Exhibit 10.12

 

Execution Copy

 

DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT*

 

THIS DEVELOPMENT AND MANUFACTURING SERVICES AGREEMENT is made and entered into as of October 16, 2007 (the “Effective Date”) by and between RADIUS HEALTH, INC., a Delaware corporation having an address at 300 Technology Square, 5th Floor, Cambridge, MA 02139 (together with its Affiliates, “RADIUS”) and LONZA Sales Ltd, a Swiss company having an address at Muenchensteinerstrasse 38, CH-4002 Basel, Switzerland (together with its Affiliates, “Manufacturer”).

 

RECITALS:

 

WHEREAS, RADIUS desires to engage Manufacturer to perform certain Development or Manufacturing Services (as those terms are defined below), on the terms and conditions set forth below, and Manufacturer desires to perform such Services for RADIUS.

 

AGREEMENT:

 

NOW, THEREFORE, in consideration of the foregoing premises and the mutual covenants of the parties set forth in this Agreement, the parties hereto agree as follows:

 

1.             Definitions.  Unless this Agreement expressly provides to the contrary, the following terms, whether used in the singular or plural, have the respective meanings set forth below:

 

1.1           “Affiliate” means, with respect to a party, any person or entity which controls, is controlled by or is under common control with such party.  As used in this Section, “control”  means (a) in the case of corporate entities, direct or indirect ownership of at least fifty percent (50%) of the stock or shares having the right to vote for the election of directors, and (b) in the case of non-corporate entities, the direct or indirect power to manage, direct or cause the direction of the management and policies of the non-corporate entity or the power to elect at least fifty percent (50%) of the members of the governing body of such non-corporate entity.

 

1.2           “Agreement” means this Development and Manufacturing Services Agreement, together with all Appendices attached hereto, as amended from time to time by the parties in accordance with Section 15.6, and all fully signed Work Orders entered into by the parties.

 

1.3           “API/Drug Substance”  means the active pharmaceutical ingredient identified on the applicable Work Order or any intermediate of such active pharmaceutical ingredient.

 

1.4           “Applicable Law” means all applicable ordinances, rules, regulations, laws, guidelines, guidances, requirements and court orders of any kind whatsoever of any Authority, as amended from time to time, including without limitation, cGMP (if applicable).

 

1.5           “Authority” means any government regulatory authority responsible for granting approvals for the performance of Services under this Agreement or for issuing regulations

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

CONFIDENTIAL

 

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pertaining to the Manufacture and/or use of Product in the intended country of use, including, without limitation, the FDA.

 

1.6           “Batch” means a specific quantity of Product that is intended to be of uniform character and quality, within specified limits, and is produced during the same cycle of Manufacture as defined by the applicable Batch Record.

 

1.7           “Batch Documentation” has the meaning set forth in Section 6.2.

 

1.8           “Certificate of Analysis” means a document, signed by an authorized representative of Manufacturer, describing Specifications for, and testing methods applied to, Product, and the results thereof.

 

1.9           “Certificate of Compliance” means a document, signed by an authorized representative of Manufacturer, certifying that a particular Batch was Manufactured in accordance with cGMP (if applicable), all other Applicable Law, and the Specifications.

 

1.10         “cGMP” means current good manufacturing practices applicable to the Manufacture of Product promulgated by any Authority.

 

1.11         “Change Order” has the meaning set forth in Section 5.3.

 

1.12         “Confidential Information”  has the meaning set forth in Section 10.

 

1.13         “Develop” or “Development” means the studies and other activities conducted by Manufacturer under this Agreement to develop all or any part of a Manufacturing Process including, without limitation, analytical tests and methods, formulations and dosage forms.

 

1.14         “Equipment” means any equipment or machinery used by Manufacturer in the Development and/or Manufacturing of Product, or the holding, processing, testing, or release of Product.

 

1.15         “Facility” means the facilities of Manufacturer’s Affiliate Lonza S.A., Chausée de Tubize 297, B-1420 Braine l’Alleud, Belgium, unless otherwise identified in the applicable Work Order.

 

1.16         “FDA” means the United States Food and Drug Administration, and any successor agency having substantially the same functions.

 

1.17         “FDCA” means the United States Federal Food, Drug and Cosmetic Act, 21 U.S.C.  §321 et seq., as amended from time to time.

 

1.18         “force majeure” has the meaning set forth in Section 15.3.

 

1.19         “Improvements” means all Technology and discoveries, inventions, developments, modifications, innovations, updates, enhancements, improvements, writings or rights (whether or not protectable under patent, trademark, copyright or similar laws) that are

 

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conceived, discovered, invented, developed, created, made or reduced to practice in the performance of Services under this Agreement.

 

1.20         “IND” means an Investigational New Drug application filed with the FDA in accordance with Applicable Law.

 

1.21         “Manufacture” and “Manufacturing” means any steps, processes and activities necessary to produce Product, including without limitation, the manufacturing, processing, packaging, labeling, quality control testing, release, storage or supply of Product.

 

1.22         “Manufacturer Indemnitee” has the meaning set forth in Section 12.2.

 

1.23         “Manufacturer Technology” means the Technology of Manufacturer (a) existing prior to the Effective Date, or (b) developed or obtained by or on behalf of Manufacturer independent of this Agreement and without reliance upon Confidential Information of RADIUS.

 

1.24         “Manufacturing Process” means any and all processes (or any step in any process) used or planned to be used by Manufacturer to Manufacture Product, consistent with the relevant Work Order and as evidenced in the Batch Documentation or master Batch Documentation.

 

1.25         “Product” means any API/Drug Substance or drug product comprised of API/Drug Substance, and any intermediates of the foregoing, in each case as specified in the applicable Work Order, including, if applicable, bulk packaging and/or labeling as provided in such Work Order.

 

1.26         “Quality Agreement” has the meaning set forth in Section 2.2.

 

1.27         “RADIUS Indemnitee” has the meaning set forth in Section 12.1.

 

1.28         “RADIUS Equipment” means the Equipment, if any, identified on the applicable Work Order as being provided by RADIUS or purchased or otherwise acquired by Manufacturer at RADIUS’ expense.

 

1.29         “RADIUS Materials” means the materials, and any intermediates or derivatives thereof, identified in the applicable Work Order as being provided by RADIUS including labels (if any) for Product.

 

1.30         “RADIUS Technology” means (a) RADIUS Materials, (b) Product and any intermediates or derivatives thereof, (c) Specifications, and (d) the Technology of RADIUS owned, developed or obtained by or on behalf of RADIUS prior to the Effective Date, or developed or obtained by or on behalf of RADIUS independent of this Agreement and without reliance upon the Confidential Information and Technology of Manufacturer.

 

1.31         “Records” has the meaning set forth in Section 5.4(a).

 

1.32         “Representative” has the meaning set forth in Section 3.1.

 

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1.33         “Reprocess” and “Reprocessing” means introducing a Product back into the process and repeating appropriate manipulation steps that are part of the established Manufacturing Process.  Continuation of a process step after an in-process control test show the process to be incomplete is not considered reprocessing.

 

1.34         “Rework” and “Reworking” means subjecting a Product to one or more processing steps that are different from the established Manufacturing Process.

 

1.35         “Services” means the Development, Manufacturing and/or other services described in a Work Order entered into by the parties.

 

1.36         “Specifications” means the list of tests, references to any analytical procedures and appropriate acceptance criteria which are numerical limits, ranges or other criteria for tests described in order to establish a set of criteria to which Product at any stage of Manufacture should conform to be considered acceptable for its intended use that are provided by or approved by RADIUS, as such specifications are amended or supplemented from time to time by RADIUS in writing.

 

1.37         “Technology” means all methods, techniques, trade secrets, copyrights, know-how, data, documentation, regulatory submissions, specifications and other intellectual property of any kind (whether or not protectable under patent, trademark, copyright or similar laws).

 

1.38         “Work Order” means a written work order, substantially in the form attached hereto as Appendix A, for the performance of Services by Manufacturer under this Agreement.

 

2.             Engagement of Manufacturer.

 

2.1           Services and Work Orders.  From time to time, RADIUS may wish to engage Manufacturer to perform Services for RADIUS.  Such Services will be set forth in a Work Order.  Each Work Order will be appended to this Agreement and will set forth the material terms for the project, and may include the scope of work, specified Services, Specifications, deliverables, estimated timelines, milestones (if any), quantity, budget, payment schedule and such other details and special arrangements as are agreed to by the parties with respect to the activities to be performed under such Work Order.  No Work Order will be effective unless and until it has been agreed to and signed by authorized representatives of both parties.  Documents relating to the relevant project, including without limitation Specifications, proposals, quotations and any other relevant documentation, will be attachments to the applicable Work Order and incorporated in the Work Order by reference.  Each fully signed Work Order will be subject to the terms of this Agreement and will be incorporated herein and form part of this Agreement.  Manufacturer will perform the Services specified in each fully signed Work Order, as amended by any applicable Change Order(s), and in accordance with the terms and conditions of such Work Order and this Agreement.  Notwithstanding the foregoing, nothing in this Agreement will obligate either party to enter into any Work Order under this Agreement.

 

2.2           Quality Agreement.  If appropriate or if required by Applicable Law, the parties will also agree upon a Quality Agreement containing quality assurance provisions for the Manufacture of Product (“Quality Agreement”), which agreement will also be attached to the applicable Work Order and incorporated by reference in the Work Order.

 

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2.3           Conflict Between Documents.  If there is any conflict, discrepancy, or inconsistency between the terms of this Agreement and any Work Order, Quality Agreement, purchase order, or other form used by the parties, the terms of this Agreement will control.

 

3.             Project Performance.

 

3.1           Representatives.  Each party will appoint a representative having primary responsibility for day-to-day interactions with the other party for the Services (each, a “Representative”), who will be identified in the applicable Work Order.  Each party may change its Representative by providing written notice to the other party in accordance with Section 15.3; provided that Manufacturer will use reasonable efforts to provide RADIUS with at least [*] ([*]) days prior written notice of any change in its Representative for the Services.  Except for notices or communications required or permitted under this Agreement, which will be subject to Section 15.3, or unless otherwise mutually agreed by the parties in writing, all communications between Manufacturer and RADIUS regarding the conduct of the Services pursuant to such Work Order will be addressed to or routed directly through the parties’ respective Representatives.

 

3.2           Communications.  The parties will hold project team meetings via teleconference or in person, on a periodic basis as agreed upon by the Representatives.  Manufacturer will make written reports to RADIUS as specified in the applicable Work Order.

 

3.3           Subcontracting.  Manufacturer may not subcontract with any third party to perform any of its obligations under this Agreement without the prior written consent of RADIUS.  Manufacturer will be solely responsible for the performance of any permitted subcontractor, and for costs, expenses, damages, or losses of any nature arising out of such performance as if such performance had been provided by Manufacturer itself under this Agreement.  Manufacturer will cause any such permitted subcontractor to be bound by, and to comply with, the terms of this Agreement, as applicable, including without limitation, all confidentiality, quality assurance, regulatory and other obligations and requirements of Manufacturer set forth in this Agreement.

 

3.4           Duty to Notify.  If Manufacturer, at any time during the term of this Agreement, has reason to believe that it will be unable to perform or complete the Services, Manufacturer will promptly notify RADIUS thereof.  Compliance by Manufacturer with this Section 3.4 will not relieve Manufacturer of any other obligation or liability under this Agreement.

 

4.             Materials and Equipment.

 

4.1           Supply of Materials.  Unless the parties otherwise agree in a Work Order, Manufacturer will supply, in accordance with the relevant approved raw material specifications, all materials to be used by Manufacturer in the performance of Services under a Work Order other than the RADIUS Materials specified in such Work Order.  RADIUS or its designees will provide Manufacturer with the RADIUS Materials.  Manufacturer agrees (a) to account for all RADIUS Materials, (b) not to provide RADIUS Materials to any third party without the express prior written consent of RADIUS, (c) not to use RADIUS Materials for any purpose other than

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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conducting the Services, including, without limitation, not to analyze, characterize, modify or reverse engineer any RADIUS Materials or take any action to determine the structure or composition of any RADIUS Materials unless required pursuant to a signed Work Order, and (d) to destroy or return to RADIUS all unused quantities of RADIUS Materials according to RADIUS’ written directions.

 

4.2           Ownership of Materials.  RADIUS will at all times retain title to and ownership of the RADIUS Materials, Product, any intermediates (and components thereof), and any work in process at each and every stage of the Manufacturing Process.  Manufacturer will provide within the Facility an area or areas where the RADIUS Materials, Product, any intermediates (and components thereof), and any work in process are segregated and stored in accordance with the Specifications and cGMP (if applicable), and in such a way as to be able at all times to clearly distinguish such materials from products and materials belonging to Manufacturer, or held by it for a third party’s account.  Manufacturer will at all times take such measures as are required to protect the RADIUS Materials, Product, any intermediates (and components thereof), and any work in process from risk of loss or damage at all stages of the Manufacturing Process.  Manufacturer will ensure that RADIUS Materials, Product, any intermediates (and components thereof), and any work in process are free and clear of any liens or encumbrances.  Manufacturer will immediately notify RADIUS if at any time it believes any Product or RADIUS Materials have been damaged, lost or stolen.

