIA under Clause 13.5 A for costs
incurred by AVECIA after termination which could not
reasonably be avoided, shall not exceed [ * ]
13.6 Termination or expiry of this Agreement, for whatever reason,
shall not prejudice the acquired rights of either party.
13.7 For the avoidance of doubt, it shall not be considered a breach
of this Agreement if an objective of the Programme is not
achieved so long as AVECIA uses all reasonable commercial
endeavours to perform its obligations.
13.8 The provisions of Clauses 3, 6.2, 6.4, 6.5, 9, 11, 12, 13.7 - 26
shall survive the termination or expiry of this Agreement. In the
event that RPI or any Nominated Manufacturer breaches any of the
surviving clauses of this Agreement, any licence granted as a
result of the operation of consequence E under Clause 13.5 above
shall terminate.
14. Payment
-------
All amounts payable to AVECIA under this Agreement shall be paid in US
Dollars in accordance with the following details:-
[ * ]
S-23
15. Announcements And Publicity
---------------------------
15.1 Subject to Clause 15.2, the parties agree that neither of them
will make any official press release, announcement or other
formal publicity relating to the transactions which are the
subject of this Agreement, or any ancillary matter, including
without limitation use the name of the other in any form of
advertising or public promotion, without first obtaining in each
case the prior written consent of the other party (which consent
will not be unreasonably withheld), except as required by law.
15.2 The parties agree that any publication, abstract or patent
application resulting from this Agreement will be sent to the
other at least 60 days prior to filing or submission for prior
approval. The authorship on any publication and/or abstract will
be based on mutual agreement between the parties or as deemed
scientifically appropriate. A publication resulting from this
Agreementwill be delayed or prohibited if, in the reasonable
opinion of the other party, it will be necessary to delay or
prohibit such publication in order to file or procure patent
application or rights protection in respect of any invention or
discovery arising from this Agreement.Notwithstanding the
foregoing, AVECIA shall have no right to publish or disclose to a
third party, any information relating to the Products without the
prior written permission of RPIunless such information falls
within any of the exceptions in Clause 12.2.
16. Assignment and Transfer
-----------------------
16.1 This Agreement shall inure to the benefit of, and be binding
upon, the successors and assignees of the parties. This Agreement
may not be assigned or transferred by either of the parties
hereto without the prior written consent of the other, which will
not be unreasonably withheld; provided, however, that either
party may assign or transfer its rights and obligations under
this Agreement to an affiliate of that party or a successor to
all or substantially all of its assets or business relating to
this Agreement, whether by sale, merger, operation of law or
otherwise by giving written notice to the other party.
16.2 AVECIA may transfer this Agreement to any entity which AVECIA may
establish to undertake its contract manufacturing of Product,
provided that AVECIA owns or controls at least 50% of the voting
stock of such entity and such transfer is pre-approved by RPI.
17. Variation
---------
No variation or amendment of this Agreement shall bind either party unless
made in writing in the English language and agreed to in writing by duly
authorised officers of both parties.
S-24
18. Illegality
----------
If any provision of this Agreement is agreed by the parties to be illegal
void or unenforceable under any law that is applicable hereto or if any
court of competent jurisdiction in a final decision so determines, this
Agreement shall continue in force save that such provision shall be deemed
to be excised herefrom with effect from the date of such agreement or
decision or such earlier date as the parties may agree.
19. Waiver
------
A failure by either party hereto to exercise or enforce any rights
conferred upon it by this Agreement shall not be deemed to be a waiver of
any such rights or operate so as to bar the exercise or enforcement thereof
at any subsequent time or times.
20. Notices
-------
20.1 All notices, instructions and other communications given hereunder
or in connection herewith shall be in writing. Any such notice,
instruction or communication shall be sent either (i) by registered
or certified mail, return receipt requested, postage prepaid, or
(ii) via a reputable nationwide overnight courier service, in each
case to the address set forth below. Any such notice, instruction or
communication shall be deemed to have been delivered upon receipt.
If made to RPI, all notices shall be addressed to:
Ribozyme Pharmaceuticals, Inc.
0000 Xxxxxxxxxx Xxxxx
Xxxxxxx, XX 00000
Attention: Vice President Corporate Development
Tel: (000) 000-0000
Fax: (000) 000-0000
with a copy to:
Rothgerber, Xxxxxxx and Xxxxx
0000 00xx Xxxxxx, Xxxxx 0000
Xxxxxx, XX 00000
Attention: Xxxxxxx X. Xxxxx III, Esq.
Tel: (000) 000-0000
Fax: (000) 000-0000
If made to AVECIA, all notices shall be addressed to:
Avecia Limited
Xxxxxxx Xxxxx
Xxxxxxxx, Xxxxxxxxxx, X0 0XX
Attention: Vice-President, LifeScience Molecules
Business
S-25
Tel: 0000 000 0000
Fax: 0000 000 0000
with a copy to:
Legal Affairs Department
Avecia Limited
Hexagon House
Blackley, Manchester, M9 8ZS
Attention: Company Secretary
Tel: 0000 000 0000
Fax: 0000 000 0000
or, in each case, to such other address as may be specified in
writing to the other parties.
20.2 Any party may give any notice, instruction or communication in
connection with this Agreement using any other means (including
personal delivery, telecopy or ordinary mail), but no such notice,
instruction or communication shall be deemed to have been delivered
unless and until it is actually received by the party to whom it was
sent. Any party may change the address to which notices,
instructions or communications are to be delivered by giving the
other parties to this Agreement notice thereof in the manner set
forth in this Clause 20.
21. Force Majeure
-------------
Neither party shall be liable to the other party in any manner whatsoever
for any failure or delay in performing its obligations under this Agreement
if and to the extent, and for the duration, that such is due to force
majeure, which expression for the purposes of this Agreement means any
cause beyond the reasonable control of the party in question which for the
avoidance of doubt and without prejudice to the generality of the
foregoing shall include governmental actions, war, riots, civil commotion,
fire, flood, epidemic, labour disputes (excluding labour disputes involving
the work force or any part thereof of the party in question, restraints or
delays affecting shipping or carriers, inability or delay in obtaining
supplies of adequate or suitable materials and act of God. Without
prejudice to Clause 13.1, any said failure or delay shall not give either
party the right to terminate this Agreement except, and to the extent that
such force majeure continues for a period exceeding three months.
Termination as a result of Force Majeure shall give rise to consequences
[ * ] as set out in the table at Clause 13.5.
22. Good Faith and Duty to Mitigate
-------------------------------
22.1 Each of the parties shall at all times act in good faith in carrying
out the terms of this Agreement.
S-26
22.2 Each of the parties shall use all reasonable endeavours to mitigate
any costs, losses or expenses due to be incurred or suffered by the
other party in connection with the performance or non-performance of
this Agreement.
23. Further Assurances
------------------
At any time or from time to time on and after the Effective Date,
each of AVECIA and RPI shall at the request, cost and expense of
the other:
(a) deliver to the other such records, data or other documents
consistent with the provisions of this Agreement;
(b) execute, and deliver or cause to be delivered, all such
assignments, consents, documents or further instruments of
transfer or licence required by this Agreement; and
(c) take or cause to be taken all such other actions, as may
reasonably be deemed necessary or desirable in order to obtain
the full benefits of this Agreement and the transactions
contemplated hereby.
