Manual – 005 Procedure for Quality Assurance Management of Contractors

Note: When it is proposed to select a contractor to carry out part or all of manufacture ofclinical trial material/product with the intention that the chosen contractor will later supplycommercial material/product, the QA (Formulated Products) and (APIs, Intermediates and Starting Materials) shall collaborate to ensure that the contractor selected will be acceptable to both R&D and Operations.

5.1 Selection Phase

It is essential that the Lead Site be assigned as early as possible in the contractor selectionphase. The supply chain mgt. shall assign the Lead Site when the decision is taken to outsource manufacture of a material/product.  The Lead Site shall be represented on the project team that is responsible for selection of thecontractor. Further guidance on the process for contractor selection of is included in Section 8.1 Appendix I.

5.1.1 Quality Assurance Agreements

For contractors not previously used to manufacture, supply, test and/or distribute sponsor’s materials/products, the QA representative of the Lead Site shall:

* Agree the QA contacts between sponsor and the contractor;

* Share the principles included in this Procedure, and the criteria for certification (see Section 5.3.2) with the contractor;

* Audit the contractor with reference to the activities to be included in the Quality Assurance Agreement;

* Develop with the contractor a Quality Assurance Agreement and either approve the Agreement on behalf of sponsor or identify the person who shall approve on behalf of sponsor.

If required, develop with the contractor a GMP improvement plan to address any deficiencies highlighted during the earlier assessment;  and agree the  process for monitoring progress and maintaining regular contact with the contractor for QA issues.

For contractors previously established to carry out similar activities for the sponsors products, the Lead Site will assist the Quality Assurance Agreement Co-ordination Site in updating the Quality Assurance Agreement and other information mentioned above to include the needs of the additional material/product to be manufactured by the contractor.

The Lead site, in consultation with the Quality Assurance Agreement Co-ordination Site, shall agree with the contractor on how links will be maintained between the contractor and sponsor’s QA processes, such as:

* Manufacturing Change Management Process (MCM)

* Dossier Management group to maintain the currency and accuracy of CMC Dossier for internationally sourced or internationally marketed products(s).

* Labeling changes

* The commercial stability program, including timely Out of Specification (OOS) reporting and periodic data reporting.

* Product Defect, Customer Complaints and Product Recall procedures.

* Annual Product Reviews.

* Sponsor’s Legal Affairs shall review any new Quality Assurance Agreement:

* Quality Assurance Agreements shall be reviewed also by the Toll Manufacturing Manager in Supply and Manufacturing to eliminate conflicts with respect to tolling arrangements.

5.2 Establishment Phase

5.2.1 Technology Transfer and Validation

A project team, including technical and QA representatives of the Lead Site, and representatives of the contractor shall be constituted to manage the transfer of technology to the contractors. Dossier Management group shall be assigned to the team to ensure that the CMC aspects of the transfer are adequately covered.

5.2.2 Pre-Approval Inspection (PAI)

The Project Team referred to in Section 5.2.1 shall carry out co-ordination of PAI preparations at contractors.  In the case of contractors chosen for new products, the supply chain shall be accountable for the PAI readiness of contractors on a timescale consistent with overall business plans.

Compliance Management Group, in collaboration with the Lead Site, sponsor’s QA and the Quality Assurance Agreement Co-ordination Site, shall ensure that an appropriate team is identified to audit any contractor that has not previously supplied the sponsor product to the market and is intended to be used for the supply of product to the market.

Based on the outcome of the audits and other interactions with the contractor, the Quality Assurance Agreement Co-ordination Site and Lead Site shall advise the compliance team on the contractor’s state of PAI readiness. Compliance shall advise the state of readiness of all contractors included in a submission.

5.3 Maintenance Phase

At the beginning of the Maintenance Phase the Quality Assurance Agreement Co-ordination Site, Lead Site and Receiving Sites shall update the information in the Vendor Assurance and Contractor Database (see Section 5.5), including the status for the quality systems and compliance level of the contractor and the certification status for each material/product supplied by the contractor.

5.3.1 Contractor Status (Quality and Compliance Systems)

Contractor Status shall be assessed/assigned by the Quality Assurance Agreement Coordination Site. This status may be:

– Acceptable (approved) – no or minor issues only

– Major issues and concerns with the contractor that are being addressed.

– Disapproved/recommendation to find alternative supply or suspend supply until significant improvements are made.

The ‘Contractor Status’ is determined by the Quality Assurance Agreement Co-ordination Site and reviewed annually as a minimum, taking into account all activities performed by the contractor and any issues arising during liaison meetings, audits and ongoing product supply – see also Section 5.3.3

Note: This overall assessment may be sub-classified by manufacturing stage, e.g. API intermediates, APIs, Formulation and Packing.

5.3.2 Material/Product Certification/De-certification

The sponsor site(s) receiving the material/product, in consultation with Coordination Site and Lead Site shall decide the certification status of a material/product. If no sponsor site receives the material/product, the Lead Site shall decide the certification status.

To be certified, a material/product must have been manufactured by a contractor site that has both:

– Acceptable quality and compliance systems in place to assure that the manufacturing steps undertaken by the supplier contractor site are under control. and

– Demonstrated that it can consistently manufacture the material/product within its pre-determined specifications and quality attributes.

These criteria may already have been met by the end of the establishment phase.

The contractor shall provide to the site receiving the ‘certified’ material/product, on a batch-by-batch basis:

– A Certificate of Analysis conforming to the agreed format;

– A Certificate of Manufacturing/cGMP Compliance (this may be combined with the Certificate of Analysis);  and

– Deviation reports where there are excursions outside the acceptable ranges given in the Batch Record.