 

4.3           Supply of Equipment.  Unless otherwise agreed in a Work Order, Manufacturer will supply all Equipment necessary to perform the Services.

 

5.             Development and Manufacture of Product.

 

5.1           Resources; Applicable Law.  Manufacturer will comply with all Applicable Law in performing Services.

 

5.2           Facility.

 

(a)           Performance of Services.  Manufacturer will perform all Services at the Facility, provide all staff necessary to perform the Services in accordance with the terms of the applicable Work Order and this Agreement, and hold at such Facility all Equipment, RADIUS Equipment, RADIUS Materials and other items used in the Services.  Manufacturer will not change the location of such Facility or use any additional facility for the performance of Services under this Agreement without at least [*] ([*]) days prior written notice to, and prior written consent from, RADIUS, which consent will not be unreasonably withheld or delayed (it being understood and agreed that RADIUS may withhold consent pending satisfactory completion of a quality assurance audit and/or regulatory impact assessment of the new location or additional facility, as the case may be).  Manufacturer will maintain, at its own expense, the Facility and all Equipment required for the Manufacture of Product in a state of repair and operating efficiency consistent with the requirements of the cGMP (if applicable) and all Applicable Law.

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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(b)           Validation.  Manufacturer will be responsible for performing all validation of the Facility, Equipment and cleaning and maintenance processes employed in the Manufacturing Process in accordance with cGMP, Manufacturer’s internal SOPs, the applicable Quality Agreement, Applicable Law, and in accordance with any other reasonable validation procedures established by RADIUS and made known in writing to Manufacturer.  Manufacturer will also be responsible for ensuring that all such validated processes are carried out in accordance with their terms.

 

(c)           Licenses and Permits.  Manufacturer will be responsible for obtaining, at its expense, any Facility or other licenses or permits, and any regulatory and government approvals necessary for the performance of Services by Manufacturer under this Agreement.  At RADIUS’ request, Manufacturer will provide RADIUS with reasonable copies of all such approvals and submissions to Authorities, and RADIUS will have the right to use any and all information contained in such approvals or submissions in connection with regulatory approval and/or commercial development of Product.

 

(d)           Access to Facility.  Upon prior notice, Manufacturer will permit RADIUS or its duly authorized representatives, such representatives having to enter into a reasonable separate confidentiality agreement with Manufacturer, to reasonably observe and consult with Manufacturer during the performance of Services under this Agreement, including without limitation the Manufacturing of any Batch of Product.  Manufacturer also agrees that RADIUS and its duly authorized agents, upon prior notice, will have reasonable access, during operational hours and during active Manufacturing, to inspect the Facility and Manufacturing Process to ascertain compliance by Manufacturer with the terms of this Agreement, including, without limitation, inspection of (i) the Equipment and materials used in the performance of Services, (ii) the holding facilities for such materials and Equipment, and (iii) all Records relating to such Services and the Facility.  RADIUS will also have the right, at its expense, to reasonably conduct “mock” pre-approval audits upon prior notice to Manufacturer, and Manufacturer agrees to cooperate with RADIUS in such “mock audits.”

 

5.3           Changes to Work Orders, Manufacturing Process and Specifications.

 

(a)           Changes to Work Orders.  If the scope of work of a Work Order changes, especially the estimated timelines, then the applicable Work Order may be amended as provided in this Section 5.3(a).  If a required modification to a Work Order is identified by RADIUS, or by Manufacturer, the identifying party will notify the other party in writing as soon as reasonably possible.  Manufacturer will provide RADIUS with a change order containing a description of the required modifications and their effect on the scope, fees and estimated timelines specified in the Work Order (“Change Order”) and will use reasonable efforts to do so within ten (10) business days of receiving or providing such notice, as the case may be.  No Change Order will be effective unless and until it has been signed by authorized representatives of both parties.  If RADIUS does not approve such Change Order, and has not terminated the Work Order, but requests the Work Order to be amended to take into account the modification, then the parties will use reasonable efforts to agree on a Change Order that is mutually acceptable.  If practicable, Manufacturer will continue to work on the existing Work Order during any such negotiations, provided such efforts would facilitate the completion of the work envisioned in the

 

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proposed Change Order, but will not commence work in accordance with the Change Order until it is authorized in writing by RADIUS.

 

(b)           Process/Specifications Changes.  Any change or modification to the Manufacturing Process or Specifications for any Product must be approved in advance by both parties and will be made in accordance with the change control provisions of the applicable Quality Agreement.  Any such change or modification can result in lower or higher costs, and the parties herewith agree to enter into good-faith negotiations concerning any such price deviation; provided, however, that RADIUS will not be responsible for any increase in price unless agreed in writing by RADIUS.

 

5.4           Record and Sample Retention.

 

(a)           Records.  Manufacturer will keep complete and accurate records (including without limitation reports, accounts, notes, data, and records of all information and results obtained from performance of Services) of all work done by it under this Agreement, in form and substance as specified in the applicable Work Order, the applicable Quality Agreement, and this Agreement (collectively, the “Records”).  Manufacturer will not transfer, deliver or otherwise provide any such Records to any party other than RADIUS, without the prior written approval of RADIUS.  Upon prior notice, Records will be available at reasonable times for inspection, examination and copying by or on behalf of RADIUS.  All original Records of the Development and Manufacture of Product under this Agreement will be retained and archived by Manufacturer in accordance with cGMP (if applicable) and Applicable Law, but in no case for less than a period of [*] ([*]) years following completion of the applicable Work Order.  Upon RADIUS’ request, Manufacturer will promptly provide RADIUS with copies of such Records.  [*] ([*]) years after completion of a Work Order, all of the aforementioned records will be sent to RADIUS or RADIUS’ designee; provided, however, that RADIUS may elect to have such records retained in Manufacturer’s archives for an additional period of time at a reasonable charge to RADIUS.  For the avoidance of doubt, RADIUS herewith takes note that certain Records are written in French as the Facility is in Belgium.  RADIUS shall pay all costs incurred with any translation of such Records requested by RADIUS.

 

(b)           Sample Retention.  Manufacturer will take and retain, for such period and in such quantities as may be required by cGMP (if applicable) and the applicable Quality Agreement, samples of Product from the Manufacturing Process produced under this Agreement.  Further, Manufacturer will submit such samples to RADIUS, upon RADIUS’ written request.

 

5.5           Regulatory Matters.

 

(a)           Regulatory Approvals.  RADIUS will be responsible for obtaining, at its expense, all regulatory and governmental approvals and permits necessary for RADIUS’ use of any Product Developed and/or Manufactured under this Agreement, including, without limitation, IND submissions and any analogous submissions filed with the appropriate Authority of a country other than the United States.  Manufacturer will be responsible for providing

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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RADIUS with all supporting data and information relating to the Development and/or Manufacture of Product reasonably necessary for obtaining such approvals, including, without limitation, all Records, raw data, reports, authorizations, certificates, methodologies, Batch Documentation, raw material specifications, SOPs, standard test methods, Certificates of Analysis, Certificates of Compliance and other documentation in the possession or under the control of Manufacturer relating to the Development and Manufacture of Product (or any component thereof).

 

(b)           Regulatory Inspections.  Manufacturer will permit RADIUS or its agents to be present and participate in any visit or inspection by any Authority of the Facility (to the extent it relates in any way to any RADIUS Product) or the Manufacturing Process.  Manufacturer will give as much advance notice as possible to RADIUS of any such visit or inspection.  Manufacturer will provide to RADIUS a copy of any report or other written communication received from such Authority in connection with such visit or inspection, and any written communication received from any Authority relating to any RADIUS Product, the Facility (if it relates to or affects the Development and/or Manufacture of Product) or the Manufacturing Process, within [*] ([*]) hours after receipt thereof, and will consult with RADIUS before responding to each such communication.  Manufacturer will provide RADIUS with a copy of its final responses within [*] ([*]) business days after submission thereof.

 

5.6           Waste Disposal.  The generation, collection, storage, handling, transportation, movement and release of hazardous materials and waste generated in connection with the Services will be the responsibility of Manufacturer at Manufacturer’s sole cost and expense.  Without limiting other applicable requirements, Manufacturer will prepare, execute and maintain, as the generator of waste, all licenses, registrations, approvals, authorizations, notices, shipping documents and waste manifests required under Applicable Law.

 

5.7           Safety Procedures.  Manufacturer will be solely responsible for implementing and maintaining health and safety procedures for the performance of Services and for the handling of any materials or hazardous waste used in or generated by the Services.  Manufacturer, in consultation with RADIUS, will develop safety and handling procedures for API/Drug Substance and Product; provided, however, that RADIUS will have no responsibility for Manufacturer’s health and safety program.  Should such safety and handling procedures materially deviate from Manufacturer’s existing health and safety program and require additional investment on the part of Manufacturer, the parties shall agree in writing in advance on reasonable charges to RADIUS for such procedures.

 

5.8           Technology Transfer.  If RADIUS elects to Manufacture Product, or to have Product Manufactured by a third party, then Manufacturer will provide to RADIUS, or its designee, all Manufacturing information, including, without limitation, documentation, technical assistance, materials and cooperation by appropriate employees of Manufacturer as RADIUS or its designee may reasonably require in order to Manufacture Product.  RADIUS will compensate Manufacturer for such assistance at the hourly-rate(s) set forth in the applicable Work Order, or such other reasonable rate(s) as the parties may agree in writing.  If such a move or replication of

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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Manufacture of Product involves Manufacturer Technology incorporated into the Manufacturing Process pursuant to the express terms of any relevant Work Order, the parties will negotiate in good-faith in order to determine a reasonably royalty fee or other reasonable consideration to be paid to Manufacturer by RADIUS for the right to continue to use such Manufacturer Technology.

 

6.             Testing and Acceptance Process.

 

6.1           Testing by Manufacturer.  The Product to be Manufactured under this Agreement will be Manufactured in accordance with cGMP, unless otherwise stated in the Work Order, and the Manufacturing Process approved by RADIUS.  Each Batch of Product will be sampled and tested by Manufacturer against the Specifications, and the quality assurance department of Manufacturer will review the records relating to the Manufacture of the Batch and will assess if the Manufacture has taken place in compliance with cGMP (if applicable) and the Manufacturing Process.

 

6.2           Provision of Records.  If, based upon such tests, a Batch of Product conforms to the Specifications and was Manufactured according to cGMP (if applicable) and the Manufacturing Process, then a Certificate of Compliance will be completed and approved by the quality assurance department of Manufacturer.  This Certificate of Compliance, a Certificate of Analysis and the Specifications (collectively, the “Batch Documentation”, excluding any batch and master batch records) for each Batch of Product will be delivered to RADIUS by a reputable overnight courier or by registered or certified mail, postage prepaid, return receipt required to verify delivery date.  Upon reasonable request, Manufacturer will also deliver to RADIUS all raw data, reports, authorizations, certificates, methodologies, raw material specifications, SOPs, standard test methods, and other documentation in the possession or under the control of Manufacturer relating to the Manufacture of each Batch of Product.  If RADIUS has not received all such Batch Documentation at the time of receipt of the Batch, RADIUS will notify Manufacturer in writing.  If RADIUS requires additional copies of such Batch Documentation, these will be provided by Manufacturer to RADIUS at cost.

 

(a)           Review of Batch Documentation; Acceptance.  RADIUS will review the Batch Documentation for each Batch of Product and may test samples of the Batch of Product against the Specifications.  For the avoidance of doubt, RADIUS herewith takes note that certain parts of the Batch Documentation will be written in French as the Facility is in Belgium.  RADIUS shall pay all costs incurred with any translation of such Records requested by RADIUS.  RADIUS will notify Manufacturer in writing of its acceptance or rejection of such Batch within [*] ([*]) weeks of receipt of the complete Batch Documentation relating to such Batch.  During this review period, the parties agree to respond promptly, but in any event within [*] ([*]) days, to any reasonable inquiry by the other party with respect to such Batch Documentation.  RADIUS has no obligation to accept a Batch if such Batch does not comply with the Specifications and/or was not Manufactured in compliance with cGMP (if applicable) and the Manufacturing Process.

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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6.3           Disputes.  In case of any disagreement between the parties as to whether Product conforms to the applicable Specifications or cGMP (if applicable), the quality assurance representatives of the parties will attempt in good faith to resolve any such disagreement and RADIUS and Manufacturer will follow their respective SOPs to determine the conformity of the Product to the Specifications and cGMP (if applicable).  If the foregoing discussions do not resolve the disagreement in a reasonable time (which will not exceed [*] ([*]) days), a representative sample of such Product will be submitted to an independent testing laboratory mutually agreed upon by the parties for tests and final determination of whether such Product conforms with such Specifications.  The laboratory must meet cGMP (if applicable), be of recognized standing in the industry, and consent to the appointment of such laboratory will not be unreasonably withheld or delayed by either party.  Such laboratory will use the test methods contained in the applicable Specifications.  The determination of conformance by such laboratory with respect to all or part of such Product will be final and binding on the parties.  The fees and expenses of the laboratory incurred in making such determination will be paid by the party against whom the determination is made.