24. Maintenance of Records and Right to Inspect Manufacturing
---------------------------------------------------------
24.1 AVECIA agrees to maintain good records of sufficient detail to
allow the critical examination of all the data and the analysis
documentation in a form that is Food and Drug Administration
compliant (collectively, "Records"). Records, including those
associated with lots produced, must be kept and maintained
safely for at least two (2) years by AVECIA. Prior to disposal
of these Records, AVECIA agrees to give RPI the option of
transferring the Records and their use to RPI. If AVECIA is no
longer in the contract oligonucleotide synthesis business, then
RPI shall have the right to immediately obtain and use all
Records including the Drug Master File related to the
production of the Product covered by this Agreement.
24.2 Upon RPI's written request, AVECIA will allow RPI and/or its
Collaborator(s) to review its GMP processes and procedures as
such processes relate to bulk drug and the preparation of
Product. Such audit shall be subject to the confidentiality
provisions of Clause 12. Such reviews shall occur as soon as
reasonably practical. RPI and/or its Collaborator(s) shall have
the right to inspect all manufacturing and testing facilities
and operations (including third parties) to assure compliance
with GMP requirements and regulatory commitments. AVECIA will
assure compliance with regulatory commitments and will correct
any deficiencies prior to manufacturing of any Product
contemplated under this Agreement, subject to any provisions
set out in the Technical Agreement or any Quality Agreement.
AVECIA will promptly
S-27
notify RPI of any regulatory inspections and
inquiry/communications which involve a Product and give RPI an
opportunity to assist AVECIA in responding to any such
inquires.
25. Entire Agreement
----------------
25.1 This Agreement contains the entire agreement between the parties
and supersedes any previous agreements relating to this
Agreement and any understandings between the parties with
respect thereto, and may not be modified except by an instrument
in writing signed by the duly authorised representatives of the
parties.
25.2 In the event of any conflict between the Agreement and the
Schedules, then the former takes precedence .
26. Law and Jurisdiction
--------------------
26.1 This Agreement is governed by and shall be construed and
interpreted in accordance with the laws of the US State of
Delaware.
26.2 The parties shall meet as soon as possible to discuss and to
attempt to resolve all matters not specifically provided for in
this Agreement or in the constitution of the JRC and which
require a decision and all differences, disputes or
disagreements which may arise out of or in connection with this
Agreement or the JRC. If the parties are unable to resolve any
such matter or dispute then it shall be referred to the Vice-
President, Life Science Molecules business and the RPI Vice
President Corporate Development, who shall meet within thirty
(30) days of being requested to do so and shall in good faith
attempt to resolve the matter or dispute.
26.3 The parties agree to refer any matter or dispute which is not
able to be resolved pursuant to Clause 26.2 to the Centre for
Dispute Resolution ("CEDR") in London, England in an attempt to
settle the same in good faith by Alternative Dispute Resolution
("ADR"). The site for ADR shall be London, England, if initiated
by RPI and Boulder, Colorado, if initiated by Avecia.
26.4 Neither of the parties shall be deemed to be precluded from
taking such interim formal steps as may be considered necessary
to protect such party's position while the procedures referred
to in Clauses 26.2 and 26.3 are pursued.
26.5 In the event that the matter or dispute remains unresolved by
such ADR procedure within thirty days of commencement of such
procedure, then the parties shall be at liberty to take such
other proceedings (as defined below) as they think fit.
S-28
26.6 Except as provided for in Clauses 26.2, 26.3 and 26.4, in
relation to any legal action or proceedings to enforce this
Agreement or arising out of in connection with this Agreement
("proceedings") each of the parties irrevocably submits to the
exclusive jurisdiction of the Delaware Courts if initiated by
RPI and Denver Courts if initiated by Avecia .
27. Counterparts
------------
This Agreement may be executed in counterparts, each of which shall be
deemed an original, but all of which together shall constitute one and
the same instrument.
28. Independent Contractor
----------------------
Nothing in this Agreement shall create, or be deemed to create, a
partnership or the relationship of principal and agent or employer and
employee between the parties. Each party agrees to perform under this
Agreement solely as an independent contractor.
29. Representation by Counsel. The parties acknowledge that each of them
-------------------------
has been represented by counsel in connection with the negotiation and
drafting of this Agreement and that no rule of strict construction
should be applied to either of them as the drafter of all or any part
of this Agreement.
S-29
IN WITNESS whereof, the authorised representatives of the parties have executed
this Agreement on the date first above written.
SIGNED for and on behalf of AVECIA LIMITED
Signature .........................
Name .........................
Position .........................
SIGNED for and on behalf of RIBOZYME PHARMACEUTICALS INCORPORATED
Signature .........................
Name Xxxxx Xxxxxxx
Position Vice President, Corporate Development.
S-30
SCHEDULE 1
----------
The Programme
-------------
PROPOSAL
PROCESS SCALE UP and GMP MANUFACTURE of OLIGONUCLEOTIDE
Angiozyme
for
Ribozyme Pharmaceutical Inc.
Date Prepared: December 1999
Proposal No: PP.050 Version 3
Author: Xxxx X. Xxxxxxx, Commercial Development Manager
ABBREVIATIONS
If needed
S-1
CONTENTS
PAGE
1. Project Objective 4
2. Project Scope 4
3. Molecule Description 4
4. Project Plan 5
4.1 Technology Transfer of Process and Analytical Methods
4.2 Process Development - Deprotection and Purification scale up of Products
as determined by the JRC.
4.3 Preparation of GMP Manufacturing Documentation
4.4 Process Scale Up - GMP Manufacture of Kilo 1 mutually agreed
Product.
5. Summary Reports / Regulatory Submission 8
5.1 Preparation of Development Reports
5.2 of documentation
6. Packaging and Despatch 8
Appendix 1. Technology Transfer Plan including Oligo Pilot II production 9
Appendix 2. Provisional Product Specifications 10
Appendix 3. Development Quality Standard 11
Appendix 3.2 GMP Quality Standard 12
Appendix 4 Draft Quality Agreement 13
S-2
1. PROJECT OBJECTIVE
This proposal describes technology transfer, process development, process scale
up and manufacture of 1 kg of mutually agreed product.
The data generated from the technology transfer and scale up program is meant to
provide a degree of assurance that the process detailed in the Batch
Manufacturing Instructions will produce product suitable for use in clinical
trials.
The sequence of the oligonucleotide is described below.
2. PROJECT SCOPE
The project will consist of five stages:
* Technology Transfer of Process and Analytical Methods
* Process Development - Deprotection and Purification scale up of the ribozyme
* products as determined by the JRC
* Preparation of GMP Manufacture Documentation
* Process Scale Up - GMP Manufacture of Kilo 1 of a mutually agreed product
Prior to the start of the project and bi-weekly following initiation, a joint
review committee(JRC) composed of members from RPI and Avecia LSM will meet. A
full review of all work completed will be presented, the project plan and
specifications reviewed, and project progression agreed.
Throughout the project any changes made to the work detailed in the proposal
will be jointly agreed with RPI, managed and documented in accordance with
Avecia LSM's project management procedures.
Stability studies are not currently within the scope of this project. If
required they will be the subject of a separate quotation.
3. MOLECULE DESCRIPTION:
The oligonucleotide product is classified as Active Pharmaceutical Ingredient
"Ribozyme Sequence in Here"
Provisional Specifications listed in Appendix 2.
