Exhibit 10.15
**Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
DEVELOPMENT AND SUPPLY AGREEMENT
THIS AGREEMENT (hereinafter "AGREEMENT") is made by and between Xxxxxx GmbH &
Co. KG, having a place of business at Xxxxxxxxxxxx 00, 00000 Xxxxxxxxxxxx,
Xxxxxxx (hereinafter "XXXXXX"), and Barrier Therapeutics, Inc. having a place of
business at 000 Xxxxxxxxx Xxxxxxxx, Xxxxxxxxx, XX 00000, XXX (hereinafter
"BARRIER"). This Agreement is effective as of the date of the last signature
below (hereinafter "EFFECTIVE DATE").
WHEREAS Xxxxxx has developed inter alia Meltrex(TM) Technology (as hereinafter
defined) that can be used in the formulation of pharmaceutical products and has
rights to certain patents and patent applications claiming the same; and
WHEREAS Barrier has rights to develop, market and sell a certain pharmaceutical
Drug Substance (as hereinafter defined); and
WHEREAS Xxxxxx has previously carried out studies successfully demonstrating the
feasibility of formulating said Drug Substance using Meltrex(TM) Technology, and
WHEREAS Xxxxxx and Barrier wish to enter into a Development Programme (as
hereinafter defined) with respect to the development of Bulk Product and
Finished Product (as hereinafter defined); and
WHEREAS upon successful completion of such development and obtaining marketing
approval for Finished Product, Barrier intends to entrust the manufacturing of
both Bulk Product and Finished Product to Xxxxxx; and
WHEREAS Xxxxxx has adequate manufacturing facilities and capacity to undertake
the manufacture and to ensure the supply of both Bulk Product and Finished
Product to Barrier for Barrier's total worldwide requirements of Finished
Product.
NOW THEREFORE the parties agree as follows:
1
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
ARTICLE I
DEFINITIONS
1.1 AFFILIATE means any person or business entity which directly or indirectly
controls, is controlled by, or is under common control with a party to
this Agreement. A business entity shall be deemed to "control" another
business entity, if it owns directly or indirectly, more than fifty
percent (50%) of the outstanding voting securities, capital stock, or
other comparable equity or ownership interest of such business entity, or
exercises equivalent influence over such entity. If the laws of the
jurisdiction in which such entity operates prohibit ownership by a party
of fifty percent (50%) or more, "control" shall be deemed to exist at the
maximum level of ownership allowed by such jurisdiction.
1.2 BULK PRODUCT means Drug Substance formulated by Xxxxxx using its
Meltrex(TM) Technology according to the terms of this Agreement.
1.3 DELIMITATION OF RESPONSIBILITIES AGREEMENT means the document setting out
the respective pharmaceutical responsibilities of the parties with regard
to the preparation of Finished Product to be attached hereto as Schedule
C.
1.4 DEVELOPMENT PROGRAMME means the outline programme set out in Schedule A
hereto and all the detailed Workplans for the development of Bulk Product
and Finished Product attached hereto from time to time as Schedule B and
made a part hereof.
1.5 DRUG SUBSTANCE means the antifungal compound itraconazole, alone or as a
premix ("Triaset").
2
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
1.6 FINISHED PRODUCT means the final tablets made by milling and compressing
Bulk Product according to the terms of this Agreement and suitable for
marketing and sale.
1.7 MELTREX(TM) TECHNOLOGY means any and all know-how, proprietary data,
patents and patent applications owned or controlled by Xxxxxx or any of
its Affiliates relating to the formulation and shaping of pharmaceutical
products by melt-extrusion.
1.8 REGULATORY AGENCIES means the regulatory authorities having jurisdiction
over the clinical testing, manufacture, marketing and sale of Finished
Product.
1.9 SPECIFICATIONS means the manufacturing and test procedures for Drug
Substance, components, intermediates, Bulk Product and Finished Product,
and in-process controls, including without limitation legal label text and
unit descriptions if applicable.
1.10 WORKPLAN means each detailed programme of technical work, including the
timetable and cost, which is required for the development of Bulk Product
and Finished Product and which will be set out from time to time as
Schedule B (i.e. Schedule X-0, Xxxxxxxx X-0, etc) hereto.
ARTICLE II
DEVELOPMENT PROGRAMME
2.1 Xxxxxx hereby agrees to undertake the Development Programme as outlined in
Schedule A hereto, including, without limitation, manufacturing Bulk
Product and Finished Product in accordance with the Specifications which
shall be agreed to by the parties. On payment by Barrier of the
irrevocable sum of US$ [**] prior to commencement of Stage 2 of the
Development Programme, Xxxxxx undertakes to
3
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
develop Meltrex(TM) formulations of Drug Substance exclusively for
Barrier. Barrier represents and warrants that it shall not sell any Bulk
Product or Finished Product manufactured by Xxxxxx for use in the
Development Programme to any third party and shall only use such Bulk
Product and Finished Product in preapproval clinical and in vitro studies
until the supply agreement referred to in Article V is signed by both
parties. Schedule B shall consist of a number of Workplans which may be
added to or amended from time-to-time by mutual agreement of the parties.
The aim of such Development Programme is to enable Xxxxxx to perform all
the development and scaling-up activities required (i) to provide
sufficient samples of Finished Product for Barrier to carry out further
testing in humans; and (ii) to provide batches of Bulk Product and
Finished Product for validation and other requirements of Regulatory
Agencies; and (iii) to generate such data and documentation related to the
manufacture of Bulk Product and Finished Product as are necessary to
enable Barrier to apply to Regulatory Agencies for marketing authorisation
for Finished Product.
2.2 Xxxxxx shall use all reasonable efforts to carry out and complete each
Workplan within the agreed timetable. Both parties undertake to keep each
other informed of any possible or anticipated change in their respective
timescales of activities which may affect the Development Programme.
2.3 If at any time during the Development Programme, Xxxxxx anticipates that
for any reason whatsoever it is no longer in a position to complete any
part of the
4
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
Development Programme within the timetables provided for in Schedules A
and B, it will promptly so notify Barrier and both parties will
immediately review the situation and seek to agree any revisions to the
Development Programme.
ARTICLE III
SUPPLY OF DRUG SUBSTANCE
3.1 During the Development Programme Barrier will provide Xxxxxx with Drug
Substance at no cost to Xxxxxx in sufficient quantities to enable Xxxxxx
to carry out its obligations under the Development Programme. Xxxxxx shall
use such Drug Substance solely for the purpose of meeting said
obligations.