 

6.4           Product Non-Compliance and Remedies.  If a Batch of Product fails to conform to the Specifications due to the fault of Manufacturer or was not Manufactured in compliance with cGMP (if applicable) and the Manufacturing Process, then Manufacturer will, at RADIUS’ sole option:

 

(a)           refund in full the fees and expenses paid by RADIUS for such Batch, including the costs of RADIUS Materials used in the Manufacture of such Batch; or

 

(b)           at Manufacturer’s cost and expense, including the costs of RADIUS Materials used in the Manufacture of such Batch, produce a new Batch of Product as soon as reasonably possible; or

 

(c)           Rework or Reprocess the Product, at Manufacturer’s cost and expense, so that the Batch can be deemed to have been Manufactured in compliance with cGMP (if applicable) and the Manufacturing Process, and to conform to Specifications.

 

Moreover, the parties will meet to discuss, evaluate and analyze the reasons for and implications of the failure to comply with cGMP (if applicable) and/or the Manufacturing Process and will decide whether to proceed with or to amend the applicable Work Order, or to terminate such Work Order.

 

6.5           Disposition of Non-Conforming Product.  The ultimate disposition of non-conforming Product will be the responsibility of RADIUS’ quality assurance department and RADIUS’ expense.

 

7.             Shipping and Delivery.

 

7.1           Shipping; Delivery.  Manufacturer agrees not to ship Product to RADIUS or its designee until it has received a written approval to ship from RADIUS.  Manufacturer will

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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ensure that each Batch will be delivered to RADIUS’ designee, (a) on the estimated delivery date and to the destination designated by RADIUS in writing, and (b) in accordance with the instructions for shipping given to Manufacturer by RADIUS and packaging specified by RADIUS in the applicable Work Order or as otherwise agreed to by the parties in writing.  Delivery terms will be FCA the Facility (Incoterms 2000).  A bill of lading will be furnished to RADIUS with respect to each shipment.  For the avoidance of doubt, RADIUS will reimburse Manufacturer for any packaging materials that are outside of the packaging normally used by Manufacturer for like products as the Product.

 

8.             Price and Payments.

 

8.1           Price.  The price of Product and/or the fees for the performance of Services will be set forth in the applicable Work Order.

 

8.2           Invoice.  Upon performance of Services and/or release of Batch(es), such release to be conducted exclusively by Manufacturer, Manufacturer will invoice RADIUS according to the payment schedule in the applicable Work Order.  Payment of undisputed invoices will be due [*] ([*]) days after date of Manufacturer’s invoice.  Any undisputed invoices that remain unpaid by RADIUS after the aforementioned timeframe shall be subject to a late payment charge of [*] % ([*] percent) per [*] for each [*] that the payment remains outstanding in Manufacturer’s accounts.

 

8.3           Payments.  RADIUS will make all payments pursuant to this Agreement by check or wire transfer to a bank account designated in writing by Manufacturer.  All payments under this Agreement will be made in Euros (EUR).

 

8.4           Financial Records.  Manufacturer will keep accurate records of all Services performed and invoice calculations, and, upon the request of RADIUS, will permit an independent accountant appointed by RADIUS to examine such records upon prior notice and during normal business hours for the purpose of verifying the correctness of all such calculations.

 

8.5           Taxes.  Duty, sales, use or excise taxes imposed by any governmental entity that apply to the provision of Services will be borne by RADIUS (other than taxes based upon the income of Manufacturer).

 

9.             Intellectual Property Rights.

 

9.1           RADIUS Technology.  All rights to and interests in RADIUS Technology will remain solely in RADIUS and no right or interest therein is transferred or granted to Manufacturer.  Manufacturer acknowledges and agrees that it does not acquire a license or any other right to RADIUS Technology except for the limited purpose of carrying out its duties and obligations under this Agreement and that such limited, non-exclusive, license will expire upon the completion of such duties and obligations or the termination or expiration of this Agreement, whichever is the first to occur.

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

12











 

9.2           Manufacturer Technology.  All rights to and interests in Manufacturer Technology will remain solely in Manufacturer and no right or interest therein is transferred or granted to RADIUS.  RADIUS acknowledges and agrees that it will not acquire a license or any other right to Manufacturer Technology except as otherwise set forth in this Agreement.  If RADIUS wishes to move or replicate the Manufacture of Product, where the relevant Manufacturing Process involves Manufacturer Technology incorporated into the Manufacturing Process pursuant to the express terms of any relevant Work Order, the parties will negotiate in good-faith in order to determine a reasonably royalty fee or other reasonable consideration to be paid to Manufacturer by RADIUS for the right to continue to use such Manufacturer Technology.

 

9.3           Improvements.  Manufacturer agrees that all Improvements will be the sole and exclusive property of RADIUS and are hereby assigned to RADIUS (or its designee) without additional compensation to Manufacturer.  Manufacturer will take such steps as RADIUS may reasonably request (at RADIUS’ expense) to vest in RADIUS (or its designee) ownership of the Improvements.

 

9.4           Non-Exclusive License.  RADIUS agrees to grant to Manufacturer a non-exclusive, perpetual, fully paid-up, worldwide license, with the right to sub-license, to use Improvements that relate solely to Manufacturer Technology or the Confidential Information of Manufacturer, in the manufacture of products that do not contain an API/Drug Substance or derivative that is the subject of a Work Order under this Agreement or that use other Confidential Information of RADIUS.

 

9.5           Patent Filings.  RADIUS will have the exclusive right and option, but not the obligation, to prepare, file, prosecute, maintain and defend at its sole expense, any patents that claim and/or cover the Improvements.  If RADIUS declines to file and prosecute any patent applications, or maintain any patents, relating to Improvements, it will give Manufacturer reasonable notice to this effect and, thereafter, Manufacturer may, upon written notice to RADIUS, file and prosecute such patent applications and/or maintain such patents, in the name of RADIUS and at Manufacturer’s sole expense.

 

10.           Confidentiality.

 

10.1         Definition.  As used in this Agreement, “Confidential Information”  means any scientific, technical, trade or business information which is given by one party to the other under this Agreement or any confidentiality agreement entered into in contemplation of this Agreement and which is treated by the disclosing party as confidential or proprietary, or which is developed by one party for the other under the terms of this Agreement.  The disclosing party will, to the extent practical, use reasonable efforts to label or identify as confidential, at the time of disclosure all such Confidential Information that is disclosed in writing or other tangible form.  Confidential Information of Manufacturer includes, but is not limited to, Manufacturer Technology, whether or not labeled confidential.  Confidential Information of RADIUS includes, but is not limited to, RADIUS Technology and Improvements, whether or not labeled confidential.

 

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10.2         Obligations.  Each party agrees (a) to keep confidential the Confidential Information of the other party, (b) not to disclose the other party’s Confidential Information to any third party without the prior written consent of such other party, and (c) to use such Confidential Information only as necessary to fulfill its obligations or in the reasonable exercise of rights granted to it under this Agreement; provided, however, that the foregoing obligations shall not apply to Confidential Information that is (i) in possession of the receiving party at the time of disclosure, as reasonably demonstrated by written records and without obligation of confidentiality, (ii) later becomes part of the public domain through no fault of the receiving party, (iii) received by the receiving party from a third party without obligation of confidentiality, or (iv) developed independently by the receiving party without use of, reference to, or reliance upon the disclosing party’s Confidential Information by individuals who did not have access to Confidential Information.  Notwithstanding the foregoing, a party may disclose (y) Confidential Information of the other party to its Affiliates, and to its and their directors, employees, consultants, and agents in each case who have a specific need to know such Confidential Information and who are bound by a like obligation of confidentiality and restriction on use, and (z) Confidential Information of the other party to the extent such disclosure is required to comply with Applicable Law or the rules of any stock exchange or listing entity, or to defend or prosecute litigation; provided, however, that the receiving party provides prior written notice of such disclosure to the disclosing party and takes reasonable and lawful actions to avoid or minimize the degree of such disclosure.  Moreover, RADIUS may disclose Confidential Information of Manufacturer relating to the Development and/or Manufacture of Product to entities with whom RADIUS has (or may have) a marketing and/or development collaboration or to bona fide actual or prospective underwriters, investors, lenders or other financing sources or to potential acquirors of the business to which this Agreement relates, and who in each case have a specific need to know such Confidential Information and who are bound by a like obligation of confidentiality and restrictions on use.

 

10.3         Public Statements.  Except to the extent required by Applicable Law or the rules of any stock exchange or listing entity, neither party will make any public statements or releases concerning this Agreement or the transactions contemplated by this Agreement, or use the other party’s name in any form of advertising, promotion or publicity, without obtaining the prior written consent of the other party, which consent will not be unreasonably withheld or delayed.

 

11.           Representations and Warranties.

 

11.1         Manufacturer’s Representations and Warranties.  Manufacturer represents and warrants to RADIUS that:

 

(a)           it has the full power and right to enter into this Agreement and that there are no outstanding agreements, assignments, licenses, encumbrances or rights of any kind held by other parties, private or public, inconsistent with the provisions of this Agreement;

 

(b)           the Services will be performed with requisite care, skill and diligence, in accordance with Applicable Law and industry standards, and by individuals who are appropriately trained and qualified;

 

14











 

(c)           to the best of its knowledge, the Services will not infringe the intellectual property rights of any third party and it will promptly notify RADIUS in writing should it become aware of any claims asserting such infringement;

 

(d)           at the time of delivery to RADIUS, the Product Manufactured under this Agreement (i) will have been Manufactured in accordance with cGMP (if applicable) and all other Applicable Law, the Manufacturing Process, the applicable Quality Agreement, and Specifications, and (ii) will not be adulterated or misbranded under the FDCA or other Applicable Law; and

 

(e)           it has not been debarred, nor is it subject to a pending debarment, and that it will not use in any capacity in connection with the Services any person who has been debarred pursuant to section 306 of the FDCA, 21 U.S.C.  § 335a, or who is the subject of a conviction described in such section.  Manufacturer agrees to notify RADIUS in writing immediately if Manufacturer or any person who is performing Services is debarred or is the subject of a conviction described in section 306, or if any action, suit, claim, investigation, or proceeding is pending, or to the best of Manufacturer’s knowledge, is threatened, relating to the debarment or conviction of Manufacturer or any person performing Services.

 

11.2         RADIUS Representations and Warranties.  RADIUS represents and warrants to Manufacturer that:

 

(a)           it has the full power and right to enter into this Agreement and that there are no outstanding agreements, assignments, licenses, encumbrances or rights held by other parties, private or public, inconsistent with the provisions of this Agreement, and

 

(b)           to the best of its knowledge, the use of RADIUS Technology as contemplated in the Services will not infringe the intellectual property rights of any third party and that it will promptly notify Manufacturer in writing should it become aware of any claims asserting such infringement.

 

11.3         Disclaimer of Other Representations and Warranties.  EXCEPT AS EXPRESSLY SET FORTH IN THIS AGREEMENT, NEITHER PARTY MAKES ANY REPRESENTATIONS OR EXTENDS ANY WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR NON-INFRINGEMENT.

 

12.           Indemnification.

 

12.1         Indemnification by Manufacturer.  Manufacturer will indemnify, defend and hold harmless RADIUS, its Affiliates and their respective officers, directors, employees and agents (each a “RADIUS Indemnitee”) from and against any and all losses, damages, liabilities or expenses (including reasonable attorneys fees and other costs of defense) (collectively, “Losses”)  in connection with any and all actions, suits, claims or demands that may be brought or instituted against any RADIUS Indemnitee by any third party based on, arising out of, or resulting from, any (a) breach by Manufacturer of its representations, warranties or covenants under this

 

15











 

Agreement, or (b) negligent act or omission or the willful misconduct of any Manufacturer Indemnitees in performing obligations under this Agreement.

 

12.2         Indemnification by RADIUS.  RADIUS will indemnify, defend and hold harmless Manufacturer, its Affiliates and their respective officers, directors, employees and agents (each a “Manufacturer Indemnitee”) from and against any and all Losses in connection with any and all actions, suits, claims or demands that may be brought or instituted against any Manufacturer Indemnitee by any third party based on, or arising out of, or resulting from (a) the use of the Product, except to the extent that such Losses are within the scope of the indemnification obligation of Manufacturer under Section 12.1, (b) any breach by RADIUS of its representations, warranties or covenants under this Agreement, or (c) any negligent act or omission or the willful misconduct of any RADIUS Indemnitees in performing obligations under this Agreement.

 

12.3         Procedures.  Each party agrees to notify the other party within [*] ([*]) days of receipt of any claims made for which the other party might be liable under Section 12.1 or 12.2, as the case may be.  Subject to Section 12.4, the indemnifying party will have the right to defend, negotiate, and settle such claims.  The party seeking indemnification will provide the indemnifying party with such information and assistance as the indemnifying party may reasonably request, at the expense of the indemnifying party.  The parties understand that no insurance deductible will be credited against losses for which a party is responsible under this Section 12.