4. PROJECT PLAN
4.1 TECHNOLOGY TRANSFER OF PROCESS AND ANALYTICAL METHODS
RPI has generated experience in the manufacture of ribozymes and it is
recognised that this knowledge must be transferred to Avecia LSM manufacturing
personnel in order for the supply of products to commence. A Technology
transfer plan/agreement will be agreed. This document will detail the
activities, information requirement, success criteria and timetable for
technology transfer of the manufacturing process and the analytical methods.
It is anticipated that RPI will provide Avecia with the following information:
* Raw material suppliers, specifications and testing procedures
* RPI and [ * ] Process description and process equipment specifications
* Details of in-process tests and specifications
* Toxicological information on the oligonucleotide
* Analytical Methods(final product and intermediates) and supporting
documentation(reagent requirements, equipment etc.)
* Reference samples
S-3
The Technology Transfer project will be conducted in four phases:
* Information transfer and definition of Initial process
* Analytical methods technical transfer at Avecia LSM
* Oligo Pilot II production of development material at Avecia LSM, utilising
RPI's current process parameters
* Technical clearance to manufacture
--------------------------------------------------------------------------------
Time Requirement [ * ]
--------------------------------------------------------------------------------
Quality Standard Development (Appendix 3)
--------------------------------------------------------------------------------
Facility Multi Use Development Facility-Grangemouth
--------------------------------------------------------------------------------
4.2 PROCESS DEVELOPMENT - DEPROTECTION AND PURIFICATION
SCALE UP OF THE PRODUCTS AS DETERMINED BY THE JRC.
Deprotection
The aim of this stage is to evaluate the deprotection process and provide a
recommended route for the large scale GMP manufacture in the form of a Process
Description.
The Deprotection process development will start with a full review and analysis
of samples and records generated during the technology transfer stage.
Conditions will be defined which provide material of the appropriate purity in a
reproducible manner.
During large scale manufacture there will be opportunities to further
investigate the cleavage mixture, time course and reaction temperature.
Purification
The aim of this stage is to evaluate the purification process and provide a
recommended route for the large scale GMP manufacture in the form of a Process
Description.
The Purification process development will start with a full review and analysis
of samples and records generated during the technology transfer stage.
Procedures to ensure consistent column loading will be defined. Chromatography
gradient and flow rate will be further investigated.
Samples obtained from the OPII production runs at Avecia LSM will be utilised
to gain full understanding of the purification parameters. The material will be
loaded on small scale Biotage rig, with a view of extrapolating the data to the
large scale Biotage rig in the Grangemouth Pharmaceutical Manufacturing
Facility.
These investigations will have the following objectives:
* Define procedures to ensure consistent column loading
* Investigate the impact of variation in column gradient and flow rate
* investigate impact of increased column loading, with a view to increasing
throughput
--------------------------------------------------------------------------------
Time Requirement [ * ]
--------------------------------------------------------------------------------
Quality Standard Development (Appendix 3)
--------------------------------------------------------------------------------
Facility Multi Use Development Facility-Grangemouth
--------------------------------------------------------------------------------
S-4
4.3 PREPARATION OF GMP BATCH MANUFACTURING
DOCUMENTATION
Product specific Process Instructions (provisional Batch Manufacturing
Instructions) for oligonucleotide product will be written based on the work
carried out during the scale up studies.
--------------------------------------------------------------------------------
Time Requirement [ * ]
--------------------------------------------------------------------------------
4.4 PROCESS SCALE UP - GMP MANUFACTURE OF KILO 1 MUTUALLY AGREED PRODUCT.
Avecia LSM will carry out the GMP manufacture of mutually agreed Product at the
range of [ * ] on the Oligo Process. The objective of the scale up program
is to demonstrate the process described in the process description produces
material of the required quality and specification.
Avecia LSM will manufacture the scale up batches to the agreed specification
using the Process instructions, material generated from this stage will be
suitable for use in toxicology and human clinical trials.
Avecia LSM will manufacture 1kg oligonucleotide to the agreed specification
following the Process Instructions and documented analytical methods.
The manufacture program following oligonucleotide assembly will proceed only if
there is agreement by the joint review committee that the process for
deprotection and purification, as detailed in the process instructions, can
operate efficiently at scales above [ * ]. If it is deemed that this
process is insufficient to produce the quality and quantity of oligonucleotide
product RPI require, than the decision will be made to continue scale up
development work.
Note: Further development may be required in the GMP phase, this work will be
documented and all changes subject to QA approval.
The Oligonucleotide will be supplied in a form agreed upon by both parties.
A Certificate of Analysis will be supplied.
Avecia LSM will retain a sample of product (exact amount to be agreed) for use
as retention material and in further analytical studies.
--------------------------------------------------------------------------------
Time Requirement [ * ]
--------------------------------------------------------------------------------
Quality Standard GMP (Appendix 3.2)
--------------------------------------------------------------------------------
Facility Pharmaceutical Manufacturing Facility-Grangemouth
--------------------------------------------------------------------------------
5. SUMMARY REPORTS / REGULATORY SUBMISSION
5.1 Preparation of Development Reports
Avecia LSM will compile interim reports at each stage of the process development
programme and following GMP manufacture.
The reports will be retained in the Avecia LSM QA Archives.
--------------------------------------------------------------------------------
Time Requirement Within [ * ] weeks of each stage completion
--------------------------------------------------------------------------------
S-5
5.2 Preparation of Documentation
If required Avecia LSM will provide information to support RPI's regulatory
submissions.
--------------------------------------------------------------------------------
Time Requirement [ * ]
--------------------------------------------------------------------------------
6. PACKAGING AND DESPATCH
Specification of primary packaging of the oligonucleotide to be agreed.
7. COSTING
8. TIMELINES
S-6
SCHEDULE 2
----------
Joint Review Committee (JRC)
----------------------------
1. Purpose
-------
1.1 The purpose of the JRC is to be responsible for co-ordinating and
supervising the implementation of the Programme.
1.2 The JRC is to assist in ensuring that lines of communications are
established and maintained between the parties and to this end shall be
responsible for nominating a representative in both parties who shall be
the main but not sole point of contact for the other party.
1.3 It shall be the responsibility of the JRC to circulate copies of all
reports and information that it receives from one party to the other
without delay.
1.4 The JRC is to be the primary arena for the settlement of any disagreements
between the parties relating to the interpretation and implementation of
the Programme.
2. Period of Existence
-------------------
The JRC shall remain in being until whichever is the earlier of the
completion of the Programme or the termination of the Agreement.
3. Membership
----------
3.1 The JRC shall have four members including the Chairman. Two members
including the Chairman shall be appointed in writing by AVECIA and two
members shall be appointed in writing by RPI.
3.2 It is envisaged that the members of the JRC appointed by each party shall
vary with regard to their particular disciplines dependent on the
particular stage reached in the Programme. Either party may invite further
representatives with appropriate skills to attend meetings of the JRC in a
non-voting capacity.
3.3 Either party may at any stage change a representative member on the JRC by
giving written notice of such change to the other party.
4. Meetings
--------
4.1 The initial meeting of the JRC shall take place within the period of sixty
(60) days following the date of this Agreement at AVECIA Grangemouth,
Scotland or RPI, Boulder.
