Preparing Documentation to Support Clinical Supply Manufacture

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Pharmaceutical Technology, Pharmaceutical Technology-08-01-2007, Volume 2007 Supplement, Issue 3

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.

Interactions between a sponsor and a contractor before and during the clinical manufacture of a drug product should involve discussions about responsibilities, current good manufacturing practices (CGMPs), regulatory requirements, and company operations. Documenting this information ensures both parties have a clear understanding of their roles and how the manufacturing operation will be conducted. The preparation and the ability of both parties to understand and agree upon their responsibilities in writing before the start of manufacture leads to a smooth and successful operation.

The task of identifying the contract manufacturing organization (CMO)is beyond the scope of this article. Information about CMO selection may be available through networking with pharmaceutical colleagues or in trade journals (1–5).

Confidentiality agreement

Once a contract facility is identified, a confidentiality agreement, also known as a nondisclosure agreement, is prepared by the sponsor's or the contractor's legal department before any exchange of information. When the confidentiality agreement is written by the sponsor, the agreement is forwarded to the contractor's legal department for review. If both companies differ on the content of the agreement, they negotiate the terms until a signed agreement is executed. The confidentiality agreement may be written by the contractor when the sponsor does not have a department that writes confidentiality agreements (e.g., a small start-up company).

The agreement must be a bilateral confidential disclosure agreement. This type of agreement provides for the sharing of information on a confidential basis between both companies. Both parties agree not to disclose the other's proprietary information to any third parties other than affiliated companies and consultancy firms that are bound to the terms of the confidentiality agreement.

Confidential information should include all proprietary technical, nontechnical, and commercial information marked "confidential" or declared to be confidential by the disclosing party and given to the receiving party. The length of time this agreement should be in place also is specified (see Table I).

Table I: Confidentiality agreement.

The confidentiality agreement is approved and signed by senior management at both companies. Confirmation of an executed confidentiality agreement by the clinical manufacturing representative is important before exchanging information about the active pharmaceutical ingredient (API), drug product, and manufacturing operation and performing a CGMP audit with the contractor.

Technical assessment

After the confidentiality agreement is signed, a technical assessment of the contract facility is recommended. The technical assessment can be performed by the clinical manufacturing representative and the formulator.

A technical assessment ensures the contractor has the type of equipment required to manufacture the batch, the ability to handle the batch size, and the technical expertise to manufacture the dosage form. In addition, a technical assessment includes evaluation of the batch record documentation and processing operations with respect to the product that will be manufactured (see Table II).

Table II: Technical assessment.

Of course, the most important aspect is to get a feeling for the type of working relationship the sponsor and the contractor will have (6). A good working relationship is especially important when the sponsor's long-term goal is to commercially manufacture the new drug product at the contract facility. This project involves the two companies working together through manufacturing clinical supplies, registration batches, technology transfer, process validation (7), and the US Food and Drug Administration preapproval inspection (8).

A written report of the outcome of the technical assessment is recommended by one clinical manufacturing representative in conjunction with the formulator. This report, filed in a retrieval location within the representative's company, provides colleagues the opportunity to review the contractor's capabilities for this project and future projects. A positive technical assessment grants the go-ahead for the quality assurance (QA) audit. If the assessment is negative, then the decision may be to suggest remediation steps or evaluate another contract facility.

The clinical manufacturing representative who performs the technical assessment also should attend the clinical manufactures at the contract facility. This representative is the contact person who should work firsthand with the contractor in planning, executing, and following through to manufacturing completion.

QA audit

If questionable issues arise during the technical assessment, then a request can be made to the sponsor's QA representative to address these concerns in an audit. The technical assessment and QA audit may be performed simultaneously. Nonetheless, the purpose of performing the technical assessment before the QA audit is to ensure that the contractor has the capabilities to perform the manufacture. If the contractor does not meet manufacturing requirements, then there is no reason to pursue a relationship with the contractor for this project.