3.2 Barrier shall at all times inform Xxxxxx immediately of any reported or
potential safety hazards or side effects relating to Drug Substance, Bulk
Product or Finished Product.
ARTICLE IV
DEVELOPMENT COSTS
4.1 In consideration of Xxxxxx'x contribution to the Development Programme
Barrier shall pay the agreed development costs and fees to Xxxxxx. The
fees and costs payable to Xxxxxx and the payment timetables are set out in
Schedules A and B.
4.2 In the event that during the Development Programme Xxxxxx anticipates any
substantial (i.e. more than ten percent) increase in. the estimated total
development costs, Xxxxxx shall promptly inform Barrier and the parties
shall review the causes of such increases and seek in good faith either to
rectify such causes or to increase Xxxxxx'x reimbursement.
4.3 In the event that during the Development Programme Barrier requests Xxxxxx
to undertake additional work not included in the current Development
Programme the parties shall in good faith negotiate whether Xxxxxx shall
perform such
5
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
additional work and, if so, the additional reimbursement for Xxxxxx. If
the parties agree on such additional work, the parties shall make the
necessary revisions to the Development Programme and Workplans, including
the timetable and fees.
ARTICLE V
COMMERCIAL SUPPLY AND LICENSES
As soon as reasonably possible after Barrier submits the first New Drug
Application for Finished Product to a Regulatory Agency, the parties will enter
into a supply agreement which will include inter alia the following provisions:
5.1 Barrier will appoint Xxxxxx as its exclusive supplier for Barrier's entire
requirements of Bulk Product and Finished Product and Xxxxxx agrees to
manufacture Bulk Product in its facilities for the exclusive purpose of
using it to manufacture and supply Finished Product to Barrier or its
designee. The agreement will also provide for alternative sources of
supply of Bulk Product to Barrier in the event that Xxxxxx is unable or
unwilling to fulfill Barrier's requirements.
5.2 The obligation of the parties to adhere to the agreed Specifications.
5.3 Barrier shall provide or procure that a third party provides Xxxxxx in a
timely fashion and free of cost with sufficient quantities of Drug
Substance to enable Xxxxxx to supply Barrier's requirements of Finished
Product. Appropriate forecasting procedures will be agreed.
5.4 Barrier and Xxxxxx will agree on the supply price for Finished Product
based on Xxxxxx'x fully burdened manufacturing cost.
5.5 For the term of this Agreement and said supply agreement Barrier will
grant to Xxxxxx, or procure the grant to Xxxxxx of, a royalty-free
enabling license under
6
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
any patents relating to Drug Substance in as far as such a license is
necessary for Xxxxxx to develop and manufacture Bulk Product and Finished
Product for Barrier.
5.6 In addition to the supply price specified in paragraph 5.4 above, Barrier
shall also pay Xxxxxx a "fee" per tablet of Finished Product equivalent to
[**] percent ([**]%) [**] Finished Product.
5.7 Barrier will include wording on all packaging, labels, etc of Finished
Product to the effect that such Finished Product was formulated using
Meltrex(TM) Technology.
ARTICLE VI
INTELLECTUAL PROPERTY RIGHTS
6.1 All intellectual property rights including, but not limited to, patentable
inventions, improvements, technology, methods, applications and products
arising from the Development Programme (hereinafter "IPR") shall be: (a)
exclusively owned by Barrier if such IPR relates solely to Drug Substance
with no royalty obligations whatsoever to Xxxxxx, its employees or
affiliates; (b) exclusively owned by Xxxxxx if such IPR relates solely to
Meltrex(TM) Technology with no royalty obligations whatsoever to Barrier,
its employees or affiliates; and (c) jointly owned by the parties in equal
shares if such IPR relates to the combination of Drug Substance with
Meltrex(TM) Technology.
6.2 Each party shall be entitled at its sole discretion to file patent
applications for the IPR of which it has exclusive ownership. Any patent
applications for the jointly owned IPR shall be filed by Xxxxxx using an
independent law firm. The parties shall share equally in the cost of
filing and prosecuting applications for jointly
7
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
owned IPR, provided that if Xxxxxx desires not to file such application or
prosecute such application in certain jurisdictions or for certain claims,
it may transfer such right to Barrier by notice in writing, at which point
Xxxxxx shall no longer be obligated to pay for such prosecution and
Barrier may at that point determine whether or not to file and prosecute
such application.
6.3 In the case of jointly owned IPR, the parties shall negotiate in good
faith (a) an exclusive license for Barrier to use and sell, but not make,
Finished Product and (b) an exclusive license for Xxxxxx to use its
Meltrex(TM) Technology to make, use and sell products which do not contain
Drug Substance. Neither party shall grant any rights under such jointly
owned IPR to any third party without the prior written consent of the
other party.
ARTICLE VII
CONFIDENTIALITY
Pursuant to the purposes of this Agreement, each party may from time to time
disclose to the other party, orally, in writing or in an electronic medium,
information of a confidential or proprietary nature ("CONFIDENTIAL
INFORMATION"). Each party undertakes to keep strictly secret such Confidential
Information received from the other party and not to publish it or make
commercial or any other use of it without the express prior consent in writing
of the disclosing party, unless otherwise permitted under this Agreement. The
obligation of secrecy does not apply when and if the receiving party can prove
that the Confidential Information
a) was known to it or any of its Affiliates prior to the date it was
transferred hereunder, as evidenced by written records;
8
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
b) became or becomes known to it or any of its Affiliates through a third
party having the right to disclose the same subsequent to the date it was
received hereunder without it being responsible therefor;
c) was or becomes known to the public or generally available to the public
otherwise than through the act or default of the receiving party or its
agents;
d) is independently developed by the receiving party or any of its Affiliates
as evidenced by written records; or
e) is required by law, regulatory, administrative or judicial order to be
disclosed, in which event the receiving party shall notify the disclosing
party as soon as possible prior to such required disclosure and shall
cooperate with the disclosing party's efforts to limit such disclosure.
The foregoing obligations shall cease after the expiration of a period off ten
(10) years commencing on the Effective Date or five (5) years after the
termination of this Agreement whichever is the later.