4.2 Subsequent meetings of the JRC shall be held every two (2) months
alternating between Boulder, and Grangemouth, Scotland if not otherwise
agreed by the JRC.
4.3 If for any reason following the agreement of the Programme either party
wishes a meeting of the JRC to be held between the regular two (2) monthly
meetings, it may arrange such meeting on giving at least fifteen (15) days'
notice in writing to the other party, such meeting shall be held at the
offices of the party not requesting the meeting.
5. Procedure at Meetings
---------------------
5.1 The Chairman of the JRC shall be responsible for preparing and circulating
an agenda for any meeting of the JRC at least ten (10) days prior to the
meeting (which agenda shall include any item considered important by either
party) and appointing a secretary for such meeting, who need not be a
representative member of the Committee, who shall be responsible for the
preparation and circulation of minutes of the meeting within thirty (30)
days of the conclusion of such meeting.
S-7
5.2 Any resolution put to the JRC must, to be passed, be accepted by at least
three (3) members of the JRC present in person.
5.3 Each representative of the JRC shall have one vote. The Chairman shall not
have a second or casting vote.
5.4 Any dispute which cannot be resolved by the JRC shall so far as it comes
within the ambit of section 1.4 above be dealt with according to the
provisions of such section, any other dispute shall be dealt with in
accordance with clause 26 of the Agreement.
6. Amendment to JRC Constitution
-----------------------------
6.1 The JRC may amend its rules set out herein provided that a resolution
amending such rules is circulated in writing thirty (30) days prior to the
meeting and such resolution is passed in accordance with Section 5.2.
S-8
SCHEDULE 3
----------
Quality Agreement
-----------------
Draft QA Agreement
The attached agreement is a draft template which has yet to be discussed with
RPI's QA representatives. It's format and content may change as a result of
these discussions. It is included as part of this proposal to define the set of
assumptions that have been made in the preparation of this proposal.
S-9
Avecia LSM
Quality Assurance Agreement between Avecia LSM and RPI for the Technology
Transfer and Manufacture of Angiozyme
Issued By: _____________________________________________
Avecia LSM QA Manager
Approved By: ______________________________________________
RPI Manufacturing Director
Approved By: ______________________________________________
RPI QA Director
Approved By: ______________________________________________
Avecia Grangemouth Works QA Manager
Approved By: ______________________________________________
Avecia LSM Commercial Manager
Revision Summary
S-10
Contents
1. Introduction
2. Background information on Angiozyme
3. Responsible personnel
4. Communication
5. Technology Transfer
6. Quality Assurance
7. Purchasing, supply and testing of raw materials and packaging
8. Manufacturing Facility
9. Manufacture
10. Sampling, testing and release of bulk active pharmaceutical ingredient
11. Control and supply of samples
12. Transport and Distribution
13. Complaints and recall
14. Safety, Health and Environment
15. Stability
16. Validation
17. Subcontracting
18. Deviations and Change Control
19. Documentation and Archiving
20. Regulatory
S-11
1. Introduction
The purpose of this agreement is to ensure that the responsibilities of RPI
and Avecia LifeScience Molecules in the Technology Transfer and subsequent
manufacture of Angiozyme are clearly defined. This is to ensure that
misunderstandings are avoided, which could lead to a product or work of
unsatisfactory quality.
The agreement will address the following:-
* Roles and responsibilities in ensuring that Avecia LSM complies with cGMP
and other relevant legislation.
* Responsibility for the release of Angiozyme active pharmaceutical
ingredient for further processing for use in humans.
* Agreement on access to Avecia LSM facilities for RPI's personnel.
* Arrangements for changes or amendments to aspects of this agreement.
Channels of communication.
* Supply of relevant information following a regulatory inspection, which
may impact on the continued supply of the product.
The agreement addresses the initial issues surrounding the technology
transfer of RPI's manufacturing process to Avecia LSM and then focuses on
the Quality Assurance issues surrounding the ongoing supply of Angiozyme to
GMP for human use.
2. Background information on Angiozyme
Angiozyme is a........
It will be supplied to RPI as a powder in bulk form and subsequently
formulated under the control of RPI.
It is currently in Phase .. clinical trials for the treatment of ..........
As the drug product progresses through clinical trials, it is the
responsibility of RPI to inform Avecia LSM and to initiate a joint review of
the contents of this technical agreement, to ensure that the quality
standards described within it still meet the requirements of the regulators.
Responsible Personnel
S-12
XXX Avecia
Commercial [ * ]
Technology Manager [ * ] [ * ]
Manufacturing Technology [ * ]
Transfer
Production [ * ]
Analytical Technology Transfer [ * ]
Analytical [ * ]
Quality Assurance [ * ] [ * ]
[ * ]
Facility and Plant Commissioning
[ * ]
Safety, Health and Environment
Regulatory [ * ] [ * ]
Document Controller [ * ] [ * ]
4. Communication
S-13
The commercial representatives of each company will be informed of supply or
receipt of documents and of the occurrence of meetings or visits.
4.1 Documents
The document control representatives from each company will be responsible
for the supply or receipt of documents.
All inter-company document transfers will be logged.
The document controller in receipt of a document will formally acknowledge
receipt.
The document controller shall maintain a centralised archive of all
documents received, with copies disseminated to appropriate team members in
a controlled manner.
All documents will be numbered and, if appropriate, version controlled.
The document controller will be responsible for recalling documents that
have been replaced with new versions.
4.2 Review meetings
Meetings should be held between functional nominees as appropriate to ensure
smooth transfer of information and progress on actions.
5. Technology Transfer
The manufacturing and analytical Technology transfer activities associated
with this project are covered in more detail in the following documents:-
Manufacturing Technology Transfer Plan for Angiozyme
Analytical Technology Transfer Plan for Angiozyme
These activities will follow the general framework outlined below:-
5.1 Initiation
Agree aims of the Technology transfer and the criteria for successful
transfer.
Identify information required from each side prior to initial manufacture.
Establish review milestones to ensure transfer is proceeding smoothly.
5.2 Initial Manufacture
Agree Technical support arrangements between RPI and Avecia LSM.
5.3 Validation
S-14
Establish responsibilities for all aspects of validation. See also section
17. below.
5.4 Completion
Agree documents required and who approves against pre-agreed objectives.
6. Quality Assurance
Avecia shall manufacture Angiozyme to the best of its knowledge in
compliance with GMP as detailed in the 'Guidance for Industry;
Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients'
Draft Guidance, March 1998, published by the FDA.
RPI shall confirm their satisfaction with the compliance level applied by
Avecia LSM at audit.
Findings from audit(s) will be communicated in writing to Avecia LSM and any
corrective actions mutually agreed between representatives from the 2
companies. In the event of a difference in interpretation of the required
quality standard, the view taken by RPI will be accepted by Avecia, provided
this standard is not below that recommended by Avecia. If it is a
significantly higher standard than recommended by Avecia, then the 2 parties
will meet and agree by negotiation how the situation should be managed.
7. Purchasing, supply and testing of raw materials and packaging
RPI will provide Avecia LSM with a materials listing for the manufacture of
Angiozyme, together with purchasing specifications. RPI will inform Avecia
of any changes in these specifications as they occur.
Avecia LSM will purchase materials to the specifications provided by RPI.
