MAPGuideⓇ
Equitable Access Toolkit
Incorporating Quality Assurance Considerations into License Agreements
Quality assurance requirements are an important consideration for ensuring that best practices and standards are not compromised in the pursuit of affordable and accelerated access, and that patients receive safe and effective products. The possibility of quality control failures by licensees may also be viewed as a risk by potential licensors, potentially leading to hesitancy in using an out-licensing strategy to increase access to their products.
Quality-related risks can be mitigated through the inclusion of quality assurance obligations in license agreements, and potentially by licensing through organizations such as the Medicines Patent Pool which can provide monitoring and oversight of compliance with quality assurance requirements.
Quality assurance provisions in license agreements may include:
Compliance with national laws.
Manufacturing finished products in compliance with the quality standards of the WHO Prequalification Programme (WHO PQ) or a WHO Listed Authority or Stringent Regulatory Authority (SRA), and/or an undertaking not to sell or supply a funded product until approval has been obtained from the required regulatory authority(ies).
Where applicable (for example, diagnostic products or medical devices), manufacturing products in accordance with relevant ISO standards.
Development and manufacture of the licensed product in compliance with applicable environmental and responsible manufacturing standards.
A requirement for the licensee to establish and maintain appropriate quality assurance systems to ensure compliance with applicable standards.
A requirement for the licensee to have its own written standards of good research practice and procedures for investigating allegations of scientific misconduct.
A requirement for the licensee to promptly notify the licensor of any quality issues identified.
Rights for the licensor or its representative to inspect the licensee’s records and facilities to verify compliance with quality standards, and the available remedies if the licensee is found not to be in compliance.
Examples from the MAPGuide
Licensee will not sell any Product without WHO Prequalification or SRA approval, or through any provisional or emergency use authorisations available through WHO or an SRA, and will comply with applicable regulatory requirements in the country of manufacturing and the country of sale.
Source: taken from a license agreement between Merck (Licensor) and MPP (Licensee). Partner types: multilateral, industry; Product type: COVID-19 therapeutic (molnupiravir); Development stage at signature: late clinical/pending EUA. Read in context.
The Final Product will be developed in accordance with appropriate quality standards and Commercialisation Partners will seek, when appropriate, approval or a positive recommendation for the Final Product from the WHO Prequalification Programme (PQ), Global Fund/Unitaid Expert Review Panel (ERP), US FDA and/or another WHO Listed Regulatory Authority as agreed between [Funder], [Licensor] and [Licensee].
Source: taken from a license agreement between MedinCell (Licensor) and MPP (Licensee). The license grant to MPP was required under a related grant agreement between Unitaid and MedinCell, with terms to reflect Unitaid’s access objectives. Partner types: industry, multilateral; Product type: malaria vector control (long-acting ivermectin injectable); Development stage at signature: pre-clinical. Read in context.
In the performance by it or on its behalf of any activities under the Development and Distribution Program or any other activities contemplated hereunder (including the exercise of any rights licensed hereunder), each Party shall comply with all Applicable Laws and its own standard operating procedures. Each Party shall be responsible for obtaining all applicable Regulatory Approvals that may be necessary for it to perform its activities.
[…]
Each Party shall have the right to conduct quality assurance assessments of the other Party’s processes and systems, if necessary, audits and inspections of laboratory, clinical trial and manufacturing sites, and any associated vendors or laboratories involved in the Development Plans
Source: taken from DNDi’s template Development Collaboration and License Agreement. Partner types: PDP, industry/academic institutions; Product type: treatments for neglected diseases; Development stage at signature: template intended for use from Phase 1 clinical trials through to proof of concept in humans. Read in context.
The Sublicensee will Manufacture the Licensed Compound and the Licensed Product in a manner consistent with: (i) Good Manufacturing Practices; and (ii) the WHO Prequalification standards and specifications set out in the Sublicensee’s WHO Prequalification submission and approval.
If applicable and if requested by [Sublicensor] in the event the Facility(ies) is/are audited and approved by a Stringent Regulatory Authority (“SRA”), and as an alternative to WHO Prequalification contemplated in (ii) above, the Sublicensee will Manufacture the Licensed Compound and the Licensed Product in a manner consistent with the standards of the SRA.