ARTICLE VIII
TERM AND TERMINATION
8.1 This Agreement shall come into effect on the Effective Date and remain in
full force and effect throughout the Development Programme and until
Barrier achieves the first approval for marketing Finished Product from a
Regulatory Agency. If no such approval is obtained by [**], then either
party may terminate this Agreement upon sixty (60) days' written notice to
the other party.
8.2 Either party may terminate this Agreement for a material breach by the
other party in the performance of its obligations hereunder, or in the
event that at any time Xxxxxx revises its estimated total development
costs as set forth in Schedules
9
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
A and B by more than 50% or if by [**] Xxxxxx has not delivered to Barrier
a final feasibility report indicating a high degree of probable
achievement of the Aim of Work set forth in Schedule B-1, by giving to the
breaching party written notice specifying such breach within forty-five
(45) days after the non-breaching party becomes aware of the occurrence of
such breach and, if the breaching party has not remedied or cured the
default within sixty (60) days of such notice being given (or, if a breach
is not capable of being cured within such 60 day period, the breaching
party has not promptly provided the other party with a detailed plan for
curing such breach and has not promptly begun and continued all reasonable
efforts to execute such plan), then termination shall become effective, at
the non-breaching party's option at the end of said sixty (60) day period.
8.3 In the event of any proceedings, voluntary or involuntary, in bankruptcy
by or against Barrier or Xxxxxx, or the appointment with or without the
parties' consent of a receiver for either party, or in the event of
insolvency of the either party, the other party shall be entitled to
terminate this Agreement upon giving written notice without any liability
whatsoever.
8.4 Upon termination of this Agreement for any reason whatsoever Barrier and
Xxxxxx will cease to use any and all Confidential Information provided by
the other party.
8.5 Termination of this Agreement for any reason whatsoever will have no
effect on any rights or obligations that have accrued prior to the
effective date of such termination.
10
ARTICLE IX
MISCELLANEOUS
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
9.1 Nothing in this Agreement will be deemed or construed as providing either
party any right, title, interest, or license in or under any intellectual
property right owned or controlled by the other party other than
explicitly specified in Articles V and VI above.
9.2 Modifications and amendments to this Agreement and its Schedules require
the prior written consent of both parties.
9.3 No waiver of any requirement of this Agreement, whether by conduct or
otherwise, will be effective unless in writing. The waiver in any one or
more instances will not be deemed or construed to be a further or
continuing waiver of any such requirement or of any other requirement of
this Agreement.
9.4 If any one or more of the provisions of this Agreement will be held to be
invalid, illegal, or unenforceable, the validity, legality, or
enforceability of the remaining provisions of this Agreement will not in
any way be affected or impaired thereby.
9.5 Any notice required or permitted to be given hereunder will be deemed
sufficient if delivered by hand or sent by overnight courier to the
parties at the addresses set forth below or such other addresses as either
party may designate. Notice will be deemed given when received.
If to Barrier, to: President
Barrier Therapeutics, Inc.
000 Xxxxxxxxx Xxxxxxxx
Xxxxxxxxx, XX 00000
XXX
If to Xxxxxx, to:
Head of SOLIQS
Xxxxxx GmbH & Co. KG
Xxxxxxxxxxxx 00
00000 Xxxxxxxxxxxx
Xxxxxxx
11
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
9.6 Neither party will assign this Agreement, or subcontract any of its
obligations hereunder, to any other person or entity other than to one or
more of its Affiliates, without the prior written consent of the other
party, which consent will not be unreasonably withheld; however, in the
event of any assignment or subcontract, the party effecting such
assignment or subcontract shall guarantee the performance of the assignee
or subcontractor in a form satisfactory to the other party.
Notwithstanding the foregoing, either party may, without such written
consent, assign this Agreement, and its rights and objections hereunder,
in connection with the transfer or sale of all or substantially all of its
business, or in the event of its merger or consolidation or change in
control or similar transaction provided the permitted assignee shall have
assumed all obligations of the assignor under this Agreement.
9.7 This Agreement will be binding upon and inure to the benefit of the
permitted successors or permitted assigns of Xxxxxx and Barrier.
9.8 The parties agree to attempt to resolve any dispute involving this
Agreement in good faith through upper management meetings between the
parties and, if unresolved within sixty (60) days of the first meeting, to
arbitrate the dispute in accordance with the terms of Article 9.15.
9.9 This Agreement shall be construed, interpreted and applied in accordance
with the laws of Germany, without reference to its conflict of laws
provisions, and the place of jurisdiction shall be the Courts of Mannheim,
Germany.
12
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
9.10 Neither party shall be liable for any failure or delay in performing its
obligations hereunder when any such failure or delay shall be caused
(directly or indirectly) by fires, flood, earthquakes, accidents,
explosions, sabotage, strikes or other labour disturbances, civil
commotion, riots, invasions, wars, acts, restraints, requisitions,
regulations, or directions of governmental authorities, shortages of
labour, fuel, power, or raw material, inability to obtain equipment or
supplies, inability to obtain or delays in transportation, acts of God, or
any cause beyond the reasonable control of that party. Performance under
this Agreement of the affected party shall be delayed during the
occurrence of any of the circumstances described in this paragraph 9.10,
provided that written notice of such circumstances is provided to the
unaffected party.
9.11 Neither party shall use the name of the other party in publicity or
advertising in relation to any activities under this Agreement without the
prior written approval of the other party which shall not be unreasonably
withheld.
9.12 Each party warrants that it has the right and authority to enter into this
Agreement and that it is not under any other contractual obligation,
express or implied, inconsistent with the terms hereof. Barrier represents
and warrants to Xxxxxx that it shall comply with all applicable laws,
rules and regulations in the development and commercialisation of the Drug
Substance, Bulk Product and Finished Product. Barrier further represents
and warrants that it owns or has licensed all rights in and to the Drug
Substance and its development and commercialisation to the extent
necessary to permit the development and commercialisation contemplated
hereunder.
13
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
9.13 Neither party shall make any representation or incur any obligation in the
name or on behalf of the other party except as explicitly authorised
hereunder. Nothing in this Agreement shall be deemed to establish a
relationship of principal and agent between Barrier and Xxxxxx nor any of
their agents or employees for any purpose whatsoever. Nothing in this
Agreement shall be deemed to constitute the parties as a partnership,
association or other relationship.
9.14 This Agreement constitutes the entire agreement of Xxxxxx and Barrier with
respect to the subject matter hereof and this Agreement cancels and
supersedes all agreements of any kind related to the subject matter hereof
entered into prior to the Effective Date of this Agreement.