RPI will specify the suppliers for the critical raw materials (amidites and
CPG) in agreement with Avecia. Avecia will be responsible for selecting its
own suppliers for non-critical reagents. Avecia LSM will take responsibility
for all testing and clearance of raw materials used in the manufacture of
Angiozyme, on completion of the technology transfer of appropriate test
methods from RPI.
RPI shall confirm the suitability of Avecia's vendor certification and raw
material testing and sampling procedures at audit.
8. Manufacturing Facility
Avecia LSM and RPI will jointly conduct a risk assessment of any differences
between the Avecia and RPI manufacturing facilities and how they are
operated.
S-15
The process will be operated under class 100,000 conditions, with additional
protection provided for the later stages of the process, which may be
especially vulnerable to microbial contamination. Details of this additional
protection will be jointly discussed and agreed between representatives of
the 2 companies.
[ * ]
The facility and equipment will be qualified and cleaned prior to initial
manufacture in accordance with Avecia's procedures.
RPI will audit the manufacturing facility, equipment and supporting
documentation prior to initial manufacture to assess their suitability for
use.
Findings from the audit will be communicated to Avecia in writing and any
corrective actions mutually agreed.
9. Manufacturing
The manufacturing process will be the subject of a formal Technology
transfer programme between RPI and Avecia (see section 5 above)
RPI will provide Avecia with full details of the existing manufacturing
process, including, in process tests and specifications for both the
intermediates and the active pharmaceutical ingredient (if available)
Avecia will establish the existing process in the development laboratories
in PTD and then conduct an experimental program to scale the process up for
transfer to the manufacturing facility within Grangemouth Works. RPI will be
kept fully informed of the experimental program and of any proposed
modifications to the process, which will be approved by representatives from
both companies.
Avecia will prepare formal process instructions for manufacture to the
scaled up process. RPI Technical and QA representatives will review this
documentation and any comments shall be incorporated by Avecia.
All specifications will be formally accepted and agreed between RPI and
Avecia personnel and subject to change control.
In addition to the documents described above, RPI shall either provide the
following, or pre-approve proposals from Avecia LSM:-
Format and content of the Certificate of analysis
S-16
Labelling requirements
Definition of a batch
Lot or batch numbering system
Sampling plans
Sampling methods
10. Sampling, testing and release of active pharmaceutical ingredient
On completion of the formal technology transfer of the analytical release
methods for Angiozyme active ingredient, Avecia LSM will take responsibility
for the release of this product for further processing for human use. RPI
will conduct some repeat verification testing, this will be pre-agreed with
Avecia.
QA release will involve the QC release testing of the active ingredient,
together with a complete review of all batch documentation by Avecia
Grangemouth Works QA.
RPI will review the Avecia test procedures, to ensure that there are no
errors in the translation from RPI documentation.
RPI will be responsible for the validation of all the release test methods
and will ensure any repeat validation considered appropriate on transfer to
Avecia's analytical sites is prescribed as part of the Analytical Technology
Transfer protocol.
RPI will initially provide any necessary analytical reference standards,
together with their characterisation data. This may be reviewed at a future
date, as it becomes necessary to qualify further reference standards.
RPI will audit Avecia's laboratories to assess their suitability for use.
Audit observations will be communicated in writing to Avecia LSM and
corrective actions mutually agreed.
RPI will be responsible for specifying packaging and shipping conditions
which have been demonstrated to preserve the product's quality and integrity
during transport.
11. Control and Supply of Samples
Avecia will take and retain samples of Angiozyme in accordance with sampling
plans pre-agreed between RPI and Avecia QA representatives. As a minimum,
Avecia LSM will retain sufficient material from each batch to allow full
repeat testing at least twice.
Retention samples will be retained for at least one year after the
expiration date of the batch, or, if Angiozyme has a defined retest period,
for 3 years after the batch is distributed. Retention samples will be
packaged and stored under conditions prescribed by RPI.
S-17
RPI will provide details of any sample requirements for shipment to their
premises, prior to manufacture of the batch concerned. This is to ensure
material is manufactured at the appropriate scale to cover sample
requirements and that arrangements for sampling can be made in a timely
manner.
Responsibility for analytical reference standards is covered in section 10
above.
12. Transport and Distribution
RPI will provide Avecia LSM with formal specifications for packaging and
shipping of Angiozyme.
Avecia LSM will be responsible for ensuring the requirements of these
specifications are met.
On departure from Avecia's Grangemouth site, responsibility for the API
passes to RPI.
13. Complaints and Recall
Any complaints from RPI to Avecia LSM should be directed to the Avecia LSM
commercial representative, who will then be responsible for informing the
Avecia LSM QA representative. The Avecia LSM QA representative will assemble
a team to address the complaint and, if appropriate, carry out an
investigation. The complaint will be handled in accordance with the Avecia's
quality procedures.
Avecia shall be responsible for advising RPI immediately of any systematic
failure discovered which may cast doubt on reliability of previous
manufacture or analysis. Communication in such situations will be involve
the Commercial and QA representatives from Avecia LSM and the QA
representative at RPI. RPI will be responsible for the implementation of any
decision they might take to recall the product as a result.
14. Safety, Health and Environment
Avecia will take responsibility for ensuring that the facilities, procedures
and equipment used for manufacture are designed and operated in accordance
with relevant legislation.
RPI will be responsible for all toxicological and Eco-tox data required for
the product to gain appropriate registration for manufacture, shipment and
use within the USA and Europe.
Avecia and RPI shall advise each other of any events that give raise to
concerns about the safety profile of the process.
S-18
Avecia shall take responsibility for all on site incidents and will advise
RPI of all significant events that may have an impact on product
manufacturing rate, economics, safety profile or product quality.
RPI is responsible for the API on its departure from Avecia's Grangemouth
site.
15. Stability
RPI will take responsibility for all stability studies relating to Angiozyme
active pharmaceutical ingredient and will provide Avecia LSM with the
details of appropriate storage conditions to maintain its quality and
integrity.
RPI will provide Avecia LSM with information to allow Avecia LSM to assign
an expiry or retest date to material manufactured at Avecia LSM.
16. Validation
Avecia LSM will take responsibility for the qualification of the facilities
and equipment used in the manufacture of Angiozyme at Avecia Grangemouth
Works. RPI will audit this qualification activity.
RPI is responsible for the validation of all analytical test methods used
for the release of raw materials and in in-process testing and release of
the final active pharmaceutical ingredient.
Angiozyme is currently in Phase 1 clinical trials. As the drug moves to
later stage clinical trials RPI and Avecia LSM will discuss and agree
responsibilities for further process or analytical development and process
validation activities.
17. Subcontracting
Avecia LSM will not subcontract any activity associated with the
manufacture of Angiozyme without prior notification and approval from RPI.
Avecia LSM will take responsibility for the certification of all
subcontractors to the required regulatory standards.
Avecia LSM will make any appropriate audit reports available to RPI on
request.
18. Deviations and Change Control
S-19
QA representatives from RPI, Avecia Grangemouth Works and Avecia LSM shall
meet and agree a shared understanding of the definitions of changes and
deviations. Discussion will cover what changes are considered significant
and would require prior approval by RPI and similarly for deviations, what
would be considered significant and require notification of RPI.
Any significant change proposed by either RPI or Avecia shall be
communicated in writing via the QA representatives in each organisation. The
change will then be considered by a team of representatives from the
appropriate departments, in accordance with local change control procedures.
