1. Purpose
The purpose of this procedure is to describe the process for Quality Assurance (QA)Agreement regarding the supply of active pharmaceutical ingredients, bulk formulated products, part finished packs and finished packs to be followed by pharmaceutical operation. The QA Agreement supports the arrangements defined within the Supply Agreement and should complement the Supply arrangement by defining the responsibility of each party regarding Quality Control and Quality Assurance.
2. Scope and Applicability
Applicable to all GMP related activities between Operations manufacturing (including packing) sites. For sites that supply other areas agreements shall be generated on a needs basis. Both bipartite and tripartite contractual relationships are covered. Transfer of raw material and packing material between sites are not covered by this guideline. The QA Agreements required for batch certification within the EU by a Qualified Person are included in this procedure.
3. Definitions
3.1 Quality Assurance Agreement (QA Agreement)
A written agreement covering QA aspects of manufacture between Contract Giver and Contract Acceptor that shall clearly define the roles and responsibilities of each party. If relevant it will also include the Toll Principal.
3.2 Contract Acceptor (Contractor)
A person or entity who agrees to provide a sponsor with a service, product, projector study according to the sponsor’s specified requirements. The terms ‘Lead Site’ or ‘PROCESSOR’ are also used.
3.3 Contract Giver
A person or entity, who on behalf of the company, commissions a project or study, and/or supports the acquisition of a service or product. The terms ‘Receiving Site ‘or ‘BUYER’ are also used.
3.4 Products
Products include API, bulk formulated product, part-finished and finished product.
3.5 Receiving Site
Is the site that receives API, bulk formulated product, part or finished packed product from a Lead Site under a QA Agreement.
3.6 Toll Manufacture
The agreed and controlled use of a site or external contractor (the toll manufacturer) whereby products and services are manufactured and provided at a contracted fee tithe Toll Centre (for definition see below), for, and on behalf, of the customers of the Toll Centre. Under such an agreement all communications regarding the manufacture and supply of products must be conducted through the Toll Centre.
3.7 Toll Manufacturing Site
The manufacturer (PROCESSOR) of material and supplier to the Toll Centre. Toll Manufacturing Site can be either a buyer site or an external contractor often located in a different country from the Principal.
3.8 Toll Centre (Principal)
The administering location for Toll Manufacture also the customer of the Toll Manufacturing Site. The Toll Centre is the supplier (SELLER) of material to receiving sites and third parties.
3.9 Terminology Used in the Agreements
BUYER The company purchasing the Products, study or service. SELLER The company selling the Products, study or service. PROCESSOR The company undertaking the provision of Products, study or service. In the case obit-partite agreements, the SELLER and PROCESSOR are the same entity.
4. Responsibilities
4.1 It is the responsibility of each site nominated as a Lead Site (contract acceptor) to generate, and obtain approval for, QA Agreements for supply from their sites.
4.2 It is the responsibility of each site to nominate a QA Agreement manager or if not applicable a function whose responsibilities shall be included in a local procedure.
4.3 It is the responsibility of each site to put in place procedures for the generation, approval, review, control and archiving of QA Agreements.
4.4 It is the responsibility of each Receiving Site to support the generation and to approve QA Agreements for supply to their sites.
4.5 The Toll Centre, Lead Site and Receiving Site are responsible for representing the legal entities in the country in which they are located.
5. Guideline
5.1 Role of QA Agreement Manager
The QA Agreement manager’s role must include:
(I) Generation of draft agreements with proper index code from QA.
(ii) Circulation of draft agreements for comment; e.g. Receiving Site, local Legal Affairs and Finance (including Toll) as appropriate.
(iii) Obtaining approval of the agreement from the appropriate QA managers.
(iv) Establishing local procedures for the writing, distribution, control and archiving of QA Agreements.
(v) Amending and reviewing agreements in accordance with requests from other contract parties, e.g. Service Agreements, Distribution Agreements.
(vi) Interface with the QA & dossier management co-coordinator to ensure rapid and effective resolution of issues.
(vii) Training of local staff in local procedures.
(viii) Ensuring agreements meet company’s legal and regulatory obligations, e.g. tolling.
(ix) Supporting the establishment and updates of the QA-Agreement templates.
5.2 Role of QA & Dossier Management Group in Supply & Capability
The QA & DMG co-coordinator’s role must include:
(I) Involving Legal Affairs Department in discussions regarding agreements.
(ii) Ownership of Information technology resource to support the QA Agreement process e.g. Lead Site web site where for example the list with all Agreement Managers can be found.
(iii) Maintenance and development of Internal QA Agreement templates.
(iv) Maintenance of the QA Agreements register and retaining hard copies of the QA Agreements.