9.15 All disputes, claims or controversies arising in connection with, pursuant
to, or related to, this Agreement shall be finally determined under the
Arbitration Rules of the International Chamber of Commerce ("ICC") by
three arbitrators, knowledgeable in the field of pharmaceuticals,
conversant in the English language, and appointed by the ICC in accordance
with said Rules, except that any disputes regarding the validity, scope or
enforceability of a patent shall be submitted to a court of competent
jurisdiction. The arbitrator appointed to chair the arbitral tribunal
shall be a lawyer fluent in English. The place of arbitration shall be
London, England. The language of the arbitration shall be English.
Documents in other languages shall be permitted as exhibits but mutually
acceptable translations in English shall be provided by the offering
party. The award may grant any relief appropriate under the applicable
law, including without limitation declaratory relief and/or specific
performance. However, the
14
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
parties agree that notwithstanding the applicable law, the arbitral
tribunal shall not be empowered to award punitive damages against either
party. The parties hereby agree that there shall be no right of appeal to
any court on the merits of the dispute. Judgement on the award may be
entered in any court having jurisdiction over the award or any of the
parties or their assets.
9.16 LIMITATION OF LIABILITY: UNDER NO CIRCUMSTANCES SHALL EITHER PARTY BE
LIABLE TO THE OTHER UNDER ANY LEGAL OR EQUITABLE CLAIM OR CAUSE OF ACTION,
WHETHER IN CONTRACT, TORT OR OTHERWISE, FOR INDIRECT OR CONSEQUENTIAL
DAMAGES (INCLUDING, WITHOUT LIMITATION, LOSS OF PROFITS) REGARDLESS OF
WHETHER OR NOT SUCH PARTY WAS INFORMED OF THE POSSIBILITY OF SUCH DAMAGES.
9.17 Each party hereby agrees to indemnify, defend and hold the other party and
its Affiliates and, each of their directors, officers, shareholders,
agents, representatives and employees (the "INDEMNIFIED GROUP") harmless
from and against any and all costs, expenses (including reasonable
attorneys' fees and amounts paid in settlement), damages and liabilities
claimed by a third party ("CLAIM") resulting directly or indirectly from
activities conducted by the indemnifying party, its Affiliates or any of
their directors, officers, shareholders, agents, representatives,
employees or sublicensees (the "INDEMNIFYING GROUP"), but only to the
extent such claim results from the negligence or wilful misconduct or
breach of this Agreement by the Indemnifying Group (and, in the case of
Barrier, resulting from Barrier's commercialisation of the Bulk Product
and
15
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
Finished Product) except to the extent such claim Claim results from the
negligence or wilful misconduct or breach of this Agreement by the
Indemnified Group. In the event that a party is seeking indemnification
under this Section, it shall inform the other party of a Claim as soon as
reasonably practicable after it receives notice of the Claim, shall permit
the indemnifying party to assume direction and control of the defence of
the Claim (including the right to settle the Claim solely for monetary
consideration), and shall cooperate as requested in the defence and
settlement of the Claim. The Indemnified Group shall not voluntarily make
any payment or incur any expense in connection with any claim or suit
without the consent of the indemnifying party, provided that if the
indemnifying party does not assume direction and control of the defence of
the Claim, the Indemnified Group may assume direction and control of the
defence of the Claim and, if successful, shall be reimbursed by the
indemnifying party for costs incurred in connection with such defense.
16
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
IN WITNESS WHEREOF, the parties have caused this Agreement to be executed by
their authorized representatives as of the dates set forth below:
BARRIER THERAPEUTICS INC. XXXXXX GMBH & CO. KG
By: /s/ Geert Cauwenbergh By: /s/ Xxxxxx Xxxxxx
------------------------------- -------------------------------
Name: Name: Xx. Xxxxxx Xxxxxx
-------------------------------
Title: Title: Divisional Vice President
-------------------------------
Date: By: /s/ Xxxx Xxxxxxxxxxx
------------------------------- -------------------------------
Name: Xx. Xxxx Xxxxxxxxxxx
Title: Head of SOLIQS
Date: 16/5/02
-------------------------------
17
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
SCHEDULE A
DEVELOPMENT PROGRAMME
STAGE 1: [**] to ensure that Xxxxxx'x Bulk Product is equivalent to that
produced by Xxxxxxx Pharmaceutical BV ("XXXXXXX") on their [**] equipment
(analytical methods to be agreed). Abbott to carry out short-term stability
testing on selected samples of Bulk Product. Duration approximately 3 months.
STAGE 2: Barrier to procure transfer of the Xxxxxxx milling and compression
procedures to Abbott.
STAGE 3: On receipt of the US$[**] exclusivity payment from Barrier, Abbott to
prepare and supply at a cost to be agreed two formulations to Barrier for a
pilot biostudy.
STAGE 4: [**]. Barrier to pay Abbott an irrevocable milestone payment of
US$[**].
STAGE 5: Pharmaceutical development of Bulk Product and Finished Product by
Abbott.
STAGE 6: Manufacture of registration batches of Finished Product for pivotal
biostudy and long-term, stability study. Barrier to pay Abbott an irrevocable
milestone payment of US$[**] on Barrier's receipt of said registration
batches.
STAGE 7: Manufacture of validation batches.
STAGE 8: Completion of documentation for submission to Regulatory Agencies.
Barrier to pay Abbott an irrevocable milestone payment of US$[**] on receipt
of said documentation.
18
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
SCHEDULE B-1
WORKPLAN FOR STAGE 1
1. AIM OF WORK
Abbott will seek to adjust the Drug Substance extrudate previously made by its
SOLIQS business unit to meet the properties of the Drug Substance extrudate
manufactured on an [**] by Xxxxxxx Pharmaceutica NV ("Xxxxxxx") at its facility
in Beerse. Xxxxxx'x target is to manufacture reproducible and bioequivalent
batches, in accordance with ICH or FDA guidelines, with those batches used in
clinical trials [**] and [**] or with Sporanox without affecting the
composition of the formulation.
Abbott expects to achieve this target using its Meltrex(TM) Technology by
[**] The basic operating parameters for the [**] extruders are expected to be
[**]
Material will be collected for analytical testing and subsequent milling and
compression trials. Analytical testing will focus on [**]
2. RESPONSIBILITIES OF THE PARTIES
2.1 BARRIER
2.1.1 Barrier will provide Abbott with [**] kg of Triaset mixture, free of
charge, together with any information on drug handling, safety and
relevant toxicolgical data for Drug Substance (at least MDMS) which Abbott
has not previously received.
