1. Purpose
The purpose of this Guideline is to define the general requirements and provide guidance for Quality Agreements for the development, manufacture, testing, storage and distribution of intermediates, active pharmaceutical ingredients and investigational products destined for use in pre-clinical, clinical and other Research and Development studies.
2. Scope and Applicability
This Guideline applies to cGMP activities for any relevant site It is applicable to the provision of a service, product, project and study (hereafter called “service”) of any site and also to external providers of those services. The guideline also provides recommendations about when an Agreement between two parties should be considered but is not a definitive nor exhaustive list and the need for an Agreement for a particular service should be considered on a case by case basis.
3. Definitions
3.1 Quality Agreement (Contractual Agreement)
A written and binding agreement between a Contract Giver and Contract Acceptor which clearly defines the roles and responsibilities of each party in then provision of a service toensure that all quality attributes consistently meet the contract giver’s and cGMP requirements.
3.2 Contract Giver (“GIVER”)
A person or entity who on behalf of the3 site, commissions a service, product, project or study
3.3 Contract Acceptor (“ACCEPTOR”)
A person or entity who agrees to provide the contract giver with a service, product, project or study according to the givers specified requirements.
3.4 Confidentiality Agreement (Secrecy Agreement)
A legal document prepared and approved jointly by the giver site and an external contract acceptor which defines the requirement for the provision of expertise, and technical information to undertake the service whilst maintaining the intellectual property rights of both parties, and approved by the legal functions within the giver site and the contract acceptor.
3.5 Technical Agreement
A document describing in sufficient detail, all relevant technical information to enable the service to be undertaken, in a safe manner, and in accordance with the requirements of giver site specifications or defined technical attributes. The relevant functional representatives should approve the technical agreement.
In some cases it may have been appropriate to combine the Technical Agreement with the Quality Agreement into a single document and in these cases both functional and Quality Assurance representatives should approve the document.
3.6 Service Level Agreement (SLA)
A definition of agreement combining technical, quality and sometimes other aspects of the service between functions. Where the provider does not have dedicated QA personnel, the functional approval includes the quality aspects, in addition to all other aspects of the provided service.
3.7 Starting Materials
For the purposes of this guideline, starting materials include any substance used in the production of an intermediate, active pharmaceutical ingredient or investigational product and includes solvents and reagents.
3.8 Strategic Contracted Suppliers
Contractors intended to provide commercial supply of products and services. The supplier may provide product and/or services for R&D prior to commercialization of the product or service.
3.9 Tactical Contracted Suppliers
Contractors intended to provide supply of products and services exclusively for R&D.
4. Responsibilities
4.1 Management
Management is responsible for:
Ensuring this guideline is implemented and establishing local procedures and systems to support it.
Agreeing, in conjunction with QA, the quality attributes for the service for inclusion in a Quality Agreement.
Approving the Quality Agreement
Ensuring that all technical instructions necessary for the “acceptor” to provide the service are included in the Quality Agreement. Where a separate document is considered appropriate for these instructions, to prepare and approve this document.
4.2 QA
QA is responsible for:
Ensuring all cGMP requirements for the service are defined.
Preparing, where appropriate, and approving the Quality Agreement.
Ensuring that the Quality Agreement for chemical intermediates and active pharmaceutical ingredients is approved, where this responsibility is delegated to Outsourcing and Procurement.
Assuring that the “acceptor” is able to meet the cGMP requirements relevant for the service.
5. Guideline
During the development of new products it is often necessary to use the manufacturing, testing, packaging or distribution facilities and capabilities of Operations site or of external contractors
Recommendations when an Agreement between two parties should be considered are given in Appendix 1. It is not a definitive nor exhaustive list and the need for an Agreement for a particular service should be considered on a case by case basis.
The Quality Agreement for both internal and external providers should include the following general aspects given in 5.1 below. Specific, additional guidance relevant to internal and external providers is described in 5.2 and 5.3 respectively.