Until the Facilities are audited and approved by WHO Prequalification or an SRA, the Sublicensee shall if requested by [Sublicensor] allow a Third Party regulatory expert appointed by [Sublicensor] to conduct a GMP audit of the Sublicense’s Facility and Manufacturing processes (and if applicable those of any Sublicensee Contractors involved in the production of Licensed Compound of Licensed Product) and to assess and confirm the Sublicensee’s compliance with WHO Prequalification standards or a SRA’s standards, and in such case the Sublicensee will Manufacture the Licensed Compound and the Licensed Product in a manner consistent with the relevant standards.
Source: taken from a sublicense agreement between GARDP (Sublicensor) and Orchid Pharma (Sublicensee) related to a head license between GARDP and Shionogi. Partner types: PDP, industry; Product type: antibiotic (cefiderocol); Development stage at signature: licensed product on WHO EML. Read in context.
(a) Appropriate Standards. Without prejudice to Licensee’s obligations to manufacture products to the standards required under this Agreement, Licensee shall at all times manufacture by the process and to quality standards at least as high as specified in the technology transfer package (“Appropriate Quality Standards”); and (ii) on a country-by-country basis, consistent with any applicable national, regional or local standards as may be required by the specific country where Product is sold. In addition, Licensee and its permitted Affiliate sublicensees and subcontractors shall meet the Appropriate Quality Standards prior to Licensee’s and its permitted Affiliate sublicensees’ sale of Product to any country within the Territory. Additionally, Licensee shall maintain quality systems, operations and facilities in compliance with cGMP standards and all applicable laws and regulations.
(b) Audit Right. Licensee hereby agrees to allow [Licensor] reasonable access to Licensee’s books and records, facilities and employees for the purpose and to the extent required for [Licensor] to audit Licensee’s compliance with the requirements of this Section [x]. [Licensor] agrees that it shall limit its access to Licensee’s employees to the extent required to conduct the audit and that such employees shall not be required to disclose to [Licensor] information that is subject to obligations of confidentiality with third parties unless such third parties have provided consent for such disclosure. [Licensor] agrees to provide at least thirty (30) days prior notice of the proposed audit and agrees that such audits shall not be conducted more than once a year unless circumstances outside the ordinary course of business warrant such an audit (such as an investigation or other government action).
(c) Remedy for Failure. If Licensee fails at any time to meet the Appropriate Quality Standards with respect to the manufacture of [Product], and after a ninety (90) day period, Licensee fails to cure any manufacturing deficiency sufficient to meet the Appropriate Quality Standards, [Licensor] may elect, in its sole discretion and notwithstanding Section [x] or [x] hereof, to suspend the effectiveness of the licenses granted hereunder until such time [Licensor] has determined that Licensee has corrected any such failure to [Licensor]’s reasonable satisfaction. During any such suspension, [Licensor] and Licensee shall coordinate with each other to provide for the supply of [Product], as appropriate, to ensure that end-user patient requirements are not disrupted as a result of such suspension.
Source: taken from a Gilead template license agreement for generic manufacturing. Partner types: industry; Product type: multi-drug-resistant HIV treatment and PrEP (lenacapavir); Development stage at signature: licensed product (treatment), phase III clinical trials completed (PrEP). Read in context.
The Sublicensee shall:
i. obtain from the relevant authorities in each country and maintain in force, as appropriate, all health registrations, permissions, consents and regulatory authorisations relating to the importation, manufacture and sale of the Products which are necessary to enable the Products to be sold or supplied in each country in accordance with this Agreement.
ii. file for WHO Pre-qualification or any Stringent Regulatory Authority approval as soon as possible and in any event not later than within 24 months from the Effective Date in each case using the fastest approval route possible and will diligently pursue such applications following submission.
iii. manufacture and sell the Products in accordance with all laws and regulations relevant to the manufacture and sale of the Products and in accordance with good industry practice.
If the Sublicensee manufactures, sells, supplies or otherwise disposes of any Product but has not obtained the necessary compliance with laws or approvals as per this Agreement, [Sublicensor] shall be entitled to immediately terminate this Agreement by providing written notice to the Sublicensee.
Source: taken from a form of sublicense agreement annexed to a non-exclusive patent and know-how license agreement between Medigen and MPP (acting in its role as the “implementing arm” of the World Health Organization’s COVID-19 Technology Access Pool (“C-TAP”)). Partner types: multilateral, industry; Product type: COVID-19 vaccine; Development stage at signature: Emergency Use Authorisation. Read in context.
Notwithstanding the Effective Date of this Agreement, the Licensee undertakes not to sell or otherwise supply a Product in a country of the Territory prior to:
- Regulatory Approval in that country, unless the sale or supply is made pursuant to an Import Waiver; and
- WHO prequalification or Stringent Regulatory Authority approval, or through any provisional authorizations available through WHO or a Stringent Regulatory Authority.