 

12.4         Settlement.  Neither party will be responsible or bound by any settlement of any claim or suit made without its prior written consent; provided, however, that the indemnified party will not unreasonably withhold or delay such consent.  If a settlement contains an absolute waiver of liability for the indemnified party, and each party has acted in compliance with the requirements of Section 12.3, then the indemnified party’s consent will be deemed given.  Notwithstanding the foregoing, Manufacturer will not agree to settle any claim on such terms or conditions as would impair RADIUS’ ability or right to Manufacture, market, sell or otherwise use Product, or as would impair Manufacturer’s ability, right or obligation to perform its obligations under this Agreement.

 

12.5         Limitation of Liability.  NOTWITHSTANDING ANYTHING IN THIS AGREEMENT TO THE CONTRARY, IN NO EVENT WILL EITHER PARTY BE LIABLE FOR ANY SPECIAL, INCIDENTAL, CONSEQUENTIAL OR INDIRECT DAMAGES ARISING OUT OF THIS AGREEMENT, HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY.  THIS LIMITATION WILL APPLY EVEN IF THE OTHER PARTY HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGE; PROVIDED, HOWEVER, THAT THIS LIMITATION WILL NOT APPLY TO DAMAGES RESULTING FROM BREACHES BY A PARTY OF ITS DUTY OF CONFIDENTIALITY AND NON-USE IMPOSED UNDER SECTION 10 OR ITS INDEMNIFICATION OBLIGATIONS UNDER THIS SECTION 12.

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

16











 

13.           Insurance.

 

13.1         Manufacturer Insurance.  Manufacturer will secure and maintain in full force and effect throughout the term of this Agreement (and for at least [*] ([*]) years thereafter for claims made coverage), insurance with coverage and minimum policy limits set forth as follows:

 

(a)           Comprehensive General Liability and Personal Injury, including coverage for contractual liability assumed by Manufacturer and coverage for Manufacturer’s independent contractor(s), with per occurrence limits of at least [*] dollars ($[*]) each and a general aggregate limit of [*] dollars ($[*]);

 

(b)           Products Liability, exclusive of the coverage provided by the Comprehensive General Liability policy, with an aggregate limit of at least [*] dollars ($[*]); and

 

(c)           “All Risk” Property, valued at replacement cost, covering loss or damage to the Facility and RADIUS’ property and materials in the care, custody, and control of Manufacturer.

 

13.2         Evidence of Insurance.  Upon request, Manufacturer will furnish to RADIUS a certificate from an insurance carrier (having a minimum AM Best rating of A) demonstrating the insurance requirements set forth above.  [*] ([*]) days prior written notice will be given to RADIUS of cancellation or any material change in the policies.

 

13.3         Insurance Information.  Manufacturer will comply, at RADIUS’ expense, with reasonable requests for information made by RADIUS’ insurance provider representative(s), including permitting such representative(s) to inspect the Facility during operational hours and upon reasonable notice to Manufacturer.  In regard to such inspections, the representative(s) will adhere to such guidelines and policies pertaining to safety and non-disclosure as Manufacturer may reasonably require.

 

14.           Term and Termination.

 

14.1         Term.  This Agreement will take effect as of the Effective Date and, unless earlier terminated pursuant to this Section 14, will expire on the later of (a) [*] ([*]) years from the Effective Date, or (b) the completion of Services under the last Work Order executed by the parties prior to the second anniversary of the Effective Date.  The term of this Agreement may be extended by RADIUS continuously for additional [*] ([*]) year periods upon written notice to Manufacturer at least [*] ([*]) days prior to the expiration of the then current term.

 

14.2         Termination by RADIUS.  RADIUS will have the right, in its sole discretion, to terminate this Agreement and/or any Work Order (a) upon [*] ([*]) days prior written notice to Manufacturer, or (b) immediately upon written notice if (i) in RADIUS’ reasonable judgment, Manufacturer is or will be unable to perform the Services in accordance with the agreed upon timeframe and/or budget set forth in the applicable Work Order, or (ii) Manufacturer fails to

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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obtain or maintain any material governmental licenses or approvals required in connection with the Services.

 

14.3         Termination by Either Party.  Either party will have the right to terminate this Agreement or any signed Work Orders that are pending by written notice to the other party, upon the occurrence of any of the following:

 

(a)           the other party files a petition in bankruptcy, or enters into an agreement with its creditors, or applies for or consents to the appointment of a receiver or trustee, or makes an assignment for the benefit of creditors, or becomes subject to involuntary proceedings under any bankruptcy or insolvency law (which proceedings remain undismissed for [*] ([*]) days);

 

(b)           the other party fails to start and diligently pursue the cure of a material breach of this Agreement within [*] ([*]) days after receiving written notice from the other party of such breach; or

 

(c)           a force majeure event that will, or continues to, prevent performance (in whole or substantial part) of this Agreement or any pending Work Order for a period of at least [*] ([*]) days.  In the case of a force majeure event relating to a pending Work Order, the right to terminate will be limited to such Work Order.

 

14.4         Effect of Termination.  Manufacturer will, upon receipt of a termination notice from RADIUS, promptly cease performance of the applicable Services and will take all reasonable steps to mitigate the out-of-pocket expenses incurred in connection therewith.  In particular, Manufacturer will use its best efforts to:

 

(a)           immediately cancel, to the greatest extent possible, any third party obligations;

 

(b)           promptly inform RADIUS of any irrevocable commitments made in connection with any pending Work Order(s) prior to termination;

 

(c)           promptly return to the vendor for a refund all unused, unopened materials in Manufacturer’s possession that are related to any pending Work Order; provided that RADIUS will have the option, but not the obligation, to take possession of any such materials;

 

(d)           promptly inform RADIUS of the cost of any remaining unused, unreturnable materials ordered, or work in progress pursuant to any pending Work Order(s), and either deliver such materials to RADIUS (or its designee) or properly dispose of them, as instructed by RADIUS, upon which Manufacturer shall invoice RADIUS for any such associated costs; and

 

(e)           perform only those services and activities mutually agreed upon by RADIUS and Manufacturer as being necessary or advisable in connection with the close-out of any pending Work Order(s).

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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14.5         Return of Materials/Confidential Information.  Upon the expiration or termination of this Agreement, each party will promptly return all Confidential Information of the other party that it has received pursuant to this Agreement, provided however that Manufacturer is allowed to keep one copy of such Confidential Information for archival purposes only.  Manufacturer will also promptly return all RADIUS Materials, RADIUS Equipment, retained samples, data, reports and other property, information and/or know-how in recorded form that was provided by RADIUS, or developed in the performance of the Services, that are owned by or licensed to RADIUS.

 

14.6         Inventories.  Upon expiration or termination of this Agreement or a pending Work Order, RADIUS (a) will purchase from Manufacturer any existing inventories of Product conforming to the Specifications and Manufactured in accordance with cGMP (if applicable) and the Manufacturing Process, at the price for such Product set forth in the applicable Work Order, and (b) may either (i) purchase any Product in process held by Manufacturer as of the date of the termination, at a price to be mutually agreed (it being understood that such price will reflect, on a pro rata basis, work performed and non-cancelable out-of-pocket expenses actually incurred by Manufacturer with respect to the Manufacture of such in-process Product), or (ii) direct Manufacturer to dispose of such material at RADIUS’ cost.

 

14.7         Payment Reconciliation.  Within [*] ([*]) days after the close-out of a Work Order, Manufacturer will provide to RADIUS a written itemized statement of all work performed by it in connection with the terminated Work Order, an itemized breakdown of the costs associated with that work, and a final invoice for that Work Order.  If RADIUS has pre-paid to Manufacturer more than the amount in a final invoice then Manufacturer agrees to promptly refund that money to RADIUS, or to credit the excess payment toward another existing or future Work Order, at the election of RADIUS.

 

14.8         Survival.  Expiration or termination of this Agreement for any reason will not relieve either party of any obligation accruing prior to such expiration or termination or of any rights and obligations of the parties that by their terms survive termination or expiration of this Agreement or of any Work Order, including, without limitation, Sections 1, 2.3, 4, 5.2(c), 5.2(d), 5.4, 5.5, 5.6, 5.7, 5.8, 6, 9 through 13, 14.4, 14.5, 14.6, 14.7, 14.8 and 15, and the provisions of the applicable Quality Agreement.

 

15.           Miscellaneous.

 

15.1         Independent Contractor.  All Services will be rendered by Manufacturer as an independent contractor and this Agreement does not create an employer-employee relationship between RADIUS and Manufacturer.  Manufacturer will not in any way represent itself to be a partner or joint venturer of or with RADIUS.

 

15.2         Force Majeure.  Except as otherwise expressly set forth in this Agreement, neither party will have breached this Agreement for failure or delay in fulfilling or performing any term of this Agreement when such failure or delay is caused by or results from causes

 




* Confidential Treatment Requested by the Registrant. Redacted Portion Filed Separately with the Commission.

 

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beyond the reasonable control of the affected party, including, without limitation, fire, floods, embargoes, shortages, epidemics, quarantines, war, acts of war (whether war be declared or not), insurrections, riots, civil commotion, strikes, acts of God or acts, omissions, or delays in acting, by any governmental authority (“force majeure”).  The party affected by any event of force majeure will promptly notify the other party, explaining the nature, details and expected duration thereof.  Such party will also notify the other party from time to time as to when the affected party reasonably expects to resume performance in whole or in part of its obligations under this Agreement, and to notify the other party of the cessation of any such event.  A party affected by an event of force majeure will use its reasonable efforts to remedy, remove, or mitigate such event and the effects thereof with all reasonable dispatch.  If a party anticipates that an event of force majeure may occur, such party will notify the other party of the nature, details and expected duration thereof.  Upon termination of the event of force majeure, the performance of any suspended obligation or duty will promptly recommence.

 

15.3         Notices.  All notices must be written and sent to the address or facsimile number identified below or in a subsequent notice.  All notices must be given (a) by personal delivery, with receipt acknowledged, (b) by facsimile followed by hard copy delivered by the methods under (c) or (d), (c) by prepaid certified or registered mail, return receipt requested, or (d) by prepaid recognized next business day delivery service.  Notices will be effective upon receipt or at a later date stated in the notice.

 

	
If   to Manufacturer, to:
    	
Lonza   Ltd
    
	
 
    	
Legal   Department
    
	
 
    	
Muenchensteinerstrasse   38
    
	
 
    	
CH-4002   Basel
    
	
 
    	
Switzerland
    
	
 
    	
 
    
	
 
    	
Facsimile   number: +41 61 316 83 14
    
	
 
    	
 
    
	
If   to RADIUS, to:
    	
Chief   Financial Officer
    
	
 
    	
Radius   Health, Inc.
    
	
 
    	
300   Technology Square, 5th Floor
    
	
 
    	
Cambridge,   MA 02139
    


 

15.4         Assignment.  This Agreement may not be assigned or otherwise transferred by either party without the prior written consent of the other party; provided, however, that RADIUS may, without such consent, but with notice to the Manufacturer, assign this Agreement, in whole or in part, (a) in connection with the transfer or sale of all or substantially all of its assets or the line of business or Product to which this Agreement relates, (b) to a successor entity or acquirer in the event of a merger, consolidation or change of control, (c) to any Affiliate, or (d) to any licensee of RADIUS’ rights to the relevant Product.  Any purported assignment in violation of the preceding sentence will be void.  Any permitted assignee will assume the rights and obligations of its assignor under this Agreement.

 

15.5         Entire Agreement.  This Agreement, including the attached Appendices and any fully-signed Work Orders, each of which are incorporated herein, constitute the entire agreement between the parties with respect to the specific subject matter hereof and all prior agreements

 

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with respect thereto are superseded.  Each party hereto confirms that it is not relying on any representations or warranties of the other party except as specifically set forth herein.

 

15.6         No Modification.  This Agreement and and/or any Work Order or Quality Agreement may be changed only by a writing signed by authorized representatives of both parties.

 

15.7         Severability; Reformation.  Each provision in this Agreement is independent and severable from the others, and no restriction will be rendered unenforceable because any other provision may be invalid or unenforceable in whole or in part.  If the scope of any restrictive provision in this Agreement is too broad to permit enforcement to its full extent, then such restriction will be reformed to the maximum extent permitted by law.

 

15.8         Governing Law.  This Agreement will be construed and interpreted and its performance governed by the laws of the State of New York, USA, without regard to any choice of law principle that would dictate the application of the law of another jurisdiction.  The application of the 1980 United Nations Convention on Contracts for the International Sale of Goods is hereby specifically excluded.

 

15.9         Arbitration.  Any dispute which may arise between the parties in relation to this Agreement shall be settled amicably between the parties.  If, contrary to expectation, no amicable settlement can be reached, both parties hereto agree to settle the dispute by arbitration in accordance with the rules and regulations of the International Chamber of Commerce.  The number of arbitrators shall be three, the seat of the arbitration shall be in New York, New York, USA and the language that the proceedings are held in shall be English.  The decision or award rendered by the arbitrator shall be final and non-appealable, and judgment may be entered upon it in any court of competent jurisdiction.