2.1.2 Barrier will provide and/or update Abbott with full details of the draft
assay, related substances and disssolution methods which Abbott has not
previously received.
2.1.3 Barrier will provide Abbott with samples of the Drug Substance extrudate
produced on the Xxxxxxx [**]
2.2 ABBOTT
2.2.1 Abbott will carry out a maximum of ten different trials using its
Meltrex(TM) Technology, focusing on [**]
2.2.2 Abbott will carry out preliminary stability testing of the Meltrex(TM)
formulations at [**]
2.2.3 In parallel with the above steps, Abbott will also perform process
analysis of the Meltrex(TM) formulations [**]
3. TIMELINES
Abbott will use all reasonable efforts to start the programme of work set out in
this Schedule B-1 within 12 weeks of signing the Agreement, subject to Abbott
receiving in good time the Drug Substance and data requirements set out in
Section 2.1 above.
4. COSTS
Xxxxxx'x costs for carrying out the programme of work set out in this Schedule
B-1 will be US$[**] of which US$[**] will be payable within 30 days of
signature of the Agreement, US$[**] will be payable on Barrier's receipt of
the final feasibility report and US$[**] will be payable on Barrier's
receipt of the short-term stability report.
XXXXXX GMBH & CO. KG BARRIER THERAPEUTICS, INC.
By: /s/ Xxxx Xxxxxxxxxxx By: /s/ Geert Cauwenbergh
----------------------------- --------------------------
Xx. Xxxx Xxxxxxxxxxx Xx. Xxxxx Xxxxxxxxxxx
Head of SOLIQS
By: /s/ Xxxxxxx Xxxxxx Date:
----------------------------- ---------------------------
Xx. Xxxxxxx Xxxxxx
Head of Pharmaceutical
Development, SOLIQS
Date: 16/5/02
-----------------------------
19
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
SCHEDULE C
DELIMITATION OF RESPONSIBILITIES AGREEMENT
(TO BE AGREED)
20
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
ATTACHMENT TO DEVELOPMENT AND SUPPLY AGREEMENT BETWEEN
XXXXXX GMBH & CO. KG AND BARRIER THERAPEUTICS, INC.
AMENDMENT TO SCHEDULE B-1
The parties hereby agree that the short term stability testing envisaged in
Section 2.2.2 of Schedule B-1 (Stage 1) and costing US $[**] shall be
transferred to Schedule B-2 hereunder. The remaining sum to be paid by Barrier
in relation to the work undertaken by Abbott pursuant to Schedule B-1 is
therefore reduced to US $[**] payable to Abbott on Barrier's receipt of the
final feasibility report.
SCHEDULE B-2
WORKPLAN FOR STAGE 3
1. AIM OF WORK
In parallel to the results obtained from the screening Programme (Schedule B-1)
Abbott will select two process parameters to manufacture two (2) batches of Bulk
Product to be used for clinical trial supply. The selection will be made based
on technical parameters. The technical responsibilities will be described
hereinafter. The Delimitation of Pharmaceutical Responsibilities Agreement will
be separately described in Schedule C of this Agreement.
2. RESPONSIBILITIES OF THE PARTIES
2.1 BARRIER
2.1.1 Barrier will provide Abbott with [**] kg of GMP-quality Drug
Substance (as Itraconazole) and [**] kg of GMP-quality HPMC free of charge
together with a Certificate of Analysis and any information on drug handling,
safety and relevant
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
toxicolgical data for Drug Substance (at least MSDS) which Abbott has not
previously received.
2.1.2 Barrier will perform the analytical testing necessary to
release the Bulk Product for further processing.
2.1.3 Barrier will perform milling and tabletting of the Bulk
Product to manufacture the Finished Product applicable for clinical trial
supply.
2.1.4 Barrier will perform the final release of the clinical trial
samples.
2.2 ABBOTT
2.2.1 Abbott will manufacture two (2) batches of Bulk Product under
GMP conditions for human use including mixing of raw materials and extrusion.
2.2.2 In parallel with the above step 2.2.1, Abbott will also
perform [**]
2.2.3 Abbott will carry out short term stability testing of the two
(2) batches of Bulk Product obtained under step 2.2.1 above [**] according to
ICH conditions in bulk container packaging material. [**]
3. TIMELINES
Abbott will use all reasonable efforts to deliver Bulk Product for clinical
trial supply before the end of [**], subject to Abbott receiving in good time
the Drug Substance and data requirements set out in Section 2.1.1 above.
4. COSTS AND PAYMENT SCHEDULE
Xxxxxx'x costs for carrying out the programme of work set out in this Schedule
B-2 will be US$ [**], made up of:
- Manufacture and supply of 2 GMP batches US $ [**]
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
- Process analysis US $ [**]
- Short term stability study (2.2.3) US $ [**]
- (transferred from Section 2.2.2 of Schedule B-1)
Payments will be made to Abbott by Barrier as follows:
- US $ [**] within 30 days of signature of this Schedule B-2,
- US $ [**] on Barrier's receipt of the first GMP batch of Bulk Product from
Abbott,
- US $ [**] on Barrier's receipt of the second GMP batch of Bulk Product
from Abbott,
- US $ [**] exclusivity milestone payment (in accordance with Schedule A)
on Barrier's receipt of the second GMP batch of Bulk Product from Abbott,
and
- US $ [**] on Barrier's receipt of the short term stability report.
XXXXXX GMBH & CO. KG BARRIER THERAPEUTICS, INC.
By: /s/ Xxxx Xxxxxxxxxxx By: /s/ Geert Cauwenbergh
---------------------------------- ----------------------------------
Xx. Xxxx Xxxxxxxxxxx
Head of SOLIQS
By: /s/ Xxx Xxxxx Date: 30 September 2002
---------------------------------- --------------------------------
Dr. Xxx Xxxxx
Head of Business Development
SOLIQS
Date: 27 September 2002
--------------------------------
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
ATTACHMENT TO DEVELOPMENT AND SUPPLY AGREEMENT BETWEEN
XXXXXX GMBH & CO. KG AND BARRIER THERAPEUTICS, INC.