When it is proposed to use a contractor during development that may be used for future commercial activities, i.e. a Strategic Contracted Supplier, there should be close collaboration between R&D, the New Product Manager, Project
Team and for chemical intermediates and active pharmaceutical ingredients, Outsourcing and Procurement Group, to ensure that the contractor is acceptable for both development and commercial supply.
The Quality Agreement should be approved by the QA representatives at the respective sites on behalf of the “GIVER” and “ACCEPTOR”. In addition, the site functional representatives should also approve the Agreement.
Where the “ACCEPTOR” does not have dedicated QA resource, then functional signatory includes approval for all aspects.
Within the EU and where an Agreement is prepared to define the responsibilities of Qualified Persons for different manufacturing steps of an Investigational Medicinal Product as required by Annex 16 of the EU GMP, the Agreement should be signed by a Qualified Person at the respective sites.
5.1 General Requirements
The following general aspects should be considered for inclusion in the Quality Agreement between “GIVER” and “ACCEPTOR”. The extent and detail may vary depending on the nature, complexity and the duration of the service provided.
Where appropriate, a generic Agreement should be prepared which should describe the service to be undertaken, without the need to reference specific batches, studies or campaigns. This level of detail may be documented in specific, supplementary Work Orders, Plans or Schedules, which would be identified in the Agreement as providing this specific level of detail.
When an Agreement is prepared by an Operations Site, or in some cases by an external provider, the style and format may differ but would be considered acceptable if the required aspects are addressed and responsibilities clear.
5.2 Introduction and Scope
The document should describe the scope and standard of the service to be provided. It should reference other related documents for that service, for example, Confidentiality Agreements, where applicable. It should indicate other documentation that may be provided during the provision of the service, for example, specific Work Orders for batches, campaigns etc and specific sampling/analytical requirements for these.
The standards to which service is supplied, including qualification requirements for equipment and facilities, should be defined. They should meet the requirements of the site, appropriate to the phase of development.
It may be generic in nature, for example, for the provision of a microbiological analytical service by Operations to site products or more product/campaign based.
If appropriate timelines may be defined, or alternatively, indicate that these may be defined within a specific order or plan.
5.3 Personnel/Contacts
The persons responsible for quality assurance and technical matters within
The site and within the external contactor should be defined and communication paths agreed. Where appropriate, persons responsible for Project Management should be defined.
5.4 Starting Materials and Packaging Components
Responsibilities for provision of starting materials and packaging components, including those used in active pharmaceutical ingredient manufacture and packaging materials (primary, secondary, labeling, as appropriate) should be defined.
Specifications for each material should be defined. The material/component should be released for its intended use. In exceptional circumstances, material may be processed to the next stage without clearance but this should be documented in the Agreement or Work Order/Plan or Schedule.
Where materials are to be obtained from a third party supplier and not held by The giver site or the external service provider, then the responsibilities for approving the supplier should be defined in the Agreement.
Retest/expiry dates should be agreed. Where these are not stated on the containers, documentation should be provided which define these dates and should be used by the provider.
Starting materials which are provided by the giver site should be shipped in tamper evident containers, and with temperature monitors where appropriate.
Procedures should be agreed in the event that tamper evidence seals be missing or temperature monitors indicated unacceptable excursions.
Components, where applicable, should be provided in sealed containers.
Requirement for inspection, sampling and testing on receipt, where appropriate, should be defined.
Where necessary, analytical reference standards, quantities of product for “seeding purposes”, for example, for an API manufacture, should be provided with the appropriate supporting documentation, for example, a Certificate of Analysis.
5.5 Retained Sample
Retained samples of materials supplied by the giver site should already have been taken and there should be no requirement for additional retained sample taken on receipt by the service provider.
Responsibilities for sampling and retention of the finished items (whether the intermediate stage of an API, the API or drug product) should be defined.
5.6 Documentation
The Agreement should define responsibilities for provision and approval of documentation to support the service.
