Preparing Documentation to Support Clinical Supply Manufacture - Pharmaceutical Technology

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Preparing Documentation to Support Clinical Supply Manufacture
This article is written to assist clinical manufacturing representatives at pharmaceutical companies who are faced for the first time with outsourcing the manufacture of clinical supplies. The author describes the identification, writing, and execution of documents required to support the contract manufacture of products for clinical studies.

Pharmaceutical Technology

The primary objective of the audit is to ensure that clinical supplies will be manufactured under CGMP requirements and to the sponsor's expectations. Of course, this objective requires that the expectations be reasonable and that the sponsor only require of the contractor what it requires of its own company. Many companies expect the contractor to go far above a CGMP requirement because they are a paying customer. Such situations do not build good relationships. Remember that the sponsor and the contractor are a team working toward the same objective. Both companies are building a working relationship that will last not only for this but also for future projects.

Quality agreement

Once your QA department approves the contract facility for use, a quality agreement is prepared by the sponsor's or contractor's QA department. A quality agreement defines the responsibilities of both companies for clinical supplies manufacturing, testing, packaging, and distribution of a specific product.

Table IV: Quality agreement.
The quality agreement identifies the party responsible for maintaining regulatory and CGMP compliance. Additional responsibilities are outlined for the maintenance of specifications, procurement, storage, sampling, testing and release of raw materials, API, and packaging components (see Table IV). The quality agreement also specifies the party responsible for ensuring that the product complies with the approved product specifications. The role of the contractor's QA department, which is to review and approve the batch record documentation and analytical testing results, should also be stated in the quality agreement (9, 10). The quality agreement is reviewed by the sponsor's and the contractor's legal department and requires signature approval by senior management, including senior management in QA at the contractor's and sponsor's sites.

The clinical supply agreement also is an important document that focuses on the activities that the contractor will perform for the sponsor during the manufacture of clinical supplies. When the contractor requires formulation-development work before clinical supplies are manufactured, the contractor's legal department prepares a development of a manufacturing agreement. The type of agreement required depends on the activities the contractor will perform and the legal requirements of the sponsor and contractor. These agreements capture the business relationship between the contractor and sponsor, whereas the quality agreement captures the quality aspects of the product to be manufactured.

Clinical manufacturing representatives should be aware that these agreements may be required at their companies and that the company may request that they review the agreements before the start of operations. Writing these agreements may be initiated by the project manager or the business development group at the sponsor company, depending on the sponsor's internal procedures. As applicable, these agreements should be reviewed by the sponsor's legal, QA, analytical, formulation development, clinical manufacturing, and purchasing departments. Most important, the clinical manufacturing representative can ensure that all departments that provide input to these agreements are involved at the onset of the writing of these agreements. These agreements are approved and signed by senior management at both companies.

Manufacturing protocol

Table V: Manufacturing protocol.
Once there is a clear understanding of the manufacturing operation and what the sponsor is requesting, the contractor's technical group may prepare a manufacturing protocol. The manufacturing protocol includes the scope of the project and details the contractor's manufacturing responsibilities regarding the product. This document also becomes a guideline for writing the batch manufacturing record (BMR). The protocol identifies the product to be manufactured, the quantity to be manufactured, and, if applicable, the dimensions of the product, including imprinting or embossing for tablets or capsules (see Table V).

The protocol also specifies whether the raw materials tested by the contractor meet United States PharmacopeiaNational Formulary (USP–NF), European Pharmacopeia (EP), and Japanese Pharmacopeia (JP) monographs, as applicable.


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