Exhibit 10.47
MANUFACTURING AND SUPPLY AGREEMENT
This Manufacturing and
Supply Agreement ("Agreement") is entered into as of the
date signed by the last party to sign
this Agreement,
and with an
effective
date of February 8,
2006 (the "Effective
Date") by and between
Hyaluron Inc.,
with its principal place of business at 99 S. Bedford Street, Suite 2,
Burlington,
MA 01803, ("Hyaluron") and Hemispherx Biopharma, Inc.,
("Hemispherx"),
a Delaware
corporation, having its principal place of business
at 1617 JFK Boulevard,
Philadelphia, PA.
19103. Hyaluron and Hemispherx may be
referred to herein as
a "Party" or, collectively, as the "Parties".
WHEREAS, Hemispherx
is engaged in the business of developing therapeutic
product(s); and
WHEREAS, Hyaluron is in the business of developing, manufacturing, testing and
packaging sterile pharmaceutical products; and
WHEREAS, Hemispherx desires to utilize Hyaluron to develop,
manufacture,
test,
and/or package supplies of the product(s) as designated by
Hemispherx:
NOW, THEREFORE, the Parties agree as follows:
Definitions. As used
herein the following
terms will have the
following
meanings:
"API" means the raw material components of the Product, as specified
and provided to Hyaluron by Hemispherx.
"Batch" means the entire amount of Product yielded from a
manufacturing
event using a specific quantity of APIs, Excipients, and components
processed in
accordance with the Master Batch Record and the Manufacturing
Standards.
"Batch Record"
means the document
created as and after
each Batch is
Processed and
Packaged. Each Batch Record will reflect and
incorporate
all
aspects of the Master Batch Record, the applicable Certificate of Analysis, and
any Manufacturing Variance Reports issued with respect to such
Batch.
"Batch Release"
means the final sign-off by a party's quality
department marking the
culmination of the quality process through which a batch
of Product is shown to conform to all aspects of the Manufacturing
Standards.
"Bulk" means the bulk API for formulation.
"Compounded Bulk"
means the API and Excipients which have been
compounded but
not filled or packaged or finished into a final dosage
presentation.
"Certificate of Analysis" means a certificate that accompanies each
shipment of APIs or
Product certifying that the APIs or Product meets the
specifications as defined in the Manufacturing Standards.
"Date of Manufacture"
means the date of sterile filtration and/or
filling of the Compounded Bulk.
"Excipient" means any
substance other than the API used in formulating
the Compounded Bulk.
"API Reference
Standard" means a
quantity of APIs with a known assay,
supplied by Hemispherx, with which Hyaluron may perform
comparative analysis to
API samples having an unknown assay.
"API Specifications"
means the specifications with respect to the APIs
as set forth in the Master Batch Record.
"Manufacturing
Standards" means the
specifications
for Processing,
Packaging, and storing
the Product set forth in the Specifications, the Master
Batch Record,
CGMPs (as defined below), MSDSs, the QA Schedule and all
applicable U.S. laws
and regulations,
to the extent such
terms and conditions
are not inconsistent with this Agreement.
"Manufacturing
Variance Report" means a written report indicating any
significant variance
in the Processing or Packaging of a Batch from the
procedures set forth in the Master Batch Record.
"Master Batch Record"
means the document, as
may be amended from time
to time, specifying: (i) the API Specifications, (ii) the
procedures for testing
and releasing the APIs, (iii) the Excipients, (iv) the Primary Components,
(v)
Secondary Packaging,
(vi) the Specifications, (vii) the formula (listing the
APIs and the
Excipients
for the Product), and (viii) the procedures for
manufacturing the
Product (listing the APIs, the Excipients, the Primary
Components, and the Secondary Packaging).
"To Package" and "Packaging" means the act of inspecting, labeling,
and
packing the Product into units.
"Primary Components"
means the vial/syringe, stopper, and seal as
identified in the Master Batch Record.
"Process" or "Processing" means the manufacturing
procedures,
or any
part thereof,
involved in
manufacturing
the Product in
accordance
with the
Manufacturing Standards.
"Product" means finished product in final dosage presentation.
"Release Date" means
the date on which
Hyaluron notifies
Hemispherx
that the quality control samples are available and the Batch Record
is done.