SCHEDULE B-3
WORKPLAN FOR STAGE 3
1. AIM OF WORK
Abbott will manufacture [**] kg Bulk Product, or the maximum amount that can be
manufactured out of the remainder material, to be used for technical assessment
and further manufacturing trials. The selected conditions are equivalent to the
selected conditions for the manufacture under SCHEDULE B-2. The technical
responsibilities will be described hereinafter.
2. RESPONSIBILITIES OF THE PARTIES
2.1 BARRIER
2.1.1 Barrier has provided Abbott with material under the SCHEDULES
B-1 and B-2 and Abbott will now use up the remainder.
2.1.2 Barrier will perform milling and tabletting of the Bulk
Product for technical assessment.
2.2 ABBOTT
2.2.1 Abbott will manufacture [**] kg Bulk Product, or the maximum
amount that can be manufactured out of the remainder material, to be used for
technical assessment and further manufacturing trials including mixing of raw
materials and extrusion.
2.2.2 In parallel with the above step 2.2.1, Abbott will also
perform process analysis of the Meltrex(TM) formulations for [**].
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
3. TIMELINES
Abbott will use all reasonable efforts to deliver Bulk Product for technical
assessment and further manufacturing trials before the end of [**].
4. COSTS AND PAYMENT SCHEDULE
Xxxxxx'x costs for carrying out the programme of work set out in this Schedule
B-3 will be US$ [**] make up of:
- Manufacture and supply of manufacture [**] kg Bulk Product US $ [**]
- Process analysis US $ [**]
Payments will be made to Abbott by Barrier as follows:
- US$[**] within 30 days of signature of this Schedule B-3,
- US$[**] on Barrier's receipt of the report.
XXXXXX GMBH & CO. KG BARRIER THERAPEUTICS, INC.
By: /s/ Xxxx Xxxxxxxxxxx By: /s/ Xxxxxxx X. Xxxxxxx
---------------------------------- ----------------------------------
Xx. Xxxx Xxxxxxxxxxx Xxxxxxx X. Xxxxxxx
Head of SOLIQS COO
By: /s/ Xxx Xxxxx Date: 11-MAR-03
---------------------------------- --------------------------------
Dr. Xxx Xxxxx
Head of Business Development
SOLIQS
Date: 18 March 2003
---------------------------------
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
ATTACHMENT TO DEVELOPMENT AND SUPPLY AGREEMENT BETWEEN
XXXXXX GMBH & CO. KG AND BARRIER THERAPEUTICS, INC.
SCHEDULE B-4
PRE-STAGE 5 WORKPLAN
1. AIM OF WORK
Abbott will manufacture two batches of [**] kg Bulk Product to be used for
technical and analytical assessment and further manufacturing trials. The target
of these trials is to [**]. Analytical testing will be carried out with the
intention of defining methods of distinguishing between different batches of
Bulk Product. The technical responsibilities will be described hereinafter.
2. RESPONSIBILITIES OF THE PARTIES
2.1 BARRIER
2.1.1 Barrier has provided Abbott with sufficient Drug Substance.
2.1.2 Barrier will provide Abbott with reference standards of the
Drug Substance and related compounds necessary for the development and
validation of the HPLC method.
2.1.3 Barrier will perform milling and tabletting of the Bulk
Product for technical assessment. Barrier agrees to inform Abbott about all data
obtained from the tested formulations for a joint evaluation of further steps.
2.2 ABBOTT
2.2.1 Abbott will manufacture two batches each [**] kg Bulk Product
to be used for technical assessment and further assessment of mixing of raw
materials.
2.2.2 In parallel with the above step 2.2.1, Abbott will also
perform [**].
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
2.2.3 Abbott will develop and validate an HPLC method which is
suitable both for the determination of drug content and degradation products in
the Bulk Product and for submission to a Regulatory Agency as part of a New Drug
Application. Step one of the method development will be to determine a suitable
[**]. Step two will be to develop a [**], in which such variables as [**] will
be evaluated. Step three will then be the validation of the [**] which has been
developed in accordance with ICH guidelines. The validation parameters will be
[**] The results will be summarized in a validation report.
2.2.4 Abbott will thoroughly, evaluate the suitability and
reliability of [**] to distinguish between different batches of Bulk Product
with respect to manufacturing parameters such as [**]. In step one, [**] will be
optimized. In step two, the [**] will be evaluated. In step three, the batches
of Bulk Product manufactured hereunder (Section 2.2.1), which were made with the
[**], will be investigated to test the [**]. The [**] will also be evaluated.
The results will be summarized in a report.
2.2.5 Abbott will thoroughly [**] to find characteristics which are
useful in ensuring the quality of Bulk Product. The results will be summarized
in a report.
2.2.6 Based an the results of the evaluations in Sections 2.2.3,
2.2.4 and 2.2.5, Abbott and Barrier will jointly select the analytical and HPLC
methods necessary to be able to set preliminary specifications for Bulk Product
to ensure the efficacy of the Finished Product.
3. TIMELINES
Abbott will use all reasonable efforts to deliver Bulk Product for technical
assessment and further manufacturing trials, and the reports pursuant to
Sections 2.2.4 and 2.2.5, before the end of [**] provided Barrier agrees to this
Schedule B-4 by [**]. Abbott will use all reasonable efforts to complete the
HPLC method development and validation (Section 2.2.3) within [**] of receipt of
the reference samples of Drug Substance and related substances or the signature
of this Schedule B-4, whichever is the later.
4. COSTS AND PAYMENT SCHEDULE
Xxxxxx'x costs for carrying out the programme of work set out in this Schedule
B-4 will be US$ [**] made up of:
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
- Manufacture and supply of two batches each of [**] kg Bulk
Product US$ [**]
- Process analysis (Section 2.2.2) US$ [**]
- Development and validation of HPLC method (Section 2.2.3) US$ [**]
- Evaluation of microscopy methods (Section 2.2.4) US$ [**]
- Evaluation of other methods (Section 2.2.5) US$ [**]
Payments will be made by Barrier to Abbott as follows:
- US$ [**] within 30 days of signature of this Schedule B-4, and
- US$ [**] Barrier's receipt of Xxxxxx'x report.
XXXXXX GMBH & CO. KG BARRIER THERAPEUTICS, INC.