If appropriate a formal programme of work will be proposed and formally
agreed by representatives from each company.
Deviations will be handled through Avecia Grangemouth Works Deviation and
non-conformance procedure.
19. Documentation and Archiving
Avecia LSM will be responsible for the retention and storage of all batch
documentation in a secure QA archive. Documentation will be stored for a
minimum of ( whichever of those listed below is the longest):-
a) The term of the commercial agreement.
b) Five years after the expiry date of the batch manufactured.
RPI personnel may audit the batch documentation on request, given reasonable
notice.
Copies of the master batch records will be made available to RPI on request.
20. Regulatory
Avecia LSM will provide RPI with appropriate CMC information in support of
regulatory submissions.
The format and content of this information will be pre-agreed by
representatives from Avecia LSM and RPI's QA/Regulatory functions.
RPI will be responsible for submitting this information to the regulators as
part of their regulatory submission, but will allow Avecia LSM QA function
to review the information concerning Avecia prior to submission, to ensure
there are no errors in transcription which may result in Avecia being
misrepresented.
RPI will be responsible for requesting information from Avecia LSM
QA/Regulatory function as appropriate e.g. for annual updates.
S-20
Avecia LSM QA representative will be responsible for informing RPI of
proposed changes to any activity associated with the manufacture of
Angiozyme, prior to implementation, to ensure that its regulatory impact can
be assessed and any necessary action agreed.
Avecia LSM will inform RPI of any corrective actions from a regulatory
inspection that may have an impact on the continued supply of Angiozyme.
S-21
SCHEDULE 4
----------
Avecia LifeScience Molecules
DNA Medicines
Technology Transfer Plan
Manufacture of Angiozyme
at
Grangemouth Works
December 1999
_______________________________________________________________________________
Issued By:______________________________________ Date:_____________________
(Business Operations Manager)
_______________________________________________________________________________
Approved By:___________________________________ Date:_____________________
(Quality Assurance)
_______________________________________________________________________________
S-22
CONTENTS
SECTION PAGE NO.
1 Introduction..................................................... 3
2 Aims............................................................. 3
3 Initiation....................................................... 4
4 Project Nominees................................................. 5
5 Communication.................................................... 6
5.1 Documentation............................................... 6
5.2 Reviews.....................................................
6 Information Transfer............................................. 6
7 Initial manufacture.............................................. 7
7.1 Commissioning support....................................... 7
7.2 Initial manufacture......................................... 7
7.3 Change control.............................................. 7
8.1 Technology transfer completion................................... 8
8.1 Criteria for successful technology transfer.................
8.2 Technology transfer review and sign-off.....................
8.3 Post technology transfer....................................
9 Appendices 9
Appendix I: Flow chart for technical transfer
Appendix II: Timetable for RPI Technology Transfer Plan
Appendix III Information required from RPI
Appendix IV: Information required form Avecia
Appendix V : Information required to complete technology transfer
Appendix VI: Technology transfer acceptance document
S-23
1 INTRODUCTION
This plan details the mechanism by which the RPI Angiozyme process will be
technology transferred between RPI and LifeScience Molecules Grangemouth
Works and sets out the activities, information required and timetable in
order to successfully complete the technology transfer exercise.
A well managed technology transfer is key to the establishment of a
manufacturing process which is consistent in operation and generates
Angiozyme of equivalent quality to that manufactured by RPI.
Material provided by LSM in Grangemouth will be used in a process
registered in the United States and the rest of the world. As such:
technology transfer, commissioning, validation and change control must be
undertaken to ensure that material produced in the Campaign is equivalent
to material produced by RPI for submissions to the FDA.
The material produced by this manufacture will be used for: Phase ()
Clinical Trials
Technology transfer will be conducted in three phases:
Initiation: Identification of responsible personnel
agreement on information to be transferred (protocol)
transfer of information
Commissioning: Pre manufacture Technical Transfer review
Initial manufacture
Note: The pre manufacturing technical transfer review must include
agreement of and actions to minimise the risks that may result from the
differences between the facilities at RPI and that at Grangemouth
Completion: Post manufacturing review of success of technology
transfer Sign -off of Technology transfer protocol
A flow chart outlining the process is attached as Appendix I
It is intended that sign-off will take place following the initial
campaign, subject to successfully meeting the required standards and
criteria.
2 AIMS
The purpose of technology transfer is to supply technical expertise and
associated information to enable Avecia Life Science Molecules, Grangemouth
facility, to successfully undertake manufacture of RPI Angiozyme in light
of the fact that the LSM and RPI facilities are not identical.
The agreed timetable is detailed in Appendix II.
The critical success factors for successful transfer are as follows:
. Avecia Life Science Molecules, Grangemouth Works will manufacture an
initial quantity of Angiozyme by the end of [ *. ] Future
manufacture may be carried out following the initial Campaign.
. The Grangemouth Works manufacturing process will be specified by the
current RPI process. Processing will be carried out within the scope
of the pre-determined parameters.
. An established change control mechanism should be used for any changes.
S-24
. The quality of the Angiozyme supplied by Avecia Life Science Molecules
Grangemouth Works must be within specification and typical of
manufacture from RPI.
. Technology transfer, plant operation, processing and cleaning will be
carried out to Grangemouth Works Quality standards.
3 INITIATION
Technology transfer of RPI Angiozyme will be formally initiated in [ *. ]
Functional nominees are identified below and a checklist of relevant
documents is given in Appendices III and IV.
4 PROJECT NOMINEES
-------------------------------------------------------------------------------
FUNCTION RPI CONTACT No LSM CONTACT No
-------------------------------------------------------------------------------
Technology Transfer Leader [ * ] [ * ] [ * ] [ * ]
-------------------------------------------------------------------------------
Chemistry [ * ] [ * ] [ * ] [ *-]
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Process Engineering [ * ] [ * ] [ * ] [ * ]
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Quality Assurance [ * ] [ * ] [ * ] [ * ]
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Engineering [ * ] [ * ] [ * ] [ * ]
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Analytical Methods and [ * ] [ * ] [ * ] [ * ]
Specifications
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Safety, Health and Environment [ * ] [ * ] [ * ] [ * ]
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Manufacture and waste disposal [ * ] [ * ] [ * ] [ * ]
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Raw Materials and purchasing [ * ] [ * ] [ * ] [ * ]
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5 COMMUNICATION
5.1 DOCUMENTATION
The Technology transfer managers on each site will be formally responsible
for ensuring document issue and control.
All documents must be numbered and where appropriate version controlled
The transfer of all documents will must be done within a change control
system
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A copy of all documents outlined in Appendices III and IV (information
required before commissioning) and Appendix V (information required before
technology transfer completion) must be supplied via the QA
representatives. This data will form the basis of the respective sites
technology transfer documentation.
5.2 REVIEWS
Meetings should be held between functional nominees as appropriate to
ensure complete transfer of information and progress on actions.
A formal pre-commissioning review will take place to ensure information
transfer is complete and that all relevant information has been
incorporated into Grangemouth Works systems.
Performance of the initial manufacture should be reviewed and documented as
early as possible after the campaign.
Following completion of the Campaign a technology transfer review will be
held prior to sign-off to ensure documentation is complete and
satisfactory.
6 INFORMATION TRANSFER
Information requirements from RPI and LifeScience Molecules are specified
in Appendices III and IV.