5.3 Role of QA Managers
The QA manager’s role must include:
(I) Review and Approval of completed agreements
(ii) Implementation of the agreements
(iii) Ensuring that local and international Change Control procedures’. Regulatory Implication Assessment Report /Manufacturing Change Management (MCM) are used to ensure the validity of the agreements.
5.4 Key Elements of the QA Agreement
The QA Agreement must define the following:
Scope
Definition of Terms
Manufacturing (including packing)
Deviation Reporting
Inspections and Audits
Change Control
Qualification and validation
Quality Assurance and Control
Batch Specific Documentation
Sample retention
Release procedures
Product Recall
Product Quality Complaints
Stability
Agreement Review
Contacts Materials covered by agreement
Delineation of Responsibilities
Area specific Key elements to be defined:
Validation Certificate (If required)
Batch Certificate requirements (If required)
Periodic confirmation (If required)
Product Requirements (If required)
Annual Product Reviews (If required)
Product Quality Review (If required)
Each page must be labelled so as to be consistent with the title page. The agreement must also include a revision history and a list of changes from the template.
5.5 Types of Agreement
The supply and contractual relationships between most manufacturing sites are of two types. When legal ownership of materials passes simply from onsite to another in the supply chain then a bipartite agreement between the Quants of the PROCESSOR and the BUYER is required. When manufacture is taking place under toll and the legal ownership of the materials being manufactured resides with the Toll Centre then a tripartite agreement is required. The agreement is then between the QA units of the PROCESSOR, the SELLER (Toll Centre) and the BUYER. QA Agreements must be prepared to establish the QA relationship between sites for the supply of API, bulk formulated product and part packs on a site-to-site basis. Besides the supply and exchange of Products services and responsibilities may be defined e.g. the provision of analytical services or QA release activities. Because of the legal and taxation framework within the business, the number of signatories will vary from contract to contract. The QA Agreement must be approved by the PROCESSOR, BUYER and where required the SELLER (Toll Centre). The normal expectation is that contracts are bipartite but may be tripartite to describe the situation during toll manufacture. Only in exceptional circumstances should any other parties be involved in a QA Agreement. The differences in these QA Agreements reflect detailed differences in the requirements demanded by the regulatory agencies in those territories. Where there are specific QA testing and release arrangements for the supply of product to the EU from any external market e.g. the USA, the appropriate- or tri-partite agreement must be amended to reflect these requirements.
5.6 Document Control
5.6.1 QA Agreement Manager
The QA Agreement Manager must ensure that there is a system of document control in place for the QA Agreements, which should take into account the indexing system described below.
5.6.2 Indexing System
QA must retain register containing information about the parties, Products including the date of issue, date of review and the version number. Each agreement must be identified by a unique index number, which shall be assigned by QA The indexing is based on a system of letter coding that is maintained by QA and available on the Lead Site web page. The indexing of the agreements takes the following form: Letter codes together with number code such as AB 1.0.
5.6.2.1 Letter Code
Bi-partite
Site references (allocated PROCESSOR BUYER
by QA) A B
There are some letter coding of sites containing two letters and those codes are set within brackets for example A(AA) 1.1.
Tri-partite
Site references PROCESSOR SELLER BUYER
A C B
5.6.2.2 Number code (x.y)
The first number (x) is an incremental number to make a unique code starting at The second number (y) is the version number and the first version starts at 0. When various products between two sites are included in one agreement as long as the responsibilities for each of the products are the same then versions are controlled e.g. AB 1.0, AB1.1, AB1.2, ……. AB 1.11 etc. When the responsibilities between sites are not the same for all of the products then several different QA Agreements are required. Each is allocated a separate number e.g. if the responsibility for QA release is different for different product groups then agreements will be AB1.0, AB2.0…. AB12.0 etc. It is not permissible to make statements in an existing QA Agreement to the effect that a clause does not apply to a particular product. For example, if PROCESSOR Operations supply both bulk (letter code Q) products and finished packs to BUYER (letter code I) then two agreements must be set up. The first one concerning the bulk products and have therefore the code QI1.0 and the second agreement regarding QP release is assigned index code QI 2.0.
5.6.3 Dating
The normal expiry date of a QA Agreement should be 5 years from the date on which the last party signed.
5.6.4 Originals
Originals should be prepared for each of the signatories and one for QA.
5.7 Document Approval
5.7.1 QA-Agreement templates
QA must keep the appropriate template and its references up to date. It is the best practice to consider setting up a small working team to review and update the formal content of the templates when found necessary. All templates must be reviewed by Legal Department. Templates must be version controlled.
5.7.2 QA-Agreements
The respective QA managers or their nominees shall approve all bipartite agreements. All tripartite agreements must be signed by the respective QA managers or their nominees and the QA manager acting on behalf of the Toll Centre.