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
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.
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).
Table VI: Contract manufacturing request.