Amendment #2 to Manufacturing Services Agreement between the Registrant and Patheon Pharmaceuticals, Inc., effective as of August 4, 2017

1.

Article 1, Section 1.1 (Definitions) of the Agreement is amended to add the following definitions:

●

“Bulk Product” means, as described and identified in Schedule A.

2.

Article 1, Section 1.1 (Definitions) is amended as follows:

●

“Finished Product Packaging” means, the product(s) listed and identified in Schedule A.

3.

Section 2.1 (Manufacturing Services), the first paragraph, is deleted in its entirety and replaced with the following:

4.

Article 2 (Patheon’s Manufacturing Services), new Section 2.3 is added as follows:

5.

Schedules A, B and C are deleted in their entirety and replaced with the revised Schedules A, B and C attached.

6.

Conflicts, Use of Terms. If there is a conflict between the terms and conditions of the Agreement and the terms and conditions of this Amendment #2, the terms and conditions of this Amendment #2 will control.

7.

No Other Modifications. Except as provided above, the terms and conditions of the Agreement remain unchanged.

AcelRx Pharmaceuticals, Inc. 

Patheon Pharmaceuticals Inc.

By: /s/ Raffi Asadorian                 

By: /s/ Amanda Bosse             

Title:   Chief Financial Officer      

Title: VP and GM Cincinnati Regional Operations

Date: 8/22/17  

Date: 8/18/17

1.

2.

Zalviso Pricing Tables

Product

Annual Volume Tier per SKU

(Cartons)

Minimum Ordering Quantity

2017 Price per

Packaged - Cartridge

Material Price

Conversion Price

Full Service Price

1 carton of 20 cartridges

(40 tablets per Cartridge)

[*]

[*] Cartridges

[*]

[*]

[*]

1 carton of 20 cartridges

(40 tablets per Cartridge)

[*]

[*] Cartridges

[*]

[*]

[*]

1 carton of 20 cartridges

(40 tablets per Cartridge)

[*]

[*] Cartridges

[*]

[*]

[*]

1 carton of 20 cartridges

(40 tablets per Cartridge)

[*]

[*] Cartridges

[*]

[*]

[*]

1 carton of 20 cartridges

(40 tablets per Cartridge)

[*]

[*] Cartridges

[*]

[*]

[*]

●

LG1 – Tier 2 ([*] Cartons)

●

LG2 – Tier 1 ([*] Cartons)

●

LG3 – Tier 1 ([*] Cartons)

●

LG4 – Tier 3 ([*] Cartons)

3.

Dsuvia Pricing Tables

3.1.

Commercial Manufacturing Prices – Bulk Tablets

Product

Mfg. Campaign Length

(Batches)

Minimum Ordering Quantity

(000’s)

Price per 1,000

Material Price

Conversion Price

Bulk Price

ARX-04 Tablets, [*] Tier

[*]

[*]

[*]

[*]

[*]

ARX-04 Tablets, [*] Tier

[*]

[*]

[*]

[*]

[*]

ARX-04 Tablets, [*] Tier

[*]

[*]

[*]

[*]

[*]

3.2.

Process Validation Batch Price:

3.3.

Costs Included in Price

3.3.1.

Product manufactured according to the approved and registered specifications.

3.3.2.

Estimated material costs. Material costs included in the pricing are best estimates based on Patheon’s current standards and specifications and do not include any extraordinary or custom raw materials. Final material costs will be provided after confirmation of specifications and formal quotations have been received from the suppliers. The cost of materials to AcelRx will be [*].

3.3.3.

Procurement, storage, inventory control and Quality Control (“QC”) testing of all required raw materials to supply the Product, including storage of Client-supplied components to meet firm order requirements or such time as agreed between the parties to accommodate long lead time items.

3.3.4.

Qualification and auditing of all raw material (with the exception of Client-supplied raw material).

3.3.5.

Active Pharmaceutical Ingredients (“API”) identity test. AcelRx will audit and approve the Vendor and ensure cGMP compliance. If Patheon is to release an API or other Client stipulated material based on “ID only”, AcelRx will ensure the required verification testing by an independent laboratory has been completed.

3.3.6.

Standard certificate of analysis (“COA”) and Standard certificate of compliance (“COC”)

3.3.7.

GMP batch release

3.3.8.

GMP required retention samples and executed batch records retention API, bulk product and finished packaged product retention samples, and completed batch production records, as required by the cGMP Regulations or other governing regulations, for one year past the expiration date of the product.

3.3.9.

Deviation investigations and copies of deviation reports

3.3.10.

Batch Record copies for validation batches, first ten commercial batches, and one commercial batch per Year thereafter.

3.3.11.

