CONTRACT MANUFACTURING AND THEIR AUDITING

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1.8. Monitoring The Contractor

1.8.1. Quality Assurance Initial Audits
Prior to establishing any relationship with a contractor, the quality assurance staff of a potential client must audit the contractor’s facilities. During this audit, the contractor should be willing to provide a comprehensive tour of the facilities. Following the tour, the auditors need to review all of the contractor’s standard operating procedures that may apply to their company’s proposed project. In addition, the auditors need to review the quality improvement process being used by the contractor and the results of that process. Any concerns that have been identified during the audit should be discussed with the contractor at that time. (McVean, D.E., 2007)

1.8.2. Actions to be Taken upon Receipt of Audit Report
Upon completion of the audit, the auditors should provide the contractor with a report citing any problems which they have identified with the contractor’s operation that might interfere with the contractor being able to successfully work on their company’s project. The contractor should respond in writing to the audit report and address how they will handle each observation. Based on the results of their audit and the responses of the contractor, the audit team can then make a recommendation to the responsible personnel within their organization as to the acceptability of the contractor. (McVean, D.E., 2007)

1.8.3. Representatives in Contractor’s Facilities
Once manufacturing begins, most clients elect to have a representative present. The contractor should be willing to permit that representative to observe the processes in their entirety. Before any visit, however, the client must instruct its representative to comply with all of the standard operating procedures of the contractor while on the contractor’s premises. Further, the extent a representative can be involved in the production process needs to be negotiated between the client and the contractor prior to sending a representative to the contractor’s site. (McVean, D.E., 2007)

1.8.4. Periodic Audits by Quality Assurance Staff of Client
After a client has established a working relationship with a contractor, the quality assurance staff of the client should be allowed to audit the contractor’s facilities and operations on a regular basis, but usually not more frequently than once a year. Again, any observations concerning the contractor’s operations arising from these audits require a written response from the contractor. If the responses are not satisfactory to the audit team, then the upper management of both companies must be called upon to immediately resolve the differences. Should this be necessary, the management of both parties must ensure that any proposed resolution remains within the terms of the contractual agreement. (McVean, D.E., 2007)

1.8.5. Quarterly Meetings
Finally, it is good practice to hold quarterly meetings between the decision makers of both the client and the contractor. These meetings ensure that both companies are still aligned to achieve mutual goals. These meetings allow the contractor to participate in the client’s decision making process as performance for the previous quarter is reviewed and plans for the following quarter are presented. Topics for discussion should include the contractor’s conformance to the client’s expectations, regulatory issues concerning the client’s product(s), the contractor’s recent regulatory experiences, sales forecasts, and any other items appropriate to the occasion. (McVean, D.E., 2007)

2.      CONTRACT MANUFACTURE AND ITS AUDIT AS PER INDIAN GMP & WHO GUIDELINE:-
2.1. Principle.
Contract production and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality. (WHO, 2007)

2.2. General
2.2.1. All arrangements for contract manufacture and analysis, including any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned.

2.2.2. The contract should permit the contract giver to audit the facilities of the contract accepter.

2.2.3. In the case of contract analysis, the final approval for release must be given by the authorized person. (WHO, 2007)

2.3. The contract giver
2.3.1. The contract giver is responsible for assessing the competence of the contract accepter in successfully carrying out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of GMP described in this guide are followed.

2.3.2. The contract giver should provide the contract accepter with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. The contract giver should ensure that the contract accepter is fully aware of any problems associated with the product, work or tests that might pose a hazard to premises, equipment, personnel, other materials or other products.

2.3.3. The contract giver should ensure that all processed products and materials delivered by the contract accepter comply with their specifications or that the product has been released by the authorized person. (WHO, 2007)

2.4. The contract accepter
2.4.1. The contract accepter must have adequate premises, equipment, knowledge, and experience and competent personnel to carry out satisfactorily the work ordered by the contract giver. Contract manufacture may be undertaken only by a manufacturer who holds a manufacturing authorization.

2.4.2. The contract accepter should not pass to a third party any of the work entrusted to him or her under the contract without the contract giver’s prior evaluation and approval of the arrangements. Arrangements made between the contract accepter and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract accepter.

2.4.3. The contract accepter should refrain from any activity that may adversely affect the quality of the product manufactured and/or analysed for the contract giver. (WHO, 2007)

2.5. The contract
2.5.1. There must be a written contract between the contract giver and the contract accepter which clearly establishes the responsibilities of each party.

2.5.2. The contract must clearly state the way in which the authorized person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the marketing authorization.

2.5.3. Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis and GMP.

2.5.4. All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties.

2.5.5. The contract should describe clearly who is responsible for purchasing, testing and releasing materials and for undertaking production and quality controls, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract should state whether or not the contract accepter should take samples at the premises of the manufacturer.

2.5.6. Manufacturing, analytical, distribution records and reference samples should be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the contract giver.

2.5.7. The contract should describe the handling of starting materials, intermediate and bulk products and finished products if they are rejected. It should also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected. (WHO, 2007)

2.6. QUALITY AUDITS:- (WHO, 2007)
2.6.1. Principle.

A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors

2.6.2 .Items for inspection
Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include questionnaires on GMP requirements covering at least
The following items:
(a) Personnel;
(b) Premises including personnel facilities;
(c) Maintenance of buildings and equipment;
(d) Storage of starting materials and finished products;
(e) Equipment;
(f) Production and in-process controls;
(g) Quality control;
(h) Documentation;
(i) Sanitation and hygiene;
(j) Validation and revalidation programmes;
(k) Calibration of instruments or measurement systems;
(l) Recall procedures;
(m) Complaints management;
(n) Labels control;
(o) Results of previous self-inspections and any corrective steps taken.

2.6.3. Inspection team
Management should appoint a inspection team consisting of experts in their respective fields and familiar with GMP. The members of the team may be appointed from inside or outside the company.

2.6.4. Frequency of inspection
The frequency at which inspections are conducted may depend on company requirements but should preferably be at least once a year. The frequency should be stated in the procedure.

2.6.5. Inspection report
A report should be made at the completion of a self-inspection. The report should include:
(a) Inspection results;
(b) Evaluation and conclusions;
(c) Recommended corrective actions.

2.6.6. Follow-up action
There should be an effective follow-up programme. The company management should evaluate both the inspection report and the corrective actions as necessary.

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