"Specifications" means the specifications for the APIs, the
Excipients,
the Primary Components, the Secondary Packaging, and the
in-process and release
specifications for
the Product, as set forth initially in the applicable
Statement or Work and,
subsequently in the
Master Batch Record.
Revisions to
Specifications may be
made by the Parties
from time to time and
such changes
will be reflected in the Master Batch Record.
"Qualified Supplier"
means a supplier of
materials or components that
has been audited and/or assessed by Hyaluron and has passed
Hyaluron's
quality
assurance standards.
"Secondary Packaging" means any component other than Primary
Components
used to convert primary units into units.
"Shipping
Components" means
the packaging, boxes, and shipping
containers into which the Product is placed for shipment to
Hemispherx.
"Variance" or "Deviation" means a departure from an established
quality
standard (e.g., CGMP standard operating procedure, manufacturing work order,
Packaging order,
raw material or Product Specification, analytical control
procedure, water
monitoring procedure,
equipment maintenance
schedule, or any
unusual occurrence), which may be either anticipated or
unanticipated departures
from established
quality standards and may have the potential to affect the
safety, identity, strength, quality or purity of the Product or
Compounded Bulk.
1. Quotation. Hyaluron
will provide to Hemispherx the manufacturing and related
services (the "Services") as described in the applicable Quotation (the
"Quotation"),
a form of which is
attached hereto as Exhibit A and incorporated
herein by reference.
The Parties will
mutually agree to the contents of each
Quotation and any
amendments thereto. Each Quotation will, in addition to other
matters, address the quality assurance and
control procedures.
The Quotation
may specify
that Hemispherx will provide certain materials to Hyaluron or
require that Hyaluron
acquire certain
materials from a particular source. If
Hemispherx
provides materials to Hyaluron,
title in and risk of
loss of such
materials will remain with Hemispherx. In the event Hemispherx requests
additional services
relating to this Agreement, the Parties may mutually agree
upon such services and the costs related thereto in a separate written
agreement,
which must be signed
by authorized
representatives of both Parties
before any such costs
are incurred.
2.
Compensation for Services.
-------------------------
Compensation for the
Services will be as specified in the Quotation.
Hyaluron will bill
Hemispherx for the
Services as specified in the applicable
Purchase Order.
Such invoices will be
payable upon receipt by Hemispherx. All
pricing, payments,
credits, allowances or other monetary adjustments under this
Agreement will be in U.S. Dollars.
3. Advance
Notice For Services.
---------------------------
Hemispherx agrees,
according to CGMP
standards, to give
Hyaluron 60 days
advance written notice for each Product Order under the terms of
this Agreement.
4.
Services.
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(a) All Services will
be conducted in accordance with the applicable
Quotation and
Hyaluron's
internal Standard Operating Procedures ("SOPs"),
copies of which will be available for inspection by Hemispherx or its
designated
representatives at Hyaluron upon reasonable notice. Notwithstanding
the foregoing, unless
otherwise specified in the applicable Purchase Order, the
manufacturing
of the Product will be
conducted in accordance with EU Annex I,
ISO 13485:
2003, ISO 9001: 2000, 21 CFR 211, and Current Good
Manufacturing
Practices ("CGMPs") as described in the
relevant United
States Food and
Drug
Administration ("FDA")
regulations and guidelines for the manufacture, control
and storage of human
pharmaceutical
products, including,
without
limitation,
the FDA's guidance for industry titled "Sterile Drug Products Produced by
Aseptic Processing - Current Good
Manufacturing
Practice",
dated September
2004. If change(s) to ISO, European, CFR, and/or FDA standards affect
manufacture/production
of the Product
Hyaluron and
Hemispherx shall negotiate
in good faith
change(s) to prices being charged by Hyaluron to Hemispherx.
(b) Hyaluron will follow CGMP standards to manufacture for
Hemispherx,
or any third party
designated by Hemispherx and agreed to by Hyaluron, clinical
Batches of a finished dosage form of the Product per the Manufacturing
Standards,
and as may be
further developed by Hyaluron, using the APIs,
components and
Excipients
specified.
