TECHNICAL AGREEMENT ON THE MANUFACTURE OF CAPSULES VB-201 for VASCULAR BIOGENICS
Exhibit 10.8
TECHNICAL AGREEMENT ON THE
MANUFACTURE OF CAPSULES
VB-201
for
VASCULAR BIOGENICS
Prepared by: J McLachlan
ENCAP DRUG DELIVERY
Encap Ref: EN1378;Vascular Biogenics Technical Agreement
Revision : 03
Print date: 03 Aug 2012
Page 1 of 14
Portions of this exhibit have been omitted and filed separately with the SEC pursuant to a confidential treatment request and are indicated by [***].
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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CONTENTS
| 1. | Scope of agreement | 3 | ||||||
| 2. | Parties to agreement | 3 | ||||||
| 3. | Products | 3 | ||||||
| 4. | Quality standards | 4 | ||||||
| 4.1 | Manufacturer’s Licence | 4 | ||||||
| 4.2 | Compliance with GMP | 4 | ||||||
| 4.3 | Product specifications | 4 | ||||||
| 4.5 | Starting materials | 4 | ||||||
| 4.6 | Batch Manufacture | 4 | ||||||
| 4.7 | Storage and shipping | 4 | ||||||
| 4.8 | Third party laboratory | 4 | ||||||
| 5. | Responsibilities | 4 | ||||||
| 5.1 | General and regulatory responsibilities | 5 | ||||||
| 5.2 | Product-related responsibilities | 6 | ||||||
| 5.3 | Validation, deviations, changes, complaints and recalls | 8 | ||||||
| 5.4 | Audit | 9 | ||||||
| 6. | Signatories | 10 | ||||||
Attachments:
Attachment 1: Product manufacturing and technical release specifications
Attachment 2: Starting materials provided by Encap
Attachment 3: Manufacturing document references
Attachment 4: Contact Personnel
Page 2 of 14
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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| 1. | SCOPE OF AGREEMENT |
This Technical Agreement is made in support of Capsules VB-201 (also known as CI-201) between Encap Drug Delivery and Vascular Biogenics Ltd (VBL) and is subject to the Proposals and Standard Terms and Conditions executed between the parties in advance of each project related manufacture.
Vascular Biogenics is investigating formulations of VB-201 for use in humans and requires manufacture of bulk capsules for use in clinical trials. The new formulations for these products have been identified from project work at Encap on behalf of VBL.
This agreement details the technical terms under which the contract will operate. It defines the products, quality standards, identifies the responsibilities of each party and defines supporting documentation. It identifies contacts for quality issues The document is drawn up in accordance with Encap’s Standard Operating Procedure 0063 on generating a technical agreement for standard manufacture of licensed products (SOP 0063).
Encap and VBL may, from time to time, agree Addenda to this agreement in writing. The Addenda will apply for particular supplies (strengths and numbers) and will apply the Quality Standards and responsibilities described in this Technical Agreement. Such Addenda may also provide for related new strengths, as may be agreed from time to time.
| 2. | PARTIES TO AGREEMENT |
| Contract Giver: |
Vascular Biogenics Ltd.,6 ▇▇▇▇▇▇▇▇ Nethanyahu St. Or ▇▇▇▇▇▇, 60376 (Israel) | |
| Contract receiver |
Encap Drug Delivery, ▇▇▇▇▇▇▇ ▇▇▇▇, ▇▇▇▇▇▇▇▇▇▇, ▇▇ ▇▇▇▇ ▇▇▇ | |
| 3. | PRODUCT REGULATORY REFERENCES |
| Product |
Investigative Medicinal Product Authorisations held byVascular Biogenics |
Country | ||
| Capsules VB-201 | Individual references client responsibility. | Europe and/or USA |
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| 4. | QUALITY STANDARDS |
| 4.1 | Manufacturer’s Licence |
MW Encap Ltd, trading as Encap Drug Delivery, holds a Manufacturer’s Licence from the MHRA (UK) for the manufacture of Investigative Medicinal Products (IMP’s ) (reference MAIMP/13485).
| 4.2 | Compliance with GMP |
Batches will be manufactured and assembled to comply with all current European rules regarding Good Manufacturing Practices (EudraLex, Volume 4, 1997 and 21CFR parts 210 and 211).
| 4.3 | Product specifications |
Specifications for finished products are listed in (Attachment 1). Responsibilities for testing and release are defined in Table 5.2
| 4.4 | Starting materials and packaging components |
Specifications for starting materials are listed in (Attachment 2). Responsibilities for sourcing and approval are defined in Table 5.2
| 4.5 | Batch Manufacture |
Batch manufacturing documents are defined in Attachment 3
| 4.6 | Storage and shipping |
| 4.6.1 | API Storage: | [***] | ||
| 4.6.2 | Product Storage: | [***] | ||
| 4.6.3 | Product Shipping: | [***] | ||
| 4.7 | Sampling and sample retention |
Sampling and sample retention of starting materials and product will be done according to standard Encap procedures
| 4.8 | Third party laboratory |
(not applicable).