This data must be in place prior to the start of manufacture.
Key Elements:
Process guide and reporting ranges.
Quality Assurance.
Plant cleaning
Control of change
Analytical methods, standards and specifications
Raw material sources and specifications
Safety, Health and Environmental data
Hazard data sheets
Process Waste Streams
Pre commissioning review: Approval to manufacture
7 INITIAL MANUFACTURE
7.1 COMMISSIONING SUPPORT
Prior to commissioning, the arrangement for technical support between RPI
and LifeScience Molecules will be agreed.
Visits to each site of relevant staff of each discipline in preparation for
manufacture will be encouraged. This will include the requirements for
technical and analytical support from RPI
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Throughout the technical transfer process progress will be monitored via a
steering committee which will include
[ * ]
7.2 Initial Manufacture
A project Plan should be prepared for the plant before commissioning. The
following issues should be addressed:
. Engineering Validation including Installation and Operational
Qualifications carried out by LifeScience Molecules.
. Cleaning - Demonstration of appropriate levels of cleaning, between
different materials manufactured in the facilities and the manufacture
of RPI Angiozyme will be carried out to current Grangemouth Works
systems.
. Analytical technical transfer plan
. Training of Avecia personnel by RPI including recording of any training
received
7.3 CHANGE CONTROL
An agreed procedure will be issued defining requirements for change
control.
During Technology Transfer the starting point for Change Control will be
defined as the information supplied by RPI to define the technology.
Amendments to the RPI technology should be covered by the Grangemouth Works
change control procedure and should not be adopted without prior
authorisation from RPI.
8 TECHNOLOGY TRANSFER COMPLETION
On completion of Technology Transfer responsibility will pass to
Grangemouth Works to control change independently.
Elements that cannot be changed without prior authorisation should be
identified as part of the technology transfer completion review.
8.1 CRITERIA FOR SUCCESSFUL TECHNOLOGY TRANSFER
A number of criteria are outlined below which must be met before technology
transfer can be formally completed.
8.1.1 Process
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. Demonstrate that specified processing parameters can be operated to and
that product, which meets specification, typical of material produced
in RPI, can be manufactured.
. Demonstrate operation of an effective mechanism for control of change
opposite process technology.
. Demonstrate the ability to operate the process at the required capacity
and operational quality.
8.1.2 Raw Materials
. Demonstrate that a secure supply of raw materials and starting material
from agreed suppliers has been established.
. Demonstrate control of change procedure for raw material supplies.
8.1.3 Waste Streams
. Demonstrate that a secure suitable waste disposal routes has been
established.
8.1.4 Analytical and Specifications
. Demonstrate a complete implementation of technology.
. Demonstrate satisfactory operation of the transferred methods before
data is used for batch release.
. Operate an effective mechanism for control of change of analytical
technology.
8.1.5 Safety, Health & Environment
. Demonstrate that adequate hygiene procedures and practices are in place
to ensure that manufacture of Angiozyme does not result in adverse
occupational health effects.
. Demonstrate that adequate precautions are built into plant design and
layout and procedures to ensure the safe operation of the process.
. Demonstrate adequate environmental protection measures and secure
authorisation from relevant pollution inspectorate.
8.1.6 Regulatory Compliance
. Demonstrate that the process can be operated satisfactorily to cGMP.
. Demonstrate compliance with the agreed manufacturing process,
analytical methods and specifications.
8.1.7 Engineering
. Demonstrate that the plant has been built and validated to the
appropriate regulatory standard.
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8.2 TECHNOLOGY TRANSFER REVIEW AND SIGN-OFF
Following the initial manufacturing campaign there will be a review to
define whether the critical success factors listed in 8.1 have been met.
The review will comprise the preparation and approval of documents
(appendix V) and a meeting to agree a list of any outstanding actions.
In the event of Grangemouth Works conducting a second or subsequent
campaign of Angiozyme prior to sign-off of technology transfer a written
plan will be agreed between RPI and Grangemouth Works covering outstanding
issues.
After a final review to confirm that technology transfer has been
successfully concluded then the Technology Transfer Completion Document
will be issued for authorisation.
Completion is targeted for end of November 2000.
8.3 POST TECHNOLOGY TRANSFER
As part of technology transfer sign off a plan will be agreed in the event
of any future manufacturing campaigns. Routes of communications between
the two sites will be clearly identified emphasising the need for
continuity. A technical manager will be nominated from each site to act as
first line contacts for transfer of information.
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APPENDIX I
[FLOOR PLAN APPEARS HERE]
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APPENDIX II
Timetable for Angiozyme Technology Transfer Plan: Target Dates
Initiation of Technology Transfer [ * ]
Technology Transfer Plan Preparation [ * ]
Information Transfer [ * ]
Pre-commissioning Review
Commissioning/ Initial Manufacture
Equivalence Testing
Completion Review and Audit
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APPENDIX III
Information Required From RPI
1 PROCESS
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Information RPI Avecia Target Completion
Responsible Responsible Date Date
person Person
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1.1 Process Guide for Angiozyme in [ * ] [ * ]o
controlled format
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1.2 RPI approval that Avecia materials of [ * ] [ * ]
construction are suitable for
manufacture of Angiozyme
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1.3 Report of any know critical parameters [ * ] [ * ]
associated with the process (synthesis,
cleavage/deprotection, purification ,UF,
Lyophilisation) which may impacts on
the quality of final product
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1.4 Environmental Control standards: [ * ] [ * ]
Confirmation that LSM standards for
control of the manufacturing
environment are adequate for the
manufacture of Angiozyme
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1.5 RPI to define acceptable hold points [ * ] [ * ]
and conditions for storage of
in-process material and intermediates
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1.6 Schedule of technical support during [ * ] [ * ]
manufacture
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1.8 Report on development of manufacture [ * ] [ * ]
of Angiozyme
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1.9 Requirements for Clearance of Final [ * ] [ * ]
Product
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1.10 Ultra-filtration development reports [ * ] [ * ]
including summary of optimised
conditions and [ * ]
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1.11 Freeze drying development report [ * ] [ * ]
including agreement on any further
characterisation of technologies
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1.12 Report on assessment of risk arising [ * ] [ * ]
from differences between RPI and Avecia
facilities Scale/MOC/ Operating methods/
Process control
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PROCESS
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Information RPI Avecia Target Completion
Responsible Responsible Date Date
person Person
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1.13 Controlled copy of all documents [ * ]
associated with purification including
efficiency test and results, sample
strength (OD, %FLP), solvent
gradients, solvent temperatures,
fraction times and any associated
stability data.
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1.14 Controlled copies of all document [ ]
associated with recycle of product
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1.15 Details of lagging material used for [ * ]
insulation HPLC column.
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1.16 Detailed report of any known critical [ * ]
parameters associated with the
purification of product including all
available stability data.
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1.17 Synthesis method for manufacture of [ * ]
Angiozyme on APB Oligo Pilot
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1.18 Details of all stability trials on raw [ * ]
materials, in-process samples and
final product for assignment of shelf
life.
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1.19 Compositions of waste streams [ * ]
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1.20 Details of serious deviations from [ * ]
normal operations outlining causes,
impact and preventative measures adopted.