 

15.10       Waiver.  No waiver of any term, provision or condition of this Agreement in any one or more instances will be deemed to be or construed as a further or continuing waiver of any other term, provision or condition of this Agreement.  Any such waiver, extension or amendment will be evidenced by an instrument in writing executed by an officer authorized to execute waivers, extensions or amendments.

 

15.11       Counterparts.  This Agreement may be executed in any number of counterparts, each of which will be deemed an original and all of which together will constitute one and the same instrument.

 

15.12       Headings.  This Agreement contains headings only for convenience and the headings do not constitute or form a part of this Agreement, and should not be used in the construction of this Agreement.

 

15.13       No Benefit to Third Parties.  The representations, warranties, covenants and agreements set forth in this Agreement are for the sole benefit of the parties hereto and their successors and permitted assigns, and they will not be construed as conferring any rights on any other persons.

 

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IN WITNESS WHEREOF, the parties hereto have caused this Agreement to be executed by their duly authorized representatives as of the date first above written.

 

	
RADIUS   HEALTH, INC.
    	
LONZA   SALES LTD
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By:
    	
/s/   B.N. Harvey
    	
 
    	
By:
    	
/s/   Daniel Burgin / Y. Kesch
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print   Name:
    	
B.   Nicholas Harvey
    	
 
    	
Print   Name:
    	
Daniel   Burgin / Y. Kesch
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title:
    	
CPO
    	
 
    	
Title:
    	
Director   Director Sales & BD / legal counsel
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date:
    	
October   16, 2007
    	
 
    	
Date:
    	
October   9, 2007
    


 

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APPENDIX A

SAMPLE WORK ORDER

 

THIS WORK ORDER is by and between RADIUS HEALTH, INC. (“RADIUS”) and [FULL MANUFACTURER NAME] (“Manufacturer”), and upon execution will be incorporated into the Development and Manufacturing Services Agreement between RADIUS and Manufacturer dated [EFFECTIVE DATE OF AGREEMENT] (the “Agreement”).  Capitalized terms in this Work Order will have the same meanings as set forth in the Agreement.

 

RADIUS hereby engages Manufacturer to provide Services, as follows:

 

1.             API/Drug Substance and Product.

 

Describe the specific API/Drug Substance(s) and Product(s).

 

2.             Services.  Manufacturer will render to RADIUS the following Services:

 

Describe the specific Services to be conducted by Manufacturer (summarize) or attach Manufacturer’s proposal.  If Manufacturer Technology is to be incorporated in any Manufacturing Process, expressly indicate that here.

 

3.             Facilit(ies).  The Services described above will be rendered at the Facility unless another facility of Manufacturer is indicated below:

 

Include alternate Facility address(es).

 

4.             RADIUS Materials.  RADIUS will provide to Manufacturer the following materials to be used by Manufacturer to perform the Services:

 

Describe specific materials being provided by RADIUS to Manufacturer.

 

5.             RADIUS Equipment.

 

Include any equipment that will be provided by RADIUS to Manufacturer to be used by Manufacturer in performance of the Services.

 

6.             Manufacturer Representative.          Name and Title

 

7.             RADIUS Representative.                    Name and Title

 

8.             Compensation.  The total compensation due Manufacturer for Services under this Work Order is INSERT WRITTEN AMOUNT (numerical amount).  Such compensation will be paid INSERT PAYMENT SCHEDULE OR REFERENCE PROPOSAL.  RADIUS and Manufacturer must agree in advance of either party making any change in compensation.  Manufacturer will invoice RADIUS to the attention of INSERT NAME for Services rendered under this Agreement.  Manufacturer will invoice RADIUS for all amounts due under this Work Order.  All undisputed payments will be made by RADIUS within thirty (30) days of date of invoice.

 

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9.             [Quality Agreement.  The provisions of the Quality Agreement, attached hereto as Attachment 1, are incorporated herein by reference.]

 

All other terms and conditions of the Agreement will apply to this Work Order.

 

WORK ORDER AGREED TO AND ACCEPTED BY:

 

	
RADIUS   HEALTH, INC.
    	
 
    	
LONZA   SALES LTD
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
By:
    	
 
    	
 
    	
By:
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Print   Name:
    	
 
    	
 
    	
Print   Name:
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Title:
    	
 
    	
 
    	
Title:
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
Date:
    	
 
    	
 
    	
Date:
    	
 
    


 

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[Attachment 1]

 

	
 
    	
 
    	
Lonza
    
	
Radius - Lonza QUALITY AGREEMENT
    


 

Radius Health
 300 Technology Square, 5th Floor
 Cambridge, MA 02139 USA

 

and

 

Lonza Sales Ltd
 Muenchensteinerstrasse 38
 4002 Basel, Switzerland

 

1











 

Supplier’s & Client’s Name

 

Lonza Sales Ltd (“Supplier”) and Radius Health (“Client”) wish to define the individual responsibilities of the parties as to the quality aspects of manufacturing and release of Product as defined in Appendix 1 to ensure compliance with the approved Product application and/or Client requirements.

 

In order to do so, this Quality Agreement (“Quality Agreement”) takes the form, in part, of a detailed listing of activities associated with manufacture, supply, production, analysis, and release of Product. Unless otherwise indicated, responsibility for each activity is assigned to either Client, Supplier, or is assigned to both Supplier and Client.

 

In consideration of the parties’ agreement to perform the activities provided in this Quality Agreement and for other valuable consideration the receipt dad sufficiency of which is hereby acknowledged, and intending to be legally bound, Supplier and Client agree as provided in this Quality Agreement as follows:

 

2











 

1.                                      Effective Date

 

The Effective Date of this Quality Agreement shall be the date of last signature (the “Effective Date”).

 

2.                                      Scope

 

The purpose of this Quality Agreement between Supplier and Client is to formalize an agreement with regard to the quality responsibilities and activities between companies and is based on the quality procedures in place.

 

3.                                      Other Agreements

 

This Agreement is primarily a technical agreement, not a business agreement. Examples of some standard items excluded from this Agreement are: general business terms and conditions, pricing and escalator clauses, forecasting, delivery terms, confidentiality obligations, liability limitations and the protocol for resolution of disputes; which are described in the Development and Manufacturing Service Agreement as of 16 October 2007 (DMA). Therefore, if there are any inconsistencies between the DMSA and the Quality Agreement, the DMSA will take precedence over the Quality Agreement; except with respect to any specific quality issue that may adversely Regulatory Compliance or product quality and safety.

 

4.                                      Amendments to the Quality Agreement

 

This Quality Agreement may be amended by the written consent of both parties.  The parties agree to amend tees of this Qualify Agreement that must be amended in order that the Product continue to meet regulator y requirements of applicable regulatory agencies, as may exist from time to time.

 

If an amendment to this Quality Agreement is proposed, the proposing party will circulate the proposed amendment to the appropriate contact person at Supplier and Client for review and internal approval. The appropriate contact person at Supplier and Client is listed in Appendix 2 (Contacts and Responsibilities).

 

5.                                      Object of the Agreement

 

The provisions of this Agreement apply to all orders for the manufacture of drug products or other services provided by Supplier to Client after the Effective Date and prior to its termination in effect. This Agreement also applies to existing orders issued by CLIENT, which have not been completed at the date of signing.

 

6.                                      Subcontracting

 

As defined in Section 3.3 of the DMSA.

 

3











 

If client request the use of a specific subcontractor, the client remains fully responsible for the quality of the materials or services provided by subcontractors and for all commitments as agreed upon with this Quality Agreement.

 

7.                                      Survival Clause

 

All regulatory obligations contained herein that are required of either party or both parties by an applicable regulatory authority shall survive termination of this Quality Agreement.

 

8.                                      Assignment

 

As defined in Section 15.4 of the DMSA.

 

9.                                      Product Specifications

 

Changes to the agreed upon specifications must be mutually agreed upon and communicated in writing between the parties to this Quality Agreement via the Change Control process, except for applicable compendia changes which can be ;implemented without mutual agreement. Compendia changes must be implemented by the compendia implementation date.

 

10.                               Resolution of Quality Issues

 

Quality related disagreements between Supplier and Client that are not resolved in the normal course of business shall be brought to the attention of the appropriate contact person for notices at the Supplier and Client; in writing, as listed in Appendix 2 (Contacts and Responsibilities). If both parties agree that a resolution of the disagreement is reasonably possible, then both Supplier and Client shall agree to work jointly to develop a strategy for such resolution. Supplier and Client further Wee to record such resolution in writing.

 

11.                               Debarment

 

Supplier warrants and represents that it is not debarred under the Generic Drug Enforcement Act of 1992, 21 U.S.C. 335[a] (the “Generic Drug Enforcement Act”), and that it has not been convicted of a crime for which it could be debarred under the Generic Drug Enforcement Act. In connection with the Product, the Supplier further warrants and represents, in that it shall not use in any capacity the services of any person debarred under the Generic Drug Enforcement Act, or convicted of a crime for which a person can be debarred under the Generic Drug Enforcement Act.

 

12.                               Confidentiality

 

The contents of this Agreement and all information, representations, documents, etc. received from Supplier or its Affiliates are confidential in accordance with Section 10 of the DMSA.

 

4











 

13.                               Choice of Law: Jurisdiction/Miscellaneous

 

The applicable law shall be as defined in Section 15.8 of the DMSA. Any dispute shall be resolved in according to clause 15.9 of the DMSA.

 

All appendices to this Quality Agreement are attached hereto and incorporated herein by reference. In this Quality Agreement, unless the contrary intention appears: (a) the words “including” and “include” mean “including, but not limited to”;(b) the singular includes the plural and vice versa; (c) a reference to a person or entity (including Supplier or Client) includes a reference to the person’s executors, administrators, successors, substitutes and assigns; and (d) headings are for reference only and do not form part of this contract.

 

14.                               Manufacturing and Testing Locations

 

Product will be manufactured and tested at the following locations: Address:

 

Lonza Braine SA

Chaussée de Tubize 297

B-1420 Braine-l’Alleud, Belgium

 

SGS Laboratoires Simon s.a.

Vieux Chemin du Poète 10

B-1301 Wavre

Belgium

 

Any additional testing locations will go through Change Control process

 

15.                               Applicable GMP Standard

 

Supplier shall manufacture all products manufactured for Client (listed in Appendix 2) in compliance with current Good Manufacturing Practices (cGMP).

 

For the purposes of this agreement; cGMP shall mean the principles (i) described in the ICH Q7 and FDA CFR 21 Parts 11 and 211, and (ii) promulgated by any Governmental Authority having jurisdiction over the manufacture of all products manufactured for Client, in the form of laws or guidance documents, where the guidance documents are to be implemented within the pharmaceutical manufacturing industry for such products.

 

16.                               Certificate of Analysis / Conformance

 

The following documentation is required for batches of all products manufactured for Client shipped to or on behalf of Client:

 

·                                          Certificate of Analysis and Conformance for each batch, issued by the independent Quality Unit

 

5











 

·                                          Copies of investigation reports regarding quality incidents (Critical Deviations, OOS results, or similar), if applicable

 

The Certificates of Analysis and Conformance shall be dated and signed by a responsible person of Supplier’s Quality Unit, or it may be produced by a computer system which provides a degree of control equivalent to that given by a signature. The Certificate of Analysis states that the batch is suitable for release, and it must include — as a minimum —

 

·                                          Supplier name and address, (original manufacturing site),

·                                          BA058 API name and grade (if applicable),

·                                          Supplier batch/lot number,

·                                          Reference to the agreed specification,

·                                          Test parameters and corresponding specification requirements,

·                                          Test results (numerical, where applicable) for each chemical, physical or microbiological test performed,

·                                          Date of release and expiration or retest date of the all products manufactured for Client.

 

17.                               Change Control

 

Supplier shall have a documented and effective Change Control system in place and is required to provide advanced notification to Client of Major Changes to the process, specifications and analytical methods (API, intermediate, and raw materials), storage, labelling and primary packaging, which may have an in act on the quality of all products manufactured for Client, and/or on any regulatory applications related to all products manufactured for Client.

 

Principles:

 

·                                          All products manufactured for Client _produced -by a new process shall not be accepted unless the process change has first been reviewed and delivery approved by Client.

·                                          Change requests should be supported by appropriate technical documents to support the change and to confirm that technical performance has not been altered.

·                                          Modifications relating to specifications of product shall be processed according to Section 9 of this Agreements.

·                                          For those changes required to comply with applicable laws and regulatory agency requirements, Supplier shall notify Client of such requirements after Supplier becomes aware of the need for such change Client shall assess any change request received from Supplier in a timely manner. Unless there are justified scientific reasons to reject the change request, Client will not unreasonably withhold its approval of the request.

·                                          Client is responsible for the submission of all necessary change notifications to all competent authorities in full compliance with the applicable regulations, respectively.