Common HPLC/GC columns, reagents, and lab supplies

3.3.12.

Copy of the Annual Product Review Report. Patheon will supply on an annual basis all Product data in its control, including release test results, complaint test results, and all investigations (in manufacturing, testing, and storage), that Client reasonably requires in order to complete any filing under any applicable regulatory regime, including any Annual Report that Client is required to file with the FDA.

3.3.13.

First Product Approval Inspection (“PAI”) and copy of FDA Report. Additional PAI support will be subject to additional fees.

3.4.

Costs Not Included in Price

API, reference standards, and Client-supplied materials to be supplied by AcelRx at no cost to Patheon.

3.4.2.

API complete QC testing or special API testing requests.  NOTE: This testing will be mandatory if AcelRx has not performed the verification testing specified in 3.3.5.

3.4.3.

Stability testing program − Patheon can store and test in accordance with an agreed protocol and ICH guidelines. See proposal C-CRC-101285-R0.

3.4.4.

Regulatory support and CTD files updating

3.4.5.

Routine periodic auditing of component suppliers not currently on Patheon’s approved list

3.4.6.

Annual Review (“AR”). Any additional data or report requested by AcelRx beyond the scope of cGMPs and customary FDA or other regulatory agencies requirements will be subject to an additional fee to be agreed upon between Patheon and AcelRx.

3.4.7.

Technology transfer fees including packaging serialization readiness.

3.4.8.

Artworks origination and update costs including one off costs at suppliers.

3.4.9.

Label copy change and batch record changes initiated by AcelRx.

3.4.10.

Any specific visual inspection of the bulk or of the finished products outside of standard release testing.

3.4.11.

Testing required to support OOS results or stability failures, testing required in support of complaint investigations and testing of products which exceeds routine testing that are not related to Patheon’s performance.

3.4.12.

Copy of the Annual Product Review Report. Pricing of this service will depend on the level of complexity required by AcelRx.

3.4.13.

The impact of new continued process verification (CPV) requirements.

3.5.

Capital Requirements

3.5.1.

Capital and Reservation Fee will be handled under a separate capital agreement.

3.6.

Key Technical Parameters

3.6.1.

Manufacturing Parameters

3.6.1.1.

API – API will be stored under ambient conditions

3.6.1.2.

Batch Size/Yields - The core tablet weight, theoretical manufacturing batch size and product yields considered by Patheon are summarized in the following table.

3.6.1.3.

Manufacturing campaign - The commercial pricing presented considers manufacturing in campaign. PV batches will not be produced in campaign.

3.6.1.4.

Hold times – It is assumed that the process is carried out at room temperature and the holding times throughout the process are suitable for the batch size proposed. It is assumed that amber lighting will be utilized during formulation or bulk packaging in the dedicated suite. Further details on the hold time and stability data for the drug product should be provided by AcelRx.

3.6.1.5.

Cleaning – Full cleaning occurs after each batch.

3.6.1.6.

Visual inspection – 100% visual inspection of the packs has not been included.

3.6.1.7.

Finished product storage – Finished product will be stored at room temperature (15-30°C).

3.6.1.8.

Manufacturing Equipment Train -The following manufacturing equipment train is proposed.

3.6.2.

Packaging Parameters

3.6.2.1.

Packaging Components:

3.6.2.2.

No serialisation, DataMatrix or aggregation has been considered. If any of these activities are required, they will be subject to further assessment by Patheon.

3.6.2.3.

Assumes current process will be followed until tablets are sealed into 8 in X 9.125 in pouches. These pouches will then be placed into lined bulk drum for shipment to final packager.

3.6.2.4.

Assumes 1 bulk drum per batch.

3.6.3.

Testing Conditions

3.6.3.1.

Testing for raw materials are based on information provided by AcelRx and Patheon’s best estimates.

3.6.3.2.

It is assumed that QC test methods are fully validated and robust at the time of manufacture.

3.6.3.3.

The analytical testing included in the pricing is listed below:

3.6.3.4.

Microbiological testing has not been included.

3.6.3.5.

Testing labour may be subject to change after the final agreements on testing specifications and requirements.

3.6.4.

Supply Chain

3.6.4.1.

Patheon will procure components and excipients for the manufacture of ARX-04 Tablets from Patheon qualified suppliers. Should AcelRx require Patheon to source any materials from specified suppliers, then these suppliers will remain under the quality audit control of AcelRx unless an agreement is reached for Patheon to take on this responsibility.

3.6.4.2.

Components and excipients will be supplied by Patheon in accordance with the specifications agreed. Patheon will issue formal Patheon specifications for each material.

3.6.4.3.

Each lot of incoming components and excipients will be sampled and tested according to the agreed specifications.