By: /s/ Xxxx Xxxxxxxxxxx By: /s/ Geert Cauwenbergh
---------------------------------- -----------------------------------
Xx. Xxxx Xxxxxxxxxxx
Head of SOLIQS
By: /s/ Xxx Xxxxx Date: 24/04/03
---------------------------------- --------------------------------
Dr. Xxx Xxxxx
Head of Business Development
SOLIQS
Date: 24th April 2003
--------------------------------
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
ATTACHMENT TO DEVELOPMENT AND SUPPLY AGREEMENT BETWEEN
XXXXXX GMBH & CO. KG AND BARRIER THERAPEUTICS, INC.
SCHEDULE B-5
DEVELOPMENT AND PREPARATION OF REGISTRATION BATCHES (STAGES 5 AND 6)
1. AIM OF WORK
As a result of the pilot biostudy carried out by Barrier using Bulk Product
supplied by Abbott according to Schedule B-2, Barrier now wishes Abbott to
perform the necessary additional pharmaceutical development programme and
manufacture of six (6) batches each of [**] kg Bulk Product to be used for a
pivotal study and for long-term stability testing prior to submission by Barrier
of an NDA for Finished Product.
The technical responsibilities are described hereunder.
2. RESPONSIBILITIES OF THE PARTIES
2.1 BARRIER
2.1.1 Barrier has already provided Abbott with sufficient Drug Substance for
this programme.
2.1.2 Barrier, or its nominee, will perform milling and tabletting of the Bulk
Product to produce Finished Product.
2.1.3 Barrier, or its nominee, will perform release and other testing in
accordance with the Delimitation of Pharmaceutical Responsibilities
Agreement set out in Schedule C to this Agreement.
2.2 ABBOTT
2.2.1 Abbott will carry out process development of the selected formulation of
Bulk Product on its [**] in accordance with the Development Protocol
agreed between the parties and attached hereto as Appendix A.
2.2.2 Abbott will provide Barrier, or its nominee, with samples (approximately
[**] kg) of Bulk Product resulting from this process development programme
("mock NDA lot") for Barrier, or its nominee, to carry out further milling
and tabletting experiments.
2.2.3 Abbott will then manufacture six (6) batches of Bulk Product using the
[**], each batch being [**] kg, and will supply these six (6) batches to
Barrier, or its nominee, for milling and tabletting into Finished product.
2.2.4 Abbott will carry out in process controls and analytical characterization
appropriate for NDA batches. Abbott will take forensic samples for the FDA
and will provide such samples to Barrier or its nominee.
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
2.2.5 Abbott will provide Barrier with copies of executed batch records,
including all associated documentation such as test results and any
deviation reports.
2.2.6 Abbott will provide Barrier with a final development report as soon as
reasonably possible after completing the development programme.
3. TIMELINES
Abbott will use all reasonable efforts to deliver the first [**] kg NDA batch of
Bulk Product to Barrier, or its nominee, by [**]. Abbott will use all reasonable
efforts to deliver the remaining five (5) [**] kg batches of Bulk Product to
Barrier, or its nominee, by [**]. Abbott will use all reasonable efforts to
complete the NDA documentation by end of [**].
4. COSTS AND PAYMENT SCHEDULE
Xxxxxx'x costs for carrying out the programme of work set out in this Schedule
B-5 will be E [**] made up of:
- Process development related to manufacture of NDA
batches (of which Part A + Part B = E[**]; Part C = E[**]) E[**]
- Preparation of NDA documentation E[**]
- Manufacture of six NDA batches E[**]
- Process analysis E[**]
- Development report E[**]
Payments will be made by Barrier to Abbott as follows:
- E[**] within 30 days of signature of this Schedule B-5;
- E[**] on supply by Abbott of sixth NDA batch;
- Milestone payment of US$[**] on Barrier's, or its nominee's, receipt of the
sixth NDA batch;
- E[**] on Barrier's receipt of Xxxxxx'x development report;
- E[**] on completion by Abbott of process development Part C.
** Certain information in this exhibit has been omitted and will be filed
separately with the Securities and Exchange Commission pursuant to a
confidential treatment request.
XXXXXX GMBH & CO. KG BARRIER THERAPEUTICS, INC.
By: ppa /s/ Xxxx Xxxxxxxxxxx By: /s/ Xxxxxxx X. Xxxxxxx
---------------------------------- ------------------------
Xx. Xxxx Xxxxxxxxxxx
Director, Head of SOLIQS
Date: 16-JUL-03
----------
By: /s/ Xxxxxx Xxxxxx
----------------------------------
Xx. Xxxxxx Xxxxxx
Divisional Vice President
German Operations
Date: June 17th 2003
---------------
APPENDIX A
DEVELOPMENT PROTOCOL
(ATTACHED)
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. KG - Knollstra(beta)e 50 - D-67061 Ludwigshafen
Laboratory Code GED.0032 40 % D E-Granules
Catalogue No.: 17200198
INN: Itraconazole
Protocol No.: GSD GED.0032 40% IR EP 030403 / 01
Date of Protocol: June 2003
Title: Development Protocol
Pharmaceutical Development of GED.0032 40 % DE-Granules
Trial Design
Compiled by: Xx. X. Xxxxxx
Checked by: Xx. X. Xxxxxxxx
Xx. X. Xxxxxxxxxx
Agreed by: Xx. Xxxxxxxxx Xxxxxxxx
Department: Xxxxxx GmbH & Co. KG
Soliqs
Pharmaceutical Development
Xxxxxxxxx(xxxx)x
00000 Xxxxxxxxxxxx / Xxxxxxx
Language: English
Pages total: 9
compiled by
Pharmaceutical Development:
/s/ Xxxxxxx Xxxxxx
------------------------------------
Dr. rer. nat. Xxxxxxx Xxxxxx Date: 17. June 2003
Licensed Pharmacist
checked by
Pharmaceutical Development:
/s/ X. Xxxxxxxx
------------------------------------
Dr. rer. nat. Xxxxxx Xxxxxxxx Date: 17. June 2003
Chemist
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. KG - Knollstra(beta)e 50 - D-67061 Ludwigshafen
Analytical Development:
/s/ [illegible]
------------------------------------
Dr. rer. nat. Xxxxxx Xxxxxxxxxx Date: 17. June 2003
Licensed Pharmacist
Agreed by:
Barrier Therapeutics, Inc.:
/s/ Xxxxxxxxx Xxxxxxxx
------------------------------------
Xx. Xxxxxxxxx Xxxxxxxx Date: 16 JUNE 2003
Head of Chemistry, Manufacturing & Controls
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. XX - Xxxxxxxxx(xxxx)x 00 - X-00000 Xxxxxxxxxxxx
Table of content
1 Composition............................................................ 4
2 Manufacturing flow..................................................... 5
3 Process steps considered to be subject of process development.......... 6
4 Trial design for development........................................... 6
4.1 Blending 1 - Manufacturing of powder mixture........................... 6
4.1.1 Trial design........................................................... 6
4.1.2 Acceptance criteria.................................................... 6
4.2 Extrusion/Calendering - Manufacturing of extrudate..................... 7
4.2.1 Trial design Part 1.................................................... 7
4.2.2 Trial design Part 2.................................................... 8
4.2.3 Analytical methods..................................................... 9
4.2.4 Acceptance criteria.................................................... 9
4.2.5 Sampling procedure..................................................... 9
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. KG - Knollstra(beta)e 50 - D-67061 Ludwigshafen
1 COMPOSITION
1.1 Composition of extruded granules
Quantity Quantity
No. Ingredient [mg/g] [%] Cat. No.