·                                          Client will inform Supplier of the receipt of the necessary acknowledgement of the validity of the notification and, depending on the type of change, the acceptance or approval of the change by the competent authorities.

 

6











 

18.                               Right to Audit

 

Supplier shall allow Client representatives to carry out on-site audits by appointment. Supplier shall permit all reasonable access to the manufacturing, packaging, warehousing and laboratory areas related to the manufacture of the BA058 API, including pertinent documentation, during normal business hours on reasonable prior notice.

 

The results of the audit and the observation(s) shall be sent to Supplier by means of a written report. Supplier must ensure a satisfactory follow up to the observations made during the audit performed by Client, and take corrective actions mutually agreed upon by the parties.

 

The frequency of the audit shall depend upon the results of the audit and the quality performance of Supplier. In the absence of critical quality incidents the frequency shall be not more than once per year. If quality issues arise Client shall have the right to audit more frequently.

 

19.                               Authority Inspections

 

Supplier shall notify Client of all regulatory authority inspections that take place at the facility where product is manufactured or the testing laboratory where any of the associated testing is performed. If areas of concern exist which specifically involve any products manufactured for Client, Client should be notified prior to the inspection. In all other cases information on the results of the inspection is appropriate. Such notification will include;

 

·                                          Written notification of any observation, if any, that may impact the manufacture of any products manufactured for Client

·                                          Written notification of all related corrective actions and planned completion dates

·                                          Any further correspondence with the regulatory authority (if the manufacture of any products manufactured for Client is concerned)

 

20.                               Retention of samples (BA058 API)

 

Supplier will store retention samples, sufficient to perform at least two (2) full specification analyses, in containers that are equivalent to or more protective than the commercial packaging. Samples are to be retained for 5 years.:

 

Samples should be labelled with the following information:

 

·                                          Product name

·                                          Supplier batch/lot number

·                                          Date of manufacture

 

Supplier will make retention sample available to Client promptly upon Client’s justified request.

 

7












 

21.                               Stability

 

Supplier is responsible for performing process validation stability and commercial stability studies per ICH guidelines and Client requirements.

 

Supplier is responsible for generating stability protocols, methods and specifications. Client is responsible for approving stability protocols, methods and specifications.

 

Supplier will upon request or at least annually provide updated data from the stability program to Client.

 

Supplier will inform Client if there are any adverse trends that could impact on current retest date.

 

22.                               Complaints

 

All complaints related to any products manufactured for Client reported, regardless of source (e.g., consumers, doctors, pharmacists, sales representatives) will be handled by Client and communicated to Supplier.

 

Supplier is responsible for recording and investigating all quality-related complaints on any products manufactured for Client and will maintain the complete complaint database and complaint files.

 

Supplier will complete their investigation and respond to Client in writing to all complaints within one month of receipt.

 

A formal written report on the complaint detailing identifiable root causes and corrective and preventive actions where applicable shall be prepared by Supplier and sent to Client.

 

In case the investigation could not be finalized within 20 business days, Supplier will provide an interim report to Client.

 

Supplier is responsible for implementing a corrective action plan to correct any deficiencies identified during an investigation.

 

Client will make relevant information and samples of the affected product available to assist in the investigation of Supplier.

 

23.                               Recall

 

In the event that Supplier believes a recall of any products manufactured for Client maybe necessary or appropriate, Supplier `All immediately, i.e. within twenty-four (24) business hours, notify Client. The two parties will take joint decisions on the disposition of product or (if applicable) final drug product made thereof or user information, where required. Client is responsible for. the final decision and the coordination of any recalls or field alert activities.

 

8











 

Supplier shall provide any information required by Client relating to recall or field alert activities within two (2) business days of the request, if such information is readily available at Supplier.

 

Supplier will not initiate any notifications to health authorities concerning a (potential) nonconformance without the prior agreement of Client.

 

Supplier will collaborate, if needed, in any recall of a defective batch of any products manufactured for Client.

 

24.                               Storage and distribution

 

Supplier shall make commercially reasonable efforts to exclude, during packaging and storage of any products manufactured for Client, the possibility of deterioration, contamination, or mix-ups with any other material.

 

Supplier will send a Certificate of Analysis with each shipment of product.

 

Supplier will provide an up-to-date MSDS to Client with each shipment or at least on an annual basis.

 

25.                               BSE/TSE

 

Supplier shall provide to Client a BSE/TSE certificate for any products manufactured for Client listed in accordance with the EMEA Note for Guidance EMEA/410/01 (current revision). The certificate shall indicate if any products manufactured for Client is (are) of human or animal origin, and if materials of human or animal origin are used during the manufacturing process of any products manufactured for Client. An updated BSE/TSE certificate must be issued after any change to the manufacturing process which involves new raw materials or for raw materials that have been sourced from a different Supplier.

 

26.                               Raw materials

 

Supplier shall be responsible for the purchase, storage, handling, sampling, testing and approval or rejection of materials used in manufacturing any products manufactured for Client pursuant to this agreement, with the exception of any -Material supplied by Client. Supplier shall implement a vendor qualification program for evaluating the Suppliers of critical materials, with the only exception of materials supplied by Client. Supplier shall only purchase materials from qualified Suppliers.

 

Supplier must utilize documented maternal inspection, plans and testing procedures. The results of this inspection and testing must be in accordance with specifications filed by Client. Raw materials supplied by qualified vendors and those supplied by Client can be subject to reduced testing but a minimum ID testing (or visual examination in case of hazardous or highly toxic raw materials) needs to be performed for each delivery and each lot.

 

9











 

Supplier shall store and handle materials used in manufacturing any products manufactured for Client pursuant to his Agreement under appropriate conditions, consistent with cGMPs, all applicable laws, rules and regulations, and industry standards. Client shall inform Supplier on the storage conditions of any ‘aerial supplied to Supplier.

 

Supplier shall have all necessary and appropriate controls in place to prevent cross-contamination of the raw materials and intermediates used in the manufacture of any products manufactured for Client from other chemicals stored, used, or manufactured by Supplier, including but not limited to potent hormones, cytotoxic compounds, highly potent drugs or non-pharmaceutical chemicals.

 

27.                               Qualification / Validation

 

Equipment qualification, process validation, analytical methods validation and validation of computerized systems, if used, are in place and covered by Change Control. Validation documentation shall be available for review during an audit. On request, the Client will get copies or summaries from the process validation reports.

 

Development (Early clinical phase)

Supplier’s equipment qualification and Change Control process are in place. Verification of analytical methods for intended use (see Note).

 

Note: in case API lots will be used for clinical phase 3 studies, or prior to the validation campaign at the latest, the analytical methods should be validated according to ICH Q2 (RI) guidelines.

 

28.                               Reprocessing

 

Reprocessing shall be performed according to the current regulatory dossier and reported to Client. Reasons for reprocessing have to be investigated, and the results shall be communicated with Client.

 

Development:

Reprocessed batches have to be reported and agreed with the Client.

 

29.                               Reworking

 

Reworking is only possible after approval by Client.  Additional stability tests and analytical testing of reworked batches may be required.

 

Development:

Reworked batches have to be reported and approved by Client.  Reworking process could be part of the experience through process development.

 

10











 

30.                               Deviations / OOS (incl. stability)

 

Supplier must have a formal procedure for handling deviations as well as non-conforming laboratory test results (OOS results) that is in accordance with cGMP.

 

Supplier will notify Client promptly (target: within 3 business days) in the event of any Critical Deviation(s). A Critical Deviation is defined as a departure from an approved process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the final Product meets its specification or established standard and that has an adverse impact on the final Product quality and/or stability and/or physical characteristics.

 

Client may participate in any investigation concerning the OOS results. Supplier will implement any agreed actions arising out of the completed investigation report in order to avoid the reoccurrence of similar issues in the future. In all cases, Supplier must investigate any confirmed OOS result and forward a copy of the completed investigation report to Client within a reasonable period of time. The investigation report will be maintained as part of the executed batch record.

 

For all confirmed OOS stability test results that indicate that any products manufactured for Client has (have) failed to remain within specifications, Supplier will notify and discuss with Client promptly (within 3 business days) and provide the stability data. The investigation report will be maintained as part of the stability report.

 

31.                               Labelling

 

Supplier shall comply with the requirements in ICH Q7 in relation to labelling, in particular:

 

·                                          Labelling operations shall be conducted to prevent mix ups,

·                                          Labels shall be checked for accuracy before application,

 

This agreement does not absolve Supplier from complying with any legal requirements in relation to the transportation of any products manufactured for Client.

 

32.                               Regulatory documents

 

Upon request by, and in mutual consultation with Client, Supplier shall be responsible for preparation of documentation on Manufacture of any products manufactured for Client as required for the Regulatory Submissions of Client, limited to Supplier’s activities under this agreement.

 

Client shall provide portions of Regulatory Submissions, related to any products manufactured by Supplier for Client and Supplier’s, activities performed under this agreement, to Supplier for review and written consent, prior to submission to any Regulatory Authority. Client shall, upon submission to any Regulatory Authority, provide Supplier with current copies of portions of

 

11











 

Regulatory Submissions. including amendments and supplements thereto, related to any products manufactured by Supplier for Client and Supplier’s activities performed under this agreement.

 

Supplier will provide, in mutually agreed timelines, all other information related to any products manufactured by Supplier for Client that Client may reasonably request for its Regulatory Submissions, including any data for annual reports (e.g. annual stability reports).

 

When a change is known to require, or has the potential to require a Regulatory Submission, Supplier with Client will develop a joint strategy to secure the appropriate regulatory approval prior to implementation of the change at Supplier and Client. For Change Control see section 3.

 

Supplier shall be responsible for preparation of the Drug Master File related to any products manufactured for Client and submission of such documents to any Regulatory Authority, including maintaining such submissions (hereafter altogether called ‘DMF’).

 

33.                               Product release

 

Supplier quality unit has the responsibility to review and approve the executed batch production records prior to batch release. Supplier has the responsibility to release any products manufactured by Supplier for Client for shipment to Client.

 

At the Client’s request, the executed batch production records will be sent to Client for review prior to batch disposition.

 

Supplier will not ship any products manufactured for Client to any destination, as identified by Client, until the product(s) manufactured for Client is or are released for shipment, unless prior written approval has been received from Client to perform such a shipment under quarantine.

 

Supplier is responsible for the issuance for each batch of product manufactured for Client a Certificate of Analysis and Certificate of Conformance (see also section 16).

 

34.                               Reference standards

 

All reference standards should be stored in accordance with the Suppliers recommended storage conditions and used within their given expiry or retest date.

 

Client is responsible for the purchase and certification of the reference standards.

 

Client shall provide to Supplier reasonable quantities of any non-compendial or not commercially available reference standards necessary to perform the tests included in product specifications.

 

35.                               Analytical methods

 

Analytical methods used for testing the API(s): compendial analytical methods must be verified and all others must be validated prior to use

 

12












 

Development (early clinical phase)

Supplier provides verification of analytical methods for intended use (see Note).

Note: in case API lots will be used for clinical phase 3 studies, or prior to the validation campaign at the latest, the analytical methods should be validated according to ICH Q2 (R1) guidelines.

 

Any significant changes to these analytical methods must be approved by the Client via a formal Change Control system.

 

36.                               Manufacturing

 

Supplier shall have appropriate control procedures in place to ensure that only authorised personnel has access to Supplier’s manufacturing facilities.

 

37.                               Division of Responsibilities Table

 

	
§
    	
 
    	
Responsibilities
    	
 
    	
Not
   Applicable
    	
 
    	
Client
    	
 
    	
Supplier
    
	
1.
    	
 
    	
General   Provisions
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
1.01
    	
 
    	
Follow applicable current Good   Manufacturing Practices (cGMPs), including International Conference on   Harmonization (ICH) Q7 Good Manufacturing Practice Guidance for Active   Pharmaceutical Ingredients (API)) and locally imposed requirements.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
1.02
    	
 
    	
Manufacture, package, ship, store and   test the Product and materials in an environment meeting the applicable GMP   regulations, which is designed, constructed and maintained in a manner that   a) permits the operation therein to be performed under clean, sanitary and   orderly conditions; b) permits the effective cleaning of pertinent surfaces;   and c) prevents the contamination of the Product and the addition of   extraneous material to the Product.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
1.03
    	
 
    	
Manufacture the Product in adherence to   applicable regulatory submissions, such as Drug Master File (DMF), if   applicable.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
1.04
    	
 
    	
Operate in compliance with applicable   environmental,

occupational health and safety laws and   regulations.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
2.
    	