5.7 Technical Information
Technical instructions, manufacturing and packaging methods, analytical methods, specifications and other information required to undertake the service in a safe manner should be provided by the giver site. The mechanism for the transfer of this information will vary from case to case and may include the provision of technical information, a manufacturing protocol, examples of batch documentation, analytical method, method validation data, storage conditions etc.
Safety data, such as Material Safety Data Sheets, should be included, where applicable.
It may be appropriate to include the technical information into the overall Quality
Agreement or remain as a separate document.
5.8 Analytical Testing/Product Manufacture/Packaging
If an analytical, manufacturing or packaging service is being undertaken, there should be a documented technology transfer process. If the transfer is from the giver site to an Operations site or to an external analytical testing Facility, the transfer should follow the current giver site requirements for Technology Transfer. If the transfer is to another development facility, then the transfer may be less formal but nonetheless should still be documented appropriate to the stage of development and competency by the receiving site to undertake the work should be established and/or documented. In-process control tests should be defined where necessary and methodology supplied. For analytical testing, procedures for investigating Out of Specification results should be defined.
5.9 Responsibilities for Review/Approval/Archiving of and Packaging Documentation
Responsibilities for the preparation, review and approval of master and executed Documentation for manufacture and packaging, should be defined. Duplication of reviews and approvals should be avoided wherever possible, for example, review of an executed batch record by QA in addition to the QA of the service provider, whether the giver site or external contractor should be only be undertaken if there are specific quality and business needs to do so. Responsibilities for archiving of the original documentation and copies, if taken, should be defined.
5.10 Product Release
Responsibility for product release of an API or investigational product destined for R&D purposes, lies with QA. If a commercial product, released by Operations QA for sale and is to be used for R&D use, it should be released by QA. Responsibilities for release of an API intermediate, normally destined for a sales product, should be defined in the Agreement and would normally be done by Operations QA.
Within the EU where different manufacturing steps for the manufacture/assembly of an Investigational Medicinal Product are conducted at different EU sites, responsibilities of each Qualified Person for each step, as required by Annex 16 of the EU GMP, should be defined in the Agreement, which should be approved by a Qualified Person at the respective sites.
5.11 Shipment and Distribution
Requirements for shipment and distribution where appropriate, including storage conditions of the finished material (intermediate stage of an API, the API or investigational product) to its destination, whether returned to the giver site or elsewhere in the supply chain should be defined.
5.12 Reconciliation/Unused/Rejected Materials
Requirements for reconciliation of materials should be defined as appropriate. Responsibilities for unused materials, materials to be rejected or reworked should be defined, including responsibilities for destruction of materials. Limits on wastage levels and procedures for resolution in the event of deviations should be agreed.
5.13 Deviations
Responsibilities and mechanisms for handling of deviations should be defined.
5.14 Complaints
Responsibilities and mechanisms for handling of complaints should be defined.
5.15 Recall (Product Retrieval)
Roles and responsibilities for recall (retrieval) of investigational product should be defined. Designated contacts, accessible on a 24 hours basis, should be defined with details of telephone numbers, fax, email as appropriate.
5.16 Changes
Responsibilities for reporting changes, where planned or unplanned should be defined.
5.17 Sub-Contracting
No sub-contracting of any part of the activities is permitted unless prior written approval is granted.
5.18 Audits
Responsibilities for auditing of the site providing the service, to ensure compliance with the agreed standards should be defined. Where a site is providing the service to the giver site an audit by QA would not normally be required. Consideration for joint audits with other QA groups, particularly during preparations for Pre-Approval Inspections by the FDA, should be considered. Where audits by QA are required, they should be permitted at reasonable agreed times and with adequate notice.
5.19 Review
Period for the Agreement Each Agreement should have a defined review period but which allows for earlier review, should this be required. It is recommended that periodic review meeting take place between “GIVER” and PROVIDER” to evaluate the performance of the service and identify enhancements, if appropriate. 5.20 Internal Quality Agreements The following additional guidance is provided for the preparation of a Quality Agreement internal to the site.