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 protocol lists the in-process and finished-product samples that will be pulled, when they will be pulled, sample size, and the testing to be performed. Finished-product samples may be pulled for QC release testing, microbial analysis, QC retain, and acceptance quality limit (AQL) inspection. An AQL is a visual inspection of the finished product for critical, major, and minor defects (11). The protocol identifies which samples will be tested by the contractor and which samples will be sent to the sponsor's facility for testing. The protocol should state the test method or procedure number, the acceptance criteria, and where the test results will be recorded. For example, in-process test results will be recorded in the BMR when the contractor conducts the testing. Any additional in-process testing not typically performed by the contractor but requested by the sponsor company also should be included in the protocol. Ensure that the sponsor's analytical department is aware of and is in agreement with the sampling procedure, tests to be performed, location of testing (contractor or sponsor), the specifications established, and the sample size. The sponsor's SOPs and test procedures should be used for guidance on testing in-process and finished-product samples.

The manufacturing protocol specifies special requests of the sponsor not routinely performed by the contractor. If applicable, the protocol should specify special handling procedures for API, samples, or finished product such as refrigeration during storage and shipping.

Before signing the protocol, the clinical manufacturing representative and the formulator should review the protocol and agree on the content and instructions. All the details of the contractor's responsibilities should be included in the protocol. The protocol is signed by the technical representative who wrote the protocol, the QA department at the contract facility, and the clinical manufacturing representative.

The manufacturing protocol, the quality agreement, and the clinical supply agreement become guidelines as signed agreements between both parties in the event there is an issue later concerning the contractor's or sponsor's responsibility during manufacturing. Therefore, the clinical manufacturing representative should review the quality agreement and clinical supply agreement to ensure that these documents do not contradict each other or the manufacturing protocol.

Contract manufacturing request

Regardless of whether the contractor prepares a manufacturing protocol, the sponsor may want to prepare a contract manufacturing request. The difference between the manufacturing protocol and contract manufacturing request is that the protocol captures the activities the contractor will perform and may not typically address all of the sponsor's requirements and batch-related information such as the sponsor's product lot number and storage statement. The purpose of these two documents is to capture in writing as many details as possible before the start of manufacture. Keep in mind that some of these details, including sampling and in-process testing, are captured in the BMR. In the interest of time, however, it is more efficient to discuss these issues and have the decisions made before drafting the BMR.

The manufacturing requirements section includes the product formula (qualitative and quantitative composition), raw material grade, supplier information, and a short description of the manufacturing process. If applicable, processing aids that contact the product (e.g., nitrogen and water) also are listed. This section is especially important if the formulation was developed by the sponsor.

In the raw-material section of the contract manufacturing request, include the role of each company in sourcing and releasing the raw materials and API. If the clinical study will be conducted in Europe, for example, include a statement that the raw materials will require EP testing.


Table VI: Contract manufacturing request.
The manufacturing documentation section should state that the contractor will prepare the BMR and the sponsor will review and approve the batch record within a specified time before the start of manufacture. The contract manufacturing request should include the name and address of the representative at the sponsor facility who should receive the documentation for review and approval. Include a statement that all changes or deviations in the manufacturing process must be approved by the sponsor and that all atypical occurrences must be reported to the sponsor's QA department as soon as possible or within a specified time period (see Table VI).


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