| 5. | RESPONSIBILITIES |
| 5.1 | General and regulatory responsibilities | see Table 5.1 | ||
| 5.2 | Product-related responsibilities | see Table 5.2 | ||
| 5.3 | Validation, deviations, changes, complaints and recalls | see Table 5.3 | ||
| 5.4 | Audit | see Table 5.4 | ||
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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Table 5.1: General and regulatory responsibilities
| ITEM |
Responsibilities | |||
| Encap |
Vascular Biogenics | |||
| Organisation & Personnel | • Ensure personnel have appropriate training, skills, knowledge & experience to manufacture and test Product |
• Confirm by audit | ||
| Premises & equipment | • Provide properly designed, qualified & maintained premises, utilities & equipment |
• Confirm by audit | ||
| Regulatory notifications | • Provide technical recommendations and information in support of Vascular Biogenics’s regulatory Variation (s) (eg, formulation, process outline, test methods, specification limits) |
• Prepare and submit all product-specific documentation to regulatory authorities
• Notify Encap of intended country (ies) of use (Europe or USA)
• Provide copy of regulatory approval documents to Encap to support product release
• Provide Encap with updated IMPD submissions and approvals, according to ongoing project progress | ||
| Marketing Authorisations (MA) | n/a | • Notify Encap of IMPD references and requirements arising from Variations | ||
| Regulatory controls | • Meet Vascular Biogenics’s requirements on product regulatory controls |
• Notify Encap on regulatory controls in the specific market | ||
| Use of Contract Analytical Laboratories (CAL) | • Approve Contract Analytical Laboratories (CAL)
• Notify Vascular Biogenics of CALs prior to their use |
• Consent to the proposed use of CAL’s | ||
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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Table 5.2: Product-related responsibilities
| ITEM |
Responsibilities | |||
| Encap |
Vascular Biogenics | |||
| Raw materials for process & packaging of Product | • Generate and approve internal specifications, according to initial advice from Vascular Biogenics
• Source, test & release starting materials of appropriate quality for processing of Product, primary and second packaging components
• Qualification of vendors
• Retain representative samples |
• Notify Encap of the properties (chemistry, clinical, safety and handling) of the active material
• Provide initial specifications for Starting materials, packaging components & Product
• Confirmation of compliance of materials supplied by Vascular Biogenics with TSE requirements. Approve the API supplier and notify Encap of the approval | ||
| Product specification | • Generate specifications for bulk products (includes test methods) according to Vascular Biogenics requirements |
• Define Vascular Biogenics requirements on initial specification
• Definition of product expiry date
• Agree & sign final specifications | ||
| Production & process control | • Manufacture of Product to cGMP standards
• Designate lot numbers for raw materials and Product
• Establish in-process controls
• Generate and approve Master Batch Instructions and Records for manufacture |
• Confirm by audit
• Agree in-process control testing strategy
• Regulatory pharmaceutics sections to be made available to Encap
• Approve manufacturing documentation | ||
| Laboratory controls | • Starting materials and bulk product release testing against specification
• Operate to cGMP standards
• Retain representative samples of starting materials, packaging components and products, according to the relevant specification |
• Confirm by audit
• Agree retention time of samples | ||
| Product storage, labelling and packaging prior to shipment | • Store, label and pack the bulk Product as defined in the Product Specification, for full testing and assembly by third party nominated by the client |
• Confirm by audit
• Assembly of IMP by Vascular Biogenics or third-party nominated by Vascular Biogenics | ||
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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Table 2 (ctd)
| ITEM |
Responsibilities | |||
| Encap |
Vascular Biogenics | |||
| Bulk Product Release (Investigative Medicinal product, IMP) | • Bulk product, for release to Vascular Biogenics, according to agreed specifications |
• Forward required batch-related documentation to VBL’s third-party packaging contractor
• Final technical release of bulk and assembled product, in compliance with the relevant regulatory trial authorisation
• Final release for use in clinic | ||
| Shipment | • Notify Vascular Biogenics of proposed shipment date
• Ship Product to locations designated by Vascular Biogenics under specified conditions |
• Acknowledge receipt
• Confirm by audit | ||
| Retention of records | • Retain all manufacturing and testing records including records associated with the inspection and release of raw materials / starting materials and packaging components of the Product for (15) years
• Notify Vascular Biogenics of intent to destroy records with option to return records to Vascular Biogenics |
• Confirm by audit
• Vascular Biogenics to approve destruction or return of records | ||
| Stability testing | • (under separate agreement) |
• n/a | ||
| Product Specification File (IMP) | • Generate and maintain internal file for product for trial in Europe |