– OOS investigation reports, including those conducted as a result of post-production surveillance programs, e.g. commercial stability studies.

The above information is a minimum. Other documents may be requested, e.g. specimen batch sheets and executed documentation shall be requested on a needs basis e.g. for submission to Regulatory Authorities.

The contractor shall provide also:

– Reports of stability studies conducted by the contractor to a frequency agreed with the Lead Site (and DMG for internationally sourced or marketed products).

– An Annual Product Review (If any market specifically requires Annual Product Reviews).

The Lead Site, at its own discretion, shall determine the process for the approval of updates to master batch documentation.

5.3.3 Ongoing Review of Contractor Performance

In parallel with the activities described in Section 5.3.2  a program of ongoing technical/QA liaison meetings shall be agreed between the contractor and the Quality Assurance Agreement Co-ordination Site. Lead Sites shall be represented at these meetings if there are product specific issues to be discussed.

The Quality Assurance Agreement Co-ordination Site shall institute a program of ongoing assessment of the contractor and agree corrective programs as appropriate. The Quality Assurance Agreement Co-ordination Site shall involve the Lead Sites as necessary to prepare for, and conduct, the assessment. The assessment shall include:

– A review of the Quality Assurance Agreement;

– An ongoing review of the regulatory history

– A review of any audit findings, including laboratory controls, for audits carried out by regulatory agencies or by the sponsor

– A review of the effectiveness of the contractor’s  quality and compliance systems against a pre-agreed set of criteria/targets;

– A review of the quality of the material/products supplied by the contractor, including review(s) of trends seen in Certificates of Compliance, Certificates of Analysis and commercial stability studies, customer complaints, adverse events (provided by the Lead Sites).

The Quality Assurance Agreement Co-ordination Site shall produce annually a written summary of contractor performance based on these reviews, include a copy of this in the vendor assurance and Contractor Database and update the status assigned to the contractor’s quality and compliance systems in the Database.

The Quality Assurance Agreement Co-ordination Site shall provide updates on the status of their contractors in accordance with the requirements for reporting to compliance.

In the event that the ongoing review of the performance of the contractor gives cause for Concern, the Quality Assurance Agreement Co-ordination Site in collaboration with the Lead Site(s) shall bring forward the periodic audit of the contractor and establish an agreed improvement plan with the contractor which may include product testing and documentation review until the contractor re-acquires the appropriate standard.

Exceptionally, the Quality Assurance Agreement Co-ordination Site may recommend to Compliance that supply from the contractor is suspended or that a new contractor is selected/established (Red Status).

5.4 Records and Samples Retention

The originals of all manufacturing records and samples required to satisfy cGMP requirements for the activities conducted by the contractor shall be retained by the contractor for the minimum period required by cGMP codes.

Sponsor and the contractor shall retain the originals of other records that each party creates/approves for an appropriate period. (Responsibility for records co-signed by both the contractor and sponsor shall be agreed between the signatories and documented)

Records and samples retention shall be included in the scope of audits of the contractor.

5.5 Vendor Assurance and Contractor Database

QA management shall provide and administer a database to retain summary information on vendors and contractors providing materials/products to sponsor or conducting manufacturing, packing, laboratory testing or distribution activities on behalf of sponsor.

The database shall be fully populated and kept current by the appropriate Quality Assurance Agreement Co-ordination, Lead and Receiving Sites with copies of relevant original records held within each site according to the responsibilities of the sponsor site with respect to the contractor and the materials/products/services supplied by the contractor.

The following information/records are required:

* Contractor Name

* Contractor Site Location Name

* Contractor Site Country

* Contractor Site Plant/Facility/Unit Name

* Material Name

* Material Type

* Material Manufacturing Stage

* Lead Site

* Receiving Site

* Contractor Site Address Note: include name of Contractor’s QA Contact(s) and e- mail address(es) in comments field.

* Contractor Site Phone Number

* Contractor Site Fax Number

* Quality Assurance Agreement Document

* GMP Certification Document

* QAAC Site (if assigned)

* Primary sponsor QA Contact(s) for Contractor

* Annual Contractor Review Document

* Audit Frequency

* Date of last audit.

* Manufacturing Stage Quality and Compliance Systems Status(es)

* TSE Document

* TSE Status

* Solvents Document

* AHPIS Document

* Product Certification Status

* Receiving Site Contact

* Denotes the minimum information required to create a new product record in the Database.

Further details are included in the Database User Guide.

5.6       Application to Existing Contractors

The QA Function of the Quality Assurance Agreement Co-ordination Site and Lead Sites shall adopt the activities outlined in the Maintenance Phase (5.3) and put in place a QA Agreement reflecting the relationship with the contractor.

5.7       Application to In-licensed Products

The procedure is fully applicable to in-licensed products that are manufactured at a contractor to sponsor that is not the licensor nor a contractor to the licensor.

With the following exceptions the procedure is applicable to in-licensed products that continue to be manufactured by the licensor or a contractor to the licensor:

– The selection phase and the technology transfer process from sponsor company to the licensor does not exist.

– If the licensor is registered as responsible for the release, the product has a certified status unless or until circumstances arise that warrant de-certification.

– If the licensor continues to own the Marketing Authorization it is responsible for maintaining the Authorization and providing sponsor with copies of the currently approved Chemistry, Manufacturing and Controls (CMC) documentation.

– If sponsor owns the Marketing Authorization the CMC documentation is either managed by Dossier Management Group (DMG) or more likely, by the regulatory department of the sponsor Marketing Company that owns the marketing rights.

– A technology transfer process of analytical methods from the licensor to sponsor may be needed.