 
    	
Organization and Personnel
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
2.01
    	
 
    	
Implement procedures and/or documented   training to meet obligations under this Agreement
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
2.02
    	
 
    	
There shall be a quality control unit   that shall have the responsibility and authority to approve or reject all   components, drug product containing, closures, in-process materials,   packaging material labeling, and drug products, and the authority to review   production records to assure that no errors have occurred or if errors have   occurred, that they have been full investigated.  The quality control unit shall be   responsible for approving or rejecting drug products manufactured, processed,   packed, or held under contract by another company.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    


 

13











 

	
2.03
    	
 
    	
The responsibilities and procedures   applicable to the quality control unit shall be in writing; such written   procedures shall be followed.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
2.04
    	
 
    	
Maintain a quality unit that is   independent of production that fulfils both quality assurance and quality   control responsibilities.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
2.05
    	
 
    	
Involve the quality unit in all quality   related matters and have them review and approve all quality critical related   documents.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
2.06
    	
 
    	
As it relates to this Quality Agreement,   notify the other party of name change, corporate reorganization,   consolidation, merger or acquisition or sale of the party’s company. Notify   other party of key personnel changes.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
3.
    	
 
    	
Facilities and Equipment
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
3.01
    	
 
    	
Ensure that facilities, equipment and   systems, pertaining to the product(s) outlined in this Agreement, are   qualified and maintained compliant to cGMP regulations.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
3.02
    	
 
    	
Sharing information on toxicity of API   and raw materials, process aids and intermediates, if available
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
3.03
    	
 
    	
Establishing solubility of API and   intermediates in cleaning agent used
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
3.04
    	
 
    	
Assessing/verifying cleanliness of used   equipment
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
3.05
    	
 
    	
Releasing equipment after cleaning
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.
    	
 
    	
Production and In Process Controls,   Packaging and Labelling
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
4.01
    	
 
    	
Procure, test as required, and release   raw materials and packaging and labelling materials used in manufacture of   Product.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
4.02
    	
 
    	
Establish and document specifications   for raw materials- Product labelling and packaging materials and other   materials that would likely affect product quality.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
4.03
    	
 
    	
Prepare/develop master batch production   records in accordance with applicable cGMP requirements or guidelines, as   applicable for lifecycle of product.
    	
 
    	
it
    	
 
    	
 
    	
 
    	
X
    
	
4.04
    	
 
    	
Review and approval of all master batch   documentation.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.05
    	
 
    	
Inspect, weigh and measure raw materials   used for Product manufacturing and verify critical weighing by a second   individual or validated automated system.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.06
    	
 
    	
Manufacture Product in ?Mariner that   prevents contamination by other materials including carryovers.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.07
    	
 
    	
Provide product label to include: name   and address of the manufacturer, identifying code, batch number, quantity of   contents, storage and special transport conditions if applicable, the retest   or expiry date and any special requirements. Revise label per Change Control   as necessary.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.08
    	
 
    	
Review and approval of batch production   records by quality unit prior to batch release.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.09
    	
 
    	
Release Product by quality unit for   shipment to the client.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.09
   bis
    	
 
    	
Deciding on final disposition of API
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
4.10
    	
 
    	
Provide label for intermediates,   samples, and waste. Revise label per SOP as necessary.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.11
    	
 
    	
Specifying packaging material for API
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    


 

14











 

	
4.12
    	
 
    	
Specifying packaging material for   materials before the API, if needed
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
4.13
    	
 
    	
Purchasing packaging material
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.
    	
 
    	
Documentation and Records
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
5.01
    	
 
    	
Have a controlled system to initiate,   review, revise, approve, obsolete and archive all Good Manufacturing   Practices documentation. At a minimum, all production, control, and   distribution records should be retained for at least 1 year after the expiry   date of the batch. For APIs with retest dates, records should be retained for   at least 3 years after the batch is completely distributed.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.02
    	
 
    	
Have written procedures for the review   and approval of all batch documentation.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.03
    	
 
    	
Maintain a document control system for   specifications and test methods, including: raw materials, Product labeling,   packaging materials and other materials that would likely affect product   quality.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.04
    	
 
    	
Review and approval of specifications   and test methods, including: Product labeling, packaging materials and other   materials that would likely affect product quality.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
5.05
    	
 
    	
Provide a complete Certificate of   Analysis for the Product, containing “at minimum” the following information:

Supplier Product number

Supplier lot/batch number.

Name of Product

Name of the tests Specification limit

Expiration or retest date, if applicable

Test result (as a numerical value,   unless designated

Pass/Fail in the specification limit,   statistical values can be used if data supports their use except for assays   and impurity tests), including retest results if required

Quality Assurance approval and date.

Manufacturing Site (name and address)

Manufacturing Date
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.06
    	
 
    	
Provide certification that the Product   was manufactured in a cGMP compliant facility and was tested in accordance   with and meets specifications
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.07
    	
 
    	
Where applicable, electronic  signatures used on the certificate of   analysis or other controlled documents should be authenticated and secure.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
5.08
    	
 
    	
Archiving the original documents
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
6.
    	
 
    	
Change Control
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
6.01
    	
 
    	
Have established written procedures for   control of changes impacting the Product including manufacturing components   or process, computer hardware/software, Product specifications, test methods,   vendors, and subcontractors, if applicable.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
6.02
    	
 
    	
Notify Client within a reasonable time   of intent to make Major changes that could impact the identity, strength,   safety, potency, stability, purity, or regulatory status prior to   implementation of the change.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
6.03
    	
 
    	
Issue to Client a written evaluation of   the Major Change including change justification so that Client can determine   the
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    


 

15











 

	
 
    	
 
    	
impact of use of Product in Client’s   finished product.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
6.04
    	
 
    	
Have Major Changes reviewed and approved   by the Supplier’s quality unit.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
6.05
    	
 
    	
Jointly establish a strategy to secure   regulatory approvals for Major Changes, as necessary.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
7.
    	
 
    	
Deviations
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
7.01
    	
 
    	
Have procedures for the identification,   investigation, and reporting of each departure from an approved instruction   or established standard (deviations) and Out-of-Specification (OOS) results   that occur during the manufacture and testing of the Product.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
7.02
    	
 
    	
Document and explain all deviations.   Investigate OOS results and Critical Deviations. Extend the investigation to   other lots that may have been associated with the failure as appropriate.   Include preventive actions and track these to completion.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
7.03
    	
 
    	
Evaluate deviations to determine their   impact on the predetermined criteria that ensure the Product meets its g-   specification or applicable validation/qualification study.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
7.04
    	
 
    	
Issuing notifications on atypical   results on stability (e.g.. 00E) to Client within 3 business days of   occurrence
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
7.05
    	
 
    	
Issuing reports on OOS, Critical   Deviations, failures to Client within 3 business days of occurrence
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
8.
    	
 
    	
Reprocess and Batch Adjustments   /Rework/Retest
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
8.01
    	
 
    	
Have procedures for batch adjustments   and reprocessing, if applicable. Reprocessing is defined as introducing an   intermediate or API, including one that does not conform to standards or   specifications, back into the process and repeating a crystallization step or   other appropriate chemical or physical manipulation steps (e.g. distillation,   filtration, chromatography. and milling) that are part of the manufacturing   process.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
8.02
    	
 
    	
Will not blend Out of Specification   batches with other batches for the purpose of meeting specifications.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
8.03
    	
 
    	
Have a protocol for Product requiring   rework describing the rationale and justification for rework for approved   filed rework processes, if applicable. Rework is defined as subjecting an   intermediate or API that does not conform to standards or specifications to   one or more processing steps that are different from the established   manufacturing process to obtain an acceptable quality intermediate or API   (e.g. recrystallizing with a different solvent).
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
8.04
    	
 
    	
Receive written approval by Client for   rework outside of approved filed rework processes.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
8.05
    	
 
    	
Will not perform recovery of materials   and/or solvents unless approved procedures and specifications are in place.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
9.
    	
 
    	
Laboratory Controls
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
9.01
    	
 
    	
Have written procedures for sample   management, testing, approval, disposition, recording, storage, retention and   disposal of laboratory data.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
9.02
    	
 
    	
Retain samples as required by regulatory   agencies.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
9.03
    	
 
    	
Have written procedures and   appropriately document the preparation, use and management of reagents,   solutions, and
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    


 

16











 

	
 
    	
 
    	
standards.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
9.04
    	
 
    	
Have appropriate specifications and test   procedures for the Product which are consistent with the applicable   approved  filing and/or compendia)   monograph.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
9.05
    	
 
    	
Test Product in accordance with approved   validated or qualified methods and specifications using calibrated equipment.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
9.06
    	
 
    	
Have a program for qualification,   calibration, and preventive maintenance of all analytical equipment.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
9.07
    	
 
    	
Responsible for analytical method   development, qualification and or validation as appropriate.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
9.08
    	
 
    	
Responsible for transferring any   developed methods to Supplier.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
9.09
    	
 
    	
Providing development reports, test   procedures, validation documents, etc and other source documents
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
9.10
    	
 
    	
If commercially available reference   standards are not’- available, reference standards for the Product ‘will be   provided.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
10.
    	
 
    	
Storage and Distribution
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
10.01
    	
 
    	
Maintain storage facilities appropriate   for conditions specified on the Product label. Maintain records of any   critical storage conditions.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
10.02
    	
 
    	
Have systems for controlling   quarantined, rejected or recalled materials.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
10.03
    	
 
    	
Provide Material Safety Data Sheets or   equivalent.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
10.04
    	
 
    	
Notify Client in a timely manner if   Supplier finds a quality issue post Supplier release/shipment.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
10.05
    	
 
    	
Storing API under labelled conditions
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
10.06
    	
 
    	
Qualifying of carrier
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
10.07
    	
 
    	
Preparing API for dispatch and loading   of vehicles
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
10.08
    	
 
    	
Maintaining storage conditions during   transportation until agreed transition point
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
11.
    	
 
    	
Complaints
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
11.01
    	
 
    	
Have written procedures in place to   document, investigate, and respond to all quality related complaints.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
11.02
    	
 
    	
Assist in investigations as reasonably   requested by Client for complaints associated with Product.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
11.03
    	
 
    	
Retain complaint investigation records   and evaluate trends and severity. Implement corrective and preventive actions   as necessary.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
11.04
    	
 
    	
Implementing corrective actions, if   necessary
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
11.05
    	
 
    	
Responding to external customers
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
11.06
    	
 
    	
Clarifying root cause
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
11.07
    	
 
    	
Storing or disposing returned product
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
12.
    	
 
    	
Recalls
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
12.01
    	
 
    	
In the event that either Client or   Supplier determines that an event or circumstance has occurred relating to   the manufacture or stability of the Product which may result in the need for   a recall, stock recovery or market withdrawal of Client’s finished drug   product, Supplier and Client shall consult with each other in a timely manner.   The final decision to recall any of the Client’s drug products shall be made   by
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    


 

17











 

	
 
    	
 
    	
Client.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
12.02
    	
 
    	
Notification of the recall or similar   action to the authorities, distributors and customers of the finished drug   product shall be made by Client
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
12.03
    	
 
    	
Supplier will have procedures in place   to facilitate the recall of an API as necessary. Supplier will provide   assistance to the Client for the recall of drug product incorporating the   Supplier’s API.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
13.
    	
 
    	
Annual Product Reviews
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
13.01
    	
 
    	
Have procedures to conduct and document   annual product reviews, if applicable.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
13.02
    	
 
    	
Allow viewing of the Annual Product   Review APR) for  the Product during an   on-site audit.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.
    	
 
    	
Stability
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
14.01
    	
 
    	
Maintain a documented, ongoing stability   program to monitor the stability of the Product using stability indicating   procedures.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.02
    	
 
    	
Data analysis and trending reporting   will be performed.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.03
    	
 
    	
OOS notification to Client will be   provided in a timely manner.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.04
    	
 
    	
Use data to confirm appropriateness of   storage conditions and retest or expiry date:,
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.05
    	
 
    	
Store stability samples in commercial   size and/or simulated market containers under ICH storage conditions.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.06
    	
 
    	
Place the first three commercial   production batches and at least one batch per year (if a batch is produced in   the year) on stability or as required by applicable regulatory agencies.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.07
    	
 
    	
Preparing stability protocols
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
14.08
    	
 
    	
Approving stability protocols
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
15.
    	
 
    	
Validation/Qualification
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
15.01
    	
 
    	
Determine according to Product lifecycle   and guidance documents when process validation is required.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
15.02
    	
 
    	
Have a written master validation/qualification   plan for the facilities, equipment/instruments, manufacturing process,   cleaning procedures, analytical procedures, in process control tests and   computerized systems as appropriate. These to be approved by the quality   unit.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
15.03
    	
 
    	
Responsible for developing, preparing   and maintaining validation documentation approved by the quality unit,   including protocols, reports and associated documentation.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
15.04
    	
 
    	
Qualify as necessary all critical   systems and equipment used for the manufacture and control of Product   (Installation Qualification (IQ), Operational Qualification (OQ), and/or   Performance Qualification (PQ)).
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
15.04
    	
 
    	
Allow viewing of the validation   documentation for the Product during an onsite audit.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
16.
    	