Source: taken from a form of sublicense agreement annexed to a license agreement between Novartis (Licensor) and MPP. Partner types: industry, multilateral; Product type: cancer therapeutic (nilotinib); Development stage at signature: licensed product on WHO EML. Read in context.
[Transfer Recipient] shall employ only the MANUFACTURING and other processes, and shall comply with the quality control standards, included in the [Transferor] TECHNOLOGY provided to [Transfer Recipient] and shall ensure that the PRODUCTS complies with the SPECIFICATIONS, GMP standards and all applicable [Country] LAWS. There shall be no changes made to such processes, standards, or SPECIFICATIONS without PROTALIX’s prior written consent.
[Transfer recipient] represents and warrants that the FACILITIES and [Transfer Recipient]’s MANUFACTURING practices at the FACILITIES shall at all times comply with all applicable [Country] LAWS, SPECIFICATIONS and GMP standards.
[…]
During the TECHNOLOGY TRANSFER, [Transferor] shall have the right to enter the FACILITIES, during normal business hours to check and verify the FACILITY, DRUG SUBSTANCES, PRODUCTS, SUPPLIED MATERIALS and any MANUFACTURING processes, quality control standards and other activities relating to the foregoing or this AGREEMENT that are performed at the FACILITY to ensure compliance with this AGREEMENT (including compliance with the SPECIFICATIONS, GMP standards, and applicable [Country] LAW and achievement of COMPLETION REQUIREMENTS). [Transfer recipient] shall implement any mitigation plan reasonably identified by [Transferor] to address any such findings.
[…]
For each STAGE of the TECHNOLOGY TRANSFER, [Transfer recipient] shall be responsible for validation of the MANUFACTURING and operating processes and quality control testing as conducted by [Transfer recipient] at the FACILITIES. During the TECHNOLOGY TRANSFER, upon [Transferor]’s request, [Transfer recipient] shall, at [Transfer recipient]’s sole cost and expense, (a) submit a sample of any production batch of the PRODUCTS for parallel quality control testing to be performed by [Transferor] or representatives/designees, (b) make available to [Transferor] any books and records relating to the MANUFACTURING and operating processes, quality control testing, DRUG SUBSTANCE, SUPPLIED MATERIALS and the PRODUCTS, and (c) provide to [Transferor] all documentation reasonably necessary to evidence that the [Transferor] TECHNOLOGY and SUPPLIED MATERIALS have been used only in accordance with this AGREEMENT.
Source: taken from a technology transfer and supply agreement between Protalix (Transferor) and Fiocruz (Transfer Recipient). Partner types: industry, state-owned manufacturer; Product type: Gaucher Disease therapeutic; Development stage at signature: licensed product. Read in context
As between the Parties, all matters pertaining to quality control and quality assurance, stability testing and waste under this Agreement shall be governed by a separate Quality Agreement to be entered into between the Parties. Such Quality Agreement is incorporated herein by reference hereto and shall be concluded as soon as possible following the Effective Date.
Source: taken from a license agreement between Valneva (Licensor) and Serum Institute of India (Licensee). Partner types: industry, industry; Product type: chikungunya vaccine; Development stage at signature: phase 3 clinical trials. Read in context.
The Sublicensee shall Manufacture all Licensed Compound and Licensed Product in accordance with the standards and requirements set out in Schedule K attached hereto. […] The Sublicensee shall in particular Manufacture Licensed Compound and Licensed Product in accordance with any applicable industry standards for the responsible Manufacture of antibiotics.
Source: taken from a sublicense agreement between GARDP (Sublicensor) and Orchid Pharma (Sublicensee) related to a head license between GARDP and Shionogi. Partner types: PDP, industry; Product type: antibiotic (cefiderocol); Development stage at signature: licensed product on WHO EML. Read in context.
Does the definition of affordable pricing consider achieving the lowest possible pricing while maintaining quality standards?
Are any requirements for licensing and technology transfer to alternative manufacturers contingent on the identification of partners able to manufacture the product in accordance with quality standards?
This toolkit has been built based on the data in the MAPGuide and the GHIAA team’s experience of negotiating and implementing agreements. We intend that the toolkit will evolve and expand over time based on input from MAPGuide users and availability of new agreements showing examples of alternative approaches. We welcome ongoing constructive dialogue around these materials and encourage you to contact us or fill in our feedback survey to share your thoughts, questions and suggestions.