Both Parties will
promptly notify
each
other of any new
instructions or specifications required by CGMP. Upon request,
Hyaluron will provide
Hemispherx with (a) a written description of any actions
taken to comply with
new or revised CGMPs
that affect the
Product and/or (b)
copies of Hyaluron's manufacturing records, including its Batch Records
regarding the Product, for the purposes of assuring product quality and
compliance with
agreed-upon manufacturing procedures.
(c) Hyaluron will adhere to the Specifications and requirements, as
detailed in the Master
Batch Record, the
Manufacturing
Standards and mutually
agreed upon protocols, where such specifications are in compliance and
agreement with FDA and
other applicable regulatory agency guidelines. Hyaluron
will obtain
Hemispherx's prior
approval before it implements any change in the
materials,
equipment,
process or procedures
used to manufacture
the Product
that would constitute
a significant
Deviation under CGMP, such approval not to
be withheld by
Hemispherx
unreasonably.
Hyaluron will disclose all proposed
changes in such
manufacturing
materials,
equipment,
process or procedure
to
Hemispherx.
(d) In the event that
the Bulk fails to meet
in-process
or release
specifications,
Hemispherx
may authorize a
Deviation from the Batch Record in
an attempt to salvage
the Batch.
Hemispherx
assumes responsibility for all
costs associated with batch failure(s) until such time as Hyaluron has
validated the filling
line for the Product. Hyaluron will assume responsibility
for Excipient
costs for batch
failures occurring subsequent to product fill
line validation, unless such batch failures result from negligence by
Hemispherx.
At no time will
Hyaluron be
responsible for API
costs resulting
from batch
failure.
(e) Hyaluron will obtain materials and components for production
from
Qualified Suppliers.
(f) Hyaluron and Hemispherx will mutually develop a Master Batch
Record
for the Product
following the
technical
specifications,
methods and know-how
provided by
Hemispherx.
(g) Hemispherx will transfer to Hyaluron
appropriate
methods and in
process assays for manufacturing the Product. Such methods and in process
assays will be
confirmed,
or if requested, validated by Hyaluron for their
application to the
finished Product.
(h) Hyaluron will
provide Hemispherx with copies of executed
Batch
Records, process
deviations and analytical data showing that the Specifications
have been met, following completion of the manufacture of the Product.
Hemispherx will have
the right to review and approve Master Batch Records, to
approve planned
process deviations and to receive prompt notice of
unplanned
process deviations.
(i) In the event that Hemispherx proposes any significant change to
the
Specifications or manufacturing Process, Hemispherx will deliver written
notice
to Hyaluron describing
such Change.
Hyaluron will respond to any such
notice
within 15 days after Hyaluron's receipt thereof; provided, however, that the
Specifications or
Process will not be supplemented, modified or amended in any
respect without the prior written agreement of the Parties. If any
change in the
Primary Components,
Secondary Packaging, Shipping Components, Processes or
Product testing
Specifications
materially
increases
Hyaluron's
cost to
manufacture, test, or
package the Product,
Hyaluron reserves the right to make
reasonable pricing
adjustments if needed to accommodate such changes. Prior to
initiating any work,
Hyaluron will provide
a scope of work and cost proposal.
New pricing will be effective upon implementation of the new
specifications or
process.
(j) Hyaluron will
provide Hemispherx
with all documents Hemispherx
reasonably requests regarding its manufacturing processes and
procedures for the
Product. Where
practicable,
for an additional fee, Hyaluron may assist
Hemispherx in obtaining approvals from other government or
regulatory
agencies
which may be required for the conduct of clinical trials of the
Product in other
countries. Hyaluron
agrees to cooperate with the FDA or other regulatory
agencies.
(k) Labeling and
packaging will be
approved by
Hemispherx, and
all
labels and package
inserts will be
developed in
accordance
with Hyaluron's
guidelines with regard to physical dimensions and handling
procedures.