• VBL to maintain main file | ||
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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Table 5.3 : Validation, deviations, changes, complaints and recalls responsibilities
| ITEM |
Responsibilities | |||
| Encap |
Vascular Biogenics | |||
| Validation | • Premises, utilities and equipment; cleaning procedures
• Process validation
• Analytical method validation |
• Confirm by audit | ||
| Significant deviations, out of specification reports | • Evaluate & define follow up actions & final approval of deviations, non conforming material reports (NMCR’s) & failed manufacture reports
• Notify Vascular Biogenics of all significant deviations and out of specification reports |
• Confirm by audit | ||
| Change control procedures | • Proposed changes to be accompanied with rationale for change to Product specific Process parameters, test methods, sampling plans, critical raw material specifications, process control Specifications, Product specifications, validation protocols, reports and key personnel
• Notify Vascular Biogenics of significant changes to premises, equipment, utilities and senior technical staff |
• Confirm by audit
• Should Vascular Biogenics propose changes, these will be subject discussion and agreement with Encap
• Notify in writing if audit is required prior to start of next manufacturing run | ||
| Complaints | • Provide support and responses to Vascular Biogenics |
• Receive complaint and co-ordinate relevant investigation and responses
• Notify Encap of complaint | ||
| Product recall | • Notify Vascular Biogenics of quality issues considered likely to require recall
• Provide support , implement relevant investigations and provide responses to Vascular Biogenics |
• Assess need for recall
• Co-ordinate recall
• Notification to Encap
• Notification to regulatory authority | ||
Page 8 of 14
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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Table 5.4: Audit responsibilities
| ITEM |
Responsibilities | |||
| Encap |
Vascular Biogenics | |||
| Audit | • Accommodate up to one day annual audits and ‘for cause’ (to address significant Product quality issues) audits by Vascular Biogenics at mutually agreed dates
• Provide a timely response to observations reported by Vascular Biogenics
• Allow access to areas of the manufacturing facility where the Product related activities are being performed
• Allow Vascular Biogenics to observe operations related to Product manufacture and testing provided other Vascular Biogenics confidentiality is respected
• Allow Vascular Biogenics to review all documentation associated with manufacturing and testing of Product
• Issue corrective action follow-up report
• Allow Vascular Biogenics to review all documentation associated with Process and analytical validation |
• Provide reasonable notice of intention to audit
• Hold an exit meeting to discuss observations
• Provide an audit report
| ||
| Regulatory inspection | • Notify Vascular Biogenics of pending regulatory agency inspections affecting manufacture or testing of Product |
• Comment on proposed regulatory responses to observations relevant to Product
• Provide, on Encap request, on-site representative and involvement in technical discussions | ||
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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| 6. | SIGNATURES |
| Vascular Biogenics | Encap Drug Delivery | |||
| /s/ [Illegible] |
/s/ ▇. ▇▇▇▇▇▇▇ | |||
| Name: | Name: J Darling | |||
| Title (Quality) | Title: QA Manager / QP | |||
|
|
August 6, 2012 | |||
| Date: | Date: | |||
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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ATTACHMENT 1
Listing of agreed capsule specifications
| PRODUCT |
STRENGTH (mg) |
REFERENCE | ||
| [***] | [***] | [***] |
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ATTACHMENT 2
STARTING MATERIALS
| 1. | STARTING MATERIALS PROVIDED BY CLIENT* |
| Encap raw material reference |
Raw material title | Function | Compliance | |||
| [***] | [***] | [***] | [***] |
[***]
| 2. | STARTING MATERIALS PROVIDED BY ENCAP* |
| Product reference |
Raw material reference |
Raw material title | Function | Compliance | ||||
| [***] | [***] | [***] | [***] | [***] |
[***]
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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ATTACHMENT 3
MANUFACTURING PARAMETERS
Manufacturing Process
The process is defined in specific batch processing instructions
Processing controls
Process controls are defined in specific batch processing instructions
(Fill weight)
Processing Instructions and Records
| Product Reference |
Document |
Preparation and filling | ||
| [***] | [***] | [***] |
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Technical Agreement between Encap Drug Delivery and Vascular Biogenics
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ATTACHMENT 4
Contact Personnel
| Vascular Biogenics | Encap Drug Delivery | |||
| Quality | ||||
| /s/ ▇▇▇▇▇ Mor |
/s/ ▇. ▇▇▇▇▇▇▇ | |||
| Name: ▇▇▇▇▇ Mor | Name: J Darling | |||
| Title: Head of QA | Title: QA Manager | |||
| Production | ||||
| /s/ ▇▇▇▇▇▇ ▇▇▇▇ |
/s/ J Savage | |||
| Name: ▇▇. ▇▇▇▇▇▇ ▇▇▇▇ | Name: J Savage | |||
| Title: VP RA & Drug Development | Title: Production Director | |||
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