The sponsor's QA department arranges with the contractor's QA department to conduct a facility inspection. This CGMP audit includes but is not limited to an inspection of the building and company operations. This inspection also should include an audit of the departments with which the product will come in contact such as the warehouse, manufacturing areas, packaging areas, quality control (QC), and analytical laboratories. In addition, the review of personnel training files, standard operating procedures (SOPs), equipment validation reports, equipment cleaning validation, and equipment calibration programs are subject to inspection. Another area of concern is how the contractor maintains the sponsor's confidentiality when other clients are in the contractor's facility performing audits and observing manufactures (see Table III).

Table III: Quality assurance audit.

At the conclusion of the inspection, the QA auditor conducts an exit meeting with those representatives who participated in the inspection. The exit meeting summarizes the observations of the auditor during the inspection. Inspections typically last a day and a half or longer, depending on the size of the facility, level of CGMP compliance at the contractor site, the length of time it takes for the contractor to retrieve requested information, and the number of departments that are inspected. Observations should be discussed as they are noted during the audit and agreement reached before the exit meeting. During the exit meeting, the auditor notes issues that already may have been addressed and corrected. The QA auditor then approves or denies the use of the facility. If appropriate, the auditor may conditionally approve the facility with stipulations such as:

  • Only particular equipment may be used

  • Manufacturing operations may only be conducted in a particular manufacturing area

  • Additional testing of raw materials may be required

  • Special requests may be made regarding the operations (e.g., a representative from the sponsor's company must be on-site during batch manufactures).

As a follow-up, the QA auditor issues a written report to the contractor detailing observations that were discussed during the exit meeting. In turn, the contractor responds to the observations in writing. The contractor's response should include the corrective action to take place with a timeline for implementation, or the contractor may reply that the current procedure is acceptable and include a justification for this decision. If the contractor's response is unacceptable and the observation is deemed critical, then the status of the contractor may change.

Contract facilities are usually very flexible and, within reason, special requests can be handled. After all, the contractor wants the pharmaceutical company's business and if it is making the request, chances are another client will do the same. In addition, the QA auditor often identifies the contractor's weaknesses, and it may be to the contractor's advantage to reevaluate its operations.

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.

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.

Table IV: Quality agreement.

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

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).

Table V: Manufacturing protocol.

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.

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.

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.

The contract manufacturing request also includes information about how the product is to be bulk packaged, labeled, and shipped. (Packaging the product at the contractor's facility for the clinical study is not covered in this article; however, the type of documents mentioned in this article will support the packaging operation at a contract facility.)

Include your product-lot number and any storage statement that the contractor will be required to include on the labels such as "under refrigerated conditions (2–8 °C)." The sponsor may request the contractor to ship all refrigerated product with temperature monitors to verify the conditions during transit. The temperature monitors (electronic data loggers) would be procured by the sponsor and shipped to the contractor with operating directions. Once the temperature monitors are received at the sponsor's facility with the product, the monitors can be downloaded to view the transportation conditions.

The contract manufacturing request includes the delivery date of samples, product, and batch documentation. Specify the name and address of the person at the sponsor company to whom the in-process samples, finished product, and batch record documentation are to be sent.

The clinical manufacturing request should be sent to the sponsor company's contact in the technical group at the contract facility who will prepare the batch record documentation, the contractor's project manager, or the business development representative.

Cost quotation

The contractor's business development group prepares the quote for the cost of manufacture. This document should itemize, at minimum, the costs for conducting analytical tests on the raw materials, QC support for in-process and release testing, the generation of batch documentation, the manufacture of the batch, and the QA audit of batch documentation. The document should also state that one sponsor QA facility audit per year is included in the cost (see Table VII).

Table VII: Cost quotation.

The cost quotation should be sent to the clinical manufacturing representative or the sponsor company's purchasing department. The purchasing department reviews the cost quotation to confirm that the services to be provided coincide with the cost stated and either accepts the charges or negotiates costs with the contractor.

Additional charges may include preparing