3.6.4.4.

The API will be provided free issue/released to Patheon by AcelRx or its qualified supplier.

3.6.4.5.

The API and all excipients used for the manufacture will be GMP grade and from TSE/BSE certified sources.

3.6.4.6.

Finished product will be made available at [*].

3.6.5.

Business Terms

3.6.5.1.

This pricing is based on product information provided by AcelRx and Patheon’s best estimates.

3.6.5.2.

Pricing may be adjusted after the manufacture of feasibility or validation batches to reflect any specification or process changes.

3.6.5.3.

All stated Values / Invoices are in USD ($).

3.6.5.4.

Pricing is subject to annual review.

3.6.5.5.

Invoice payment terms are 30 days from date of invoice.

3.7.

Commercial Analytical Testing Prices

Product

Mfg. Campaign Length

(Batches)

Price per Batch

ARX-04

[*]

[*]

3.7.1.

Costs Included in Price

3.7.1.1.

Product tested according to the approved and registered specifications.

3.7.2.

Costs Not Included in Price

Product manufactured and packaged according to the approved and registered specifications.

3.7.2.2.

Raw material costs and packaging components. Procurement, storage, inventory control and Quality Control (“QC”) testing of all raw materials & packaging materials.

3.7.2.3.

API, reference standards, and Client-supplied materials to be supplied by AcelRx at no cost to Patheon.

3.7.2.4.

API complete QC testing or special API testing requests.  NOTE: This testing will be mandatory if AcelRx has not performed the verification testing specified.

3.7.2.5.

Annual Review (“AR”). Any additional data or report requested by AcelRx beyond the scope of cGMPs and customary FDA or other regulatory agencies requirements will be subject to an additional fee to be agreed upon between Patheon and AcelRx.

3.7.2.6.

Testing required to support OOS results or stability failures, testing required in support of complaint investigations and testing of products which exceeds routine testing that are not related to Patheon’s performance.

3.7.3.

Key Technical Parameters

3.7.3.1.

Testing Conditions

3.7.3.1.1.

Testing for finished product is based on information provided by AcelRx and existing Patheon methods.

3.7.3.1.2.

It is assumed that QC test methods are fully validated and robust at the time of manufacture.

3.7.3.1.3.

The analytical testing included in the pricing are listed below:

3.7.3.1.4.

Microbiological testing has been included.

3.7.3.1.5.

Testing labour may be subject to change after the final agreements on testing specifications and requirements.

3.7.3.2.

Supply Chain

3.7.3.2.1.

AcelRx will provide packaged product from secondary packager for the release/stability testing of ARX-04. Patheon will not source any materials. Each lot of incoming product will be sampled and tested according to the agreed specifications.

1.

Zalviso 2017 Stability Pricing

2.

Dsuvia 2017 Stability Pricing

1.1.

Costs Included in Price

1.1.1.

Stability testing program

1.2.

Costs Not Included in Price

Product manufactured and packaged according to the approved and registered specifications.

1.2.2.

Raw material costs and packaging components. Procurement, storage, inventory control and Quality Control (“QC”) testing of all raw materials & packaging materials.

1.2.3.

API, reference standards, and Client-supplied materials to be supplied by AcelRx at no cost to Patheon.

1.2.4.

API complete QC testing or special API testing requests.  NOTE: This testing will be mandatory if AcelRx has not performed the verification testing specified.

1.2.5.

Any additional data or report requested by AcelRx beyond the scope of cGMPs and customary FDA or other regulatory agencies requirements will be subject to an additional fee to be agreed upon between Patheon and AcelRx.

1.2.6.

Regulatory support (such as preparation of Annual Report and Chemistry, Manufacturing, and Controls (“CMC”) files). Regulatory support work is subject to an additional fee and will be charged at a rate of [*].

1.2.7.

Testing required to support OOS results or stability failures, testing required in support of complaint investigations and testing of products which exceeds routine testing that are not related to Patheon’s performance.

1.3.

Key Technical Parameters

1.3.1.

Testing Conditions

1.3.1.1.

Testing for finished product is based on information provided by AcelRx and existing Patheon methods.

1.3.1.2.

It is assumed that QC test methods are fully validated and robust at the time of manufacture.

1.3.1.3.

The analytical testing included in the pricing are listed below:

1.3.1.4.

Microbiological testing has been included.

1.3.1.5.

Testing labour may be subject to change after the final agreements on testing specifications and requirements.

1.3.2.

Supply Chain

1.3.2.1.

AcelRx will provide packaged product from secondary packager for the release/stability testing of ARX-04. Patheon will not source any materials. Each lot of incoming product will be sampled and tested according to the agreed specifications.