(l) Hemispherx will
conduct release testing on quality control samples
obtained from each Batch of Hemispherx Product shipped by Hyaluron
hereunder to
confirm that
such quality control samples conform to the Manufacturing
Standards. Hyaluron
will notify Hemispherx when the quality control samples are
available and the Batch Record is done. At that point in time,
Hemispherx shall
request that the
Hemispherx Product be
shipped immediately
to Hemispherx or
another address
selected by Hemispherx. Hemispherx will be deemed to have
accepted the Batch 45 days after Hemispherx is notified that quality control
samples are available
or that the Batch Record is complete, whichever occurs
first. Hyaluron must
receive any and all comments on the Batch Record within 45
days after Hemispherx
has been notified that the Batch Record is complete;
otherwise Hemispherx
shall be deemed to accept the Batch Record as is. After 45
days, Hemispherx will
be deemed to have accepted the Batch, unless Hemispherx,
by written notice ("Notice of Rejection/Nonconformance") to
Hyaluron within the
45-day period
initiates an
investigation
into the reasons for
the failure to
allegedly conform
to the Manufacturing Standards by returning allegedly
non-conforming Product
to Hyaluron within 14
days after giving
notice of such
non-conformance. Once
Hemispherx
has been deemed to accept the Product,
Hyaluron's
responsibilities and
liabilities
for the Product will
be null and
void.
(m) Hyaluron
will have the right to
sample and retest
Product or to
have an outside
laboratory sample and
retest Product if Hemispherx claims that
such Product does not conform to the Manufacturing Standards. Disputes between
the Parties as to
whether any Product
rejected by Hemispherx
conforms to the
Manufacturing
Standards will be resolved by a mutually acceptable third party
testing laboratory.
(n) In the event
that a batch of
Compounded
Bulk is found not to
conform to the
bulk release specification set forth in the Manufacturing
Standards prior to
initiation of the fill, Hyaluron will undertake one or
more
remedial steps in an
attempt to bring the Compounded Bulk into specification.
Should these remedial steps fail to bring the Compounded Bulk into
specification
Hemispherx may direct
Hyaluron to terminate the manufacturing process at this
stage.
(o) Hyaluron
will ship Product to the destination specified by
Hemispherx in accordance with the applicable Hemispherx instructions and will
store the Product
in compliance with CGMP at Hyaluron's facilities until
delivery. All shipping costs will be the responsibility of
Hemispherx. Title
to
and risk of loss of the Product shall pass to Hemispherx as the Product is
delivered F.O.B. via a common carrier. If Hemispherx requests Hyaluron to
store
Product longer
than 2 weeks
past the Release Date, there will be a storage
charge applied which will be proportional to the quantity
stored.
5.
Representations, Warranties and Covenants.
-----------------------------------------
(a) Hyaluron
represents and warrants to Hemispherx that:
(i) All Product
furnished pursuant to this Agreement will
conform to the relevant Specifications except in case of variance or
deviation
of which Hemispherx has been notified by Hyaluron;
(ii) All Product furnished pursuant to this Agreement will
be
manufactured and
stored in accordance
with, and all packaging and labeling
operations will be conducted in compliance with, CGMPs and other applicable
FDA
and other governmental laws and regulations;
(iii) All manufacturing under this Agreement will be performed
with the degree of skill and diligence normally employed by a contract
manufacturer performing the same or similar services; and
(iv) Hyaluron's
application
of any intellectual property,
other than that provided to Hyaluron by Hemispherx, in the performance of the
Services will not infringe any third party intellectual property
rights.
(v) Hyaluron
represents as of the date of this Agreement and
continuously during
the term of this Agreement that, to the best of its
knowledge, it and its employees, affiliates, contractors, and agents have
never
been (i) debarred
or (ii) convicted of a crime for which a person can be
debarred, under Section 335(a) or 335(b) of the Federal Food, Drug,
and Cosmetic
Act (the "Act").
Hyaluron represents that it has never been and, to the best of
its knowledge, none of
its employees,
affiliates,
contractors, or agents
has
ever been (i)
threatened to be
debarred under the Act
or (ii) indicted for
a
crime or otherwise
engaged in conduct for which a person can be debarred under
the Act. Hyaluron agrees that it will promptly notify Hemispherx in
the event it
receives notification of any such debarment, conviction, threat or
indictment.
(b) Hemispherx
represents
and warrants to
Hyaluron that
Hyaluron's
application of any intellectual property provided to Hyaluron by Hemispherx
in
the performance of the
Services will not infringe any third party intellectual
property rights, and
Hemispherx agrees
under this Section and under Section 11
to fully indemnify
Hyaluron in the
event