----------------------------------------------------------------
Extruded Granules
1 GED.0032 400.0 40.0 10002046
2 HPMC 2910 5mPas Xxxxxxx 600.0 60.0 10002045
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. KG - Knollstra(beta)e 50 - D-67061 Ludwigshafen
2 MANUFACTURING FLOW
BLENDING 1
Manufacturing of powder mixture
Mixture for extrusion
EXTRUSION/CALANDERING
MANUFACTURING OF EXTRUDATES
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. KG - Knollstra(beta)e 50 - D-67061 Ludwigshafen
3 PROCESS STEPS CONSIDERED TO BE SUBJECT OF PROCESS DEVELOPMENT
Process Step Process parameter to be investigated Product parameter to be investigated
--------------------------------------------------------------------------------------------------------------------
BLENDING 1 Mixing time Blend uniformity of GED.0032
Manufacturing of powder Loading of container Bulk/tapped volume/density
mixture Container size Particle size distribution
Angle of repose
Moisture content
EXTRUSION/CALANDERING Temperature barrel Potency of GED.0032
Manufacturing of extrudates Temperature nozzle Related Substances
Screw speed Crystallinity of GED.0032
Mass flow Moisture content
Vacuum Visual content
Temperature calendar rollers
Reservoir size for calendering
Process interruption/re-start
4 TRIAL DESIGN FOR DEVELOPMENT
4.1 Blending 1 - Manufacturing of powder mixture
4.1.1 TRIAL DESIGN
PARAMETER TRIAL DESIGN PRODUCT PARAMETER TO BE INVESTIGATED
--------------------------------------------------------------------------------------------------------
Particle size
Blend Bulk/tapped distribution Moisture
uniformity volume/density Angle of repose content (LOD)
--------------------------------------------------------------------------------------------------------
Mixing time Sampling after X
different mixing
times
Mixing time Sampling at X X X X
end point
Loading of container Mixing of X X X X
different loadings
Container size Mixing in X X X X
different
container size
4.1.2 ACCEPTANCE CRITERIA
Potency of GED.0032: 95 - 105%
Content uniformity of GED.0032: rel. standard deviation < or = 6%
individual values: 85 - 115%
Bulk/tapped volume/density: only for information
Particle size distribution: only for information
Angle of repose: only for information
Moisture content (LOD): only for information
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. KG - Knollstra(beta)e 50 - D-67061 Ludwigshafen
Extrusion/Calendering - Manufacturing of extrudate
4.2 TRIAL DESIGN PART 1
Crystallinity
Content GED.0032;
Potency uniformity Related thermal Moisture content
Parameter Trial Design GED.0032 GED.0032 Substances behavior (LOD and K.F) Visual Control
------------------------------------------------------------------------------------------------------------------------------------
Baseline trial Baseline adjustments X X X X X
Temperature of Sampling at different X X X X X
barrel or nozzle / combinations of
screw speed / feed temperature / screw
rate speed / feed rate
adjustments
Mass flow Sampling at different X X X X X
mass flow adjustments
Vacuum Sampling at different X X X X X
vacuum adjustments
Process Sampling at different X X X X X X
duration product time points
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. XX - Xxxxxxxxx(xxxx)x 00 - X-00000 Xxxxxxxxxxxx
4.2.2 TRIAL DESIGN PART 2
Crystallinity
Content GED.0032; Moisture
Potency uniformity Related thermal content Visual
Parameter Trial Design GED.0032 GED.0032 Substances behavior (LOD and K.F) Control
---------------------------------------------------------------------------------------------------------------------------
Temperature barrel Sampling at different X X X X X
temperature adjustments
Temperature nozzle Sampling at different X X X X X
temperature adjustments
Screw speed Sampling at different X X X X X
screw speed adjustments
Starting procedures Sampling at different X X X X X
time points during
starting
Interruption / Sampling at different X X X X X
re-start time points before /
after interruption /
restart
Temperature Sampling at different X X X X X
calendar roller temperature adjustments
Reservoir size for Sampling at different X X X X X
calendering reservoir size
adjustments
Hold time of Baseline adjustments X X X X X X
Blend 1
Confidential property of Xxxxxx GmbH & Co. KG
Development Protocol
Soliqs
GSD - Pharm. Development Xxxxxx GmbH & Co. XX - Xxxxxxxxx(xxxx)x 00 - X-00000 Xxxxxxxxxxxx
4.2.3 ANALYTICAL METHODS
Potency and related substances: PA_X1406_LC
Content uniformity of GED.0032: PA_X1406_LC
Crystallinity of GED.0032, PA_X1406_TA
thermal behavior
Moisture content
(Xxxx Xxxxxxx Titration, K.F.) PA_X0001_KF
4.2.4 ACCEPTANCE CRITERIA
Potency of GED.0032: 95 - 105%
Content uniformity of GED.0032: rel. standard deviation < or = 6%
individual values: 85-115%
Related substances: only for information
Crystallinity of GED.0032,
thermal behavior: only for information
Moisture content (K.F.): max. 1.5%
LOD only for information
4.2.5 SAMPLING PROCEDURE
Sampling is done according SOP EX 30. Standard sampling is beginning, middle end
of process and a composite sample. Deviation is possible as fixed in the
instruction.
CU testing for extrudate: 10 individual samples are pulled from composite sample
(500 mg to 1000 mg lentils).];
Confidential property of Xxxxxx GmbH & Co. KG