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SCHEDULE 5 RAW MATERIALS
----------
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Information RPI Avecia Target Completion
Responsible Responsible Date Date
person Person
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2.1 Raw Material Master List indicating [ * ] [ * ]
critical raw materials to be purchased
from RPI named suppliers
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2.2 Reports on any audits of Raw Material [ * ] [ * ]
Vendors which Avecia will use.
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2.3 Raw Material Specifications including [ * ] [ * ]
packaging materials
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2.4 Details of any special storage or [ * ]
handling procedures for raw materials
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SCHEDULES 5 ANALYTICAL AND SPECIFICATIONS
-----------
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Information RPI Avecia Target Completion
Responsible Responsible Date Date
person Person
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3.1 Analytical Technology Transfer Plan [ * ] [ * ]
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3.2 Methods of analysis and Specification [ * ] [ * ]
for Angiozyme.
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3.3 Specification and methods for analysis [ * ] [ * ]
of Raw Materials including
packaging materials.
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3.4 Methods and specifications for [ * ] [ * ]
in-process and intermediate tests
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3.5 Methods and specifications for [ * ] [ * ]
cleaning verification tests
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3.6 Analytical reference standards [ * ] [ * ]
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3.7 Sampling requirements [ * ] [ * ]
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3.8 Analytical Technical transfer report [ * ] [ * ]
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3.9 Transfer protocol for individual methods [ * ] [ * ]
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3.10 Validation reports of method developed at RPI [ * ] [ * ]
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SCHEDULE 5 REGULATORY
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Information RPI Avecia Target Completion
Responsible Responsible Date Date
person Person
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4.1 QA agreement which outlines [ * ] [ * ]
responsibilities for validation.
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4.2 Format and content guidance for CMC [ * ]
information required for regulatory
submission
(This is Product Dependent)
Angiozyme [ * ]
Heptazyme
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SCHEDULE 5 HEALTH AND SAFETY
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Information RPI Avecia Target Completion
Responsible Responsible Date Date
person Person
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5.1 Substance Information sheets (HDS) and [ * ] [ * ]
information on RPI Operating methods
used when handling Angiozyme
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5.2 Substance information sheets on raw [ * ] [ * ]
materials (MSDS)
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5.3 Available analytical methods for [ * ] [ * ]
Angiozyme for any occupational
hygiene monitoring undertaken by RPI
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SCHEDULE 5 CONTROL OF CHANGE
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Information Responsible Avecia Target Completion
person Responsible Date Date
Person
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6.1 Procedure for obtaining RPI [ * ] [ * ]
authorisation for proposed
amendments
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SCHEDULE 5 TRAINING
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Information Responsible Avecia Target Completion
person Responsible Date Date
Person
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7.1 A plan for training personnel involved [ * ] [ * ]
in the manufacture of RPI products
including method of recording any
training received
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APPENDIX IV
Information Required From LSM
SCHEDULE 5 PROCESS
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Information Avecia RPI Target Completion
Responsible Responsible Date Date
person Person
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1.1 A commissioning plan for Angiozyme [ * ]
including engineering and equipment
qualification reports
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1.2 Justified assurance that the plant has [ * ]
been cleaned prior to start of
manufacture of Angiozyme
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1.3 Process record sheet for Angiozyme for [ * ]
RPI comments and approval
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1.4 Latest "for construction" line diagrams. [ * ]
An "as-built" plant diagram will be
provided as soon as practicable For
use as reference documents for control
of change
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1.5 Materials of construction for plant: [ * ] [ * ]
Avecia to generate MOC document for
RPI approval
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1.6 A batch timetable for the initial Campaign [ * ]
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1.7 A schedule for technical cover during [ * ]
commissioning
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SCHEDULE 5 RAW MATERIALS
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Information Avecia RPI Target Completion
Responsible Responsible Date Date
person person
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2.1 Evidence that suppliers of raw [ * ]
materials to be used in the
Grangemouth campaign have been approved
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SCHEDULE 5 ANALYTICAL AND SPECIFICATIONS
----------
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Information Avecia RPI Target Completion
Responsible Responsible Date Date
person Person
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3.1 Grangemouth Works methods of analysis [ * ]
and specifications to be used for Raw
Materials, intermediates and API for
RPI to check and approve.
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3.2 Analytical results from cross [ * ]
correlation studies.
. Raw materials
. Intermediates
. API
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SCHEDULE 5 HEALTH AND SAFETY
----------
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Information Avecia RPI Target Completion
Responsible Responsible Date Date
person Person
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2.1 Assurance that all appropriate risk [ * ]
assessments have been completed prior
to start of manufacture.
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SCHEDULE 5 ENVIRONMENTAL
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Information Avecia RPI Target Completion
Responsible Responsible Date Date
person person
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7.1 Evidence of approval for manufacture from [ * ]
the appropriate authorities.
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SCHEDULE 5 CONTROL OF CHANGE
----------
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Information Avecia RPI Target Completion
Responsible Responsible Date Date
person person
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7.1 Guidelines for Grangemouth [ * ]
Works, system of pre-approval of change
control to be agreed with RPI.
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APPENDIX V
Information And Reports Required Before Technology Transfer Can Be Concluded
1 PROCESS SOURCE
1.1 Pre Manufacturing technology transfer review LSM
1.2 Manufacturing Report LSM
SCHEDULE 5 Control of change procedure for routine manufacture
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1.4 Summary report on suitability of Angiozyme produced at Grangemouth RPI
1.5 Summary report on the suitability of the process RPI
for future manufacture
SCHEDULE 5 RAW MATERIALS
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2.1 Report on raw material sources LSM
SCHEDULE 5 ANALYTICAL
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3.1 Summary of all results, and review of operation LSM
of methods
3.2 Cross validation reports LSM
4 HEALTH, SAFETY & ENVIRONMENT
4.1 Report on health and hygiene monitoring LSM
4.2 Confirmation of acceptable occupational health LSM
position
4.3 Waste disposal routes used LSM
5 TECHNOLOGY TRANSFER
5.1 Technology Transfer Closure Report RPI/LSM
5.2 Definition of responsibilities and routes of RPI/LSM
communication post technology transfer
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APPENDIX VI :
TECHNOLOGY TRANSFER ACCEPTANCE DOCUMENT
The RPI Angiozyme process has been transferred from RPI to LifeScience
Molecules Grangemouth Works and the reports required by the Technology Transfer
Plan completed.
--------------------------------------------------------------------------------
The Product Name: Number of Stages:
--------------------------------------------------------------------------------
CAS nomenclature Stage Name:
--------------------------------------------------------------------------------
The attached completion report provides a summary of technology transfer and any
actions outstanding.
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For RPI:
Quality Assurance Manager:
_________________________________ Date: _______________________
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--------------------------------------------------------------------------------
For RPI:
Technology Transfer Manager:
_____________________________________ Date: ____________________
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--------------------------------------------------------------------------------
For Avecia:
Quality Assurance Manager:
_________________________________ Date: _______________________
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--------------------------------------------------------------------------------
For Avecia:
Technology Transfer Manager:
_____________________________________ Date: ____________________
--------------------------------------------------------------------------------
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SCHEDULE 5
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Yield and Price Matrix
----------------------
Order size (Kg)
---------------
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Raw material cost ($/g of 1 3 5
product)
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[ * ] [ * ] [ * ] [ * ]
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[ * ] [ * ] [ * ] [ * ]
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[ * ] [ * ] [ * ] [ * ]
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