 
    	
Right to Audit
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
16.01
    	
 
    	
Client has the right to audit Supplier’s   facilities and systems and review documents as they relate to the manufacture   of Product. Such inspections and document review shall be conducted by Client   at a time, date and duration mutually agreeable to the Supplier and Client   and subject to Client
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    


 

18











 

	
 
    	
 
    	
signature of a separate confidentiality   agreement with the Supplier entity owning the production site.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
16.02
    	
 
    	
Client retains the right to conduct   reasonable “for cause” audits.    Specific goals/scope of the audit, proposed dates and names of the   auditors will be agreed upon mutually by the Client and the Supplier.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
16.03
    	
 
    	
Issue Supplier a confidential audit   report summarizing audit observations within 30 days of audit.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
16.04
    	
 
    	
Issue responses to all observations   documented in the issued audit report in writing to Client Quality Assurance   within 30 days of receipt of the report.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
16.05
    	
 
    	
Maintain internal GMP audit program.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
16.06
    	
 
    	
Maintain external GMP audit program for   Suppliers of raw materials and components, or other suitable qualification   program.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
17.
    	
 
    	
Regulatory Inspections and Exchanges
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
17.01
    	
 
    	
Notify Client within three business days   of the receipt of a Regulatory Authority inspection report, deficiency letter   or written regulatory  compliance   observation, which contains any significant adverse findings that relate to   the Product or the facilities used to produce, test or warehouse the Product   sold to Client. A significant adverse finding is herein defined as the   following: conditions, practices, or processes that adversely affect or may   potentially adversely affect product or service quality and/or the rights,   safety or well being of subjects/patients and/or the quality and integrity of   data, documentation, or other materials or information addressed in the   inspection.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
17.02
    	
 
    	
Provide copies of the inspection report,   deficiency letter or written regulatory compliance observation that relate to   the Product or the facilities used to produce, test or warehouse the Product   sold to Client. This shall be edited to exclude

Supplier or other Client’s proprietary   information or a complete summary report containing the description of the adverse   finding as stated in the inspection report, deficiency letter or regulatory   compliance observation to Client by facsimile or electronically within five   (5) business days of the receipt of the inspection report.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
18.
    	
 
    	
Regulatory Filings and Regulatory Status
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
18.01
    	
 
    	
Responsible for submission, maintenance,   approvals and updates/amendments to regulatory filings for Product (including   API DMF). Client will be notified as per FDA or EU requirements.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
18.02
    	
 
    	
Responsible for providing to the   agencies all requested documentation/data required for regulatory filings.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
18.03
    	
 
    	
Responsible for communicating to the   other party approvals, deficiencies or rejections by agencies regarding   submissions, amendments or updates.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
18.04
    	
 
    	
Responsible for submission and   maintenance of drug product registration and current site registration and   obtaining labeler code as required by regulatory agencies.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
18.05
    	
 
    	
Client shall provide Supplier with the   following information regarding the use of the product:
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    


 

19











 

	
 
    	
 
    	
Clinical phase of development of the   drug product that Product is used in and any change regarding this status   Intended use of the drug product in which that Product is used Regulatory   agencies with which the drug product is filed and if Product is included in   the filing.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
18.06
    	
 
    	
Notify Supplier if Supplier will be name   in any governmental filing prior to such filing being made.
    	
 
    	
 
    	
 
    	
X
    	
 
    	
 
    
	
18.07
    	
 
    	
Coordinate the activities necessary to   ensure readiness prior to Regulatory Agency Pre-Approval Inspection (PAI).
    	
 
    	
 
    	
 
    	
X
    	
 
    	
X
    
	
18.08
    	
 
    	
Provide Letter of Authorization for   Client to permit reference to Supplier submissions in the registration of the   Client’s drug product.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    
	
19.
    	
 
    	
Animal Derived Materials:
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
19.01
    	
 
    	
Evaluate and control the risk of   Transmissible Spongiform Encephalopathy (TSE) for raw Materials and   components. Maintain appropriate records for each lot of animal derived   material to ensure traceability. Where required by local regulations,   Supplier will assure that the country of origin or slaughtering information   (either or both, which ever can be obtained from the manufacturer) will be   documented and provided to Client.
    	
 
    	
 
    	
 
    	
 
    	
 
    	
X
    


 

20












 

Glossary

 

Active Pharmaceutical Ingredient (API) — Any API or mixture of APIs, intended to be used in the manufacture of a drug (or: medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such APIs are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or any function of the body of man or animals.

 

Business day — Any day of the week, other than Saturday, Sunday, or day on which the party required to take action is regularly closed for business, i.e., Monday to Friday (European working hours) except any official national or regional bank holidays or shut down of the plant.

 

CEP — A certificate issued by the European Directorate for the Quality of Medicines which demonstrates that the Product complies with the requirements of the European Pharmacopoeia monograph and / or Transmissible Spongiform Encephalopathy (TSE) requirements. Also known as “CoS” = Certificate of Suitability.

 

Certificate of Analysis — A document identified as such, provided by the Supplier signed by its Responsible Person, or produced by a computer system which provides a degree of control equivalent to that given by a signature, which sets forth the analytical test results, obtained from testing of a representative sample, against the specifications for the batch to be delivered.

 

Certificate of Conformance  — A document identified as such, provided by the Supplier and signed by a nominated representative of its Quality Unit; or produced by a computer system which provides a degree of control equivalent to that given by a signature, which certifies that each batch of Product was produced and -tested in compliance with the agreed specifications, cGMP, and the relevant pharmacopoeial monographs, as applicable.

 

Contract — Business agreement for supply of goods or performance of work at a specified price.

 

Contract Manufacture — Performance of some aspect of manufacture, under a contract, on behalf of the original manufacturer.

 

Client — The company or organisation receiving the product (API or intermediate) once it has left the control of the Supplier; includes users and distributors.

 

Critical Deviation — Departure from an approved process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification or established standard and has an adverse impact on the final Product quality and/or stability and/or physical characteristics.

 

Distributor — Any party in the distribution/supply chain starting from the point at which an API or intermediate is transferred outside the control of the original manufacturer’s material management system including parties involved in trade and distribution, such as (re)processors,

 

21











 

(re)packagers, transport and warehousing companies, forwarding agents, brokers, traders, and Suppliers other than the original manufacturer.

 

DMF — Drug Master File. The Supplier’s dossier for providing confidential information to a regulatory authority about facilities, processes, or articles relating to product used in the manufacturing, processing, packaging, and storing of one or more drug (or: medicinal) products.

 

GMP — Good Manufacturing Practice. Requirements for the Quality System under which drug (or: medicinal) products and their (active) ingredients are manufactured. Current Good Manufacturing Practice (cGMP) is the applicable term in the United States. For the purposes of this guideline, the terms GMP and cGMP are equivalent.

 

Immediately — Generally no more than twenty-four (24) business hours. This period may be exceeded due to events or circumstances beyond the reasonable control of the responsible party.

 

Laws — All laws, statutes, rules, regulations (including, without limitation, cGMPs, NDA regulations, and other relevant provisions enforced by any applicable governmental authority), ordinances and other pronouncements having the binding effect of law of any governmental authority.

 

Major Changes — Changes to a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification or established standard that could impact the identity, strength, safety, potency, stability, purity, and/or regulatory status.

 

Manufacturing License — With respect to a country, any regulatory authorisation required to manufacture one or more products or classes of product as granted by the relevant governmental authority.

 

Non-conformance — Departure of a quality characteristic from its intended level or state such as to cause an associated material or activity not to comply with its specification, cGMP, marketing authorisation or applicable law.

 

Original Manufacturer — Person or company manufacturing a material to the stage at which it is designated as a pharmaceutical starting material.

 

Product Quality Review — The PQR is an assessment to verify the operational consistency of a process based on results trending and non-conformances.

 

Promptly — Generally no more than three (3) -business days. This period may be exceeded due to events or circumstances beyond the reasonable control of the responsible party.

 

Quality Agreement — A legally binding agreement that is mutually negotiated and concluded between (the Quality Departments of) API manufacturers and their customers. It is intended to define, in a formalised manner responsibilities relative to quality tasks to assure the manufacture, supply and use of safe in aerials acceptable for pharmaceutical use It may also include

 

22











 

commitments between the parties regarding (a) the provision of information, documents, or samples, and (b) communication and notification rules including contacts.

 

Quality Incident — An incident relating to an issue or defect which is not necessarily detected by the specification parameters but which potentially could result in a non-conformance. A “critical” quality incident is relating to a defect or fault that makes a product unsuitable for use and which could potentially result in a recall, retrieval or withdrawal.

 

Record — Document stating results obtained and/or providing evidence of activities performed. The medium may be paper, magnetic, electronic or optical, photography etc. or a combination thereof.

 

Responsible Person — The person(s) within the Quality Unit at the Supplier who is accountable for the release of batches of product.

 

Sample — A part or parts of the product taken to show the quality of the whole.

 

Site — A location where the API or intermediate manufactured. This may be any operational area within the Supplier’s facility referred to in the section “Parties to the agreement” of the Quality Agreement (see chapter 5.2, I.1 of this guideline), or at a remote facility that may be the facility of an affiliate of the Supplier or a sub-contractor.

 

Sub-Contractor — A third party contractor, engaged and qualified by the Supplier to perform any part of the Supplier’s cGMP obligations under the License, Supply or Quality Agreements.

 

Supplier — Person or company providing APIs or intermediates on request. Suppliers may be (original) manufacturers or distributors.

 

Supply chain — For the purpose of this guideline, supply chain is defined as all steps in the entire chain of distribution starting from the point at which an API or intermediate is transferred outside the control of the original manufacturer’s material a management system downstream to the final user(s).

 

Timely manner — As soon as can be expected considering the typical operations and processes at manufacturers, the defined responsibilities and the agreed communication pathways. A “reasonable period of time” is considered as practically synonymous. The exact period of time depends on the respective subject.

 

User — A party who utilises an API in the manufacture of a drug product or an intermediate in the manufacture of an API.

 

23











 

Appendices:

 

1.             List of Products manufactured by Supplier for Client

 

2.             List of Key Contacts

 

3.             Product Specifications

 

4.             Examples of Changes that do not require notification

 

5.             Examples of OOS/Critical Deviations

 

24











 

Appendix 1:

 

List of Products manufactured by Supplier for Client:

 

BA058 API

 

25











 

 

Appendix 2:

 

List of Key Contacts:

 

	
Client
    	
 
    	
Supplier
    
	
 
    	
 
    	
 
    
	
J. Guerriero
    	
 
    	
F. Mutterer
    
	
 
    	
 
    	
 
    
	
L. O’Dea
    	
 
    	
P. Loosen
    


 

26











 

Appendix 4:

 

Examples of Changes that Do Not Require Notification (not intended to be all inclusive)

 

Editorial changes to procedures, batch records, or manufacturing/testing procedures, which are of a typographical, grammatical/presentation updates or which provide additional detail/clarity in describing an existing established practice.

 

Environmental control changes, which do not affect the processes, product or service (e.g., changes in sample frequency or locations)

 

Safety changes, which do not affect the process, product or services.

 

Like-for-like changes to equipment or parts. Like-for-like changes are those that use the same replacement part from the same Supplier or parts from a different Supplier, but which are deemed and documented by the user to be identical in functionality and performance.

 

New procedures that are created to document an existing established practice, provided that the new details are in accordance with the process as described in the master batch record.

 

Routine and preventative maintenance updates that do not have an associated change to an operating parameter.

 

27











 

Appendix 5:

 

Examples of Examples of OOS/ Critical Deviations that Require Notification (not intended to be all inclusive)

 

Any manufacturing, holding, packaging, labelling, sampling or testing OOS/deviation that may affect the quality, safety, purity, or integrity of the product.

 

Any reprocessing, reworking or process amendments.

 

Any aberrant result, including yields and analytical test results.

 

Any physical contamination, cross-contamination, chemicalor microbiological contamination of the product or processes.

 

Critical departures from the master batch record, validation, analytical methods, or stability.

 

Equipment failure / calibration failure only if impact or the product quality.

 

28











 

Done in two (2) original copies, each party having received its copy.

 

 

Company Approval

 

It has been approved by:

 

RADIUS

 

	
 
    	
Signed:
    	
 
    	
Date:
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
/s/ Nick Harvey
    	
 
    	
 
    	
Dec. 13, 2010
    
	
 
    	
Nick Harvey
    	
 
    	
 
    
	
 
    	
CFO
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
Signed:
    	
 
    	
Date:
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
/s/ Louis O’Dea
    	
 
    	
 
    	
Dec. 15, 2010
    
	
 
    	
Louis   O’Dea
    	
 
    	
 
    
	
 
    	
CMO
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
LONZA
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
Signed:
    	
 
    	
Date:
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
/s/ Frederique   Mutterer
    	
 
    	
 
    	
Dec. 21, 2010
    
	
 
    	
Frederique Mutterer
    	
 
    	
 
    
	
 
    	
Head of Quality Assurance and Regulatory Affairs
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
Signed:
    	
 
    	
Date:
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
/s/ Patrick   Loosen
    	
 
    	
 
    	
Dec. 21, 2010
    
	
 
    	
Patrick Loosen
    	
 
    	
 
    
	
 
    	
General Manager Head of Operations
    	
 
    	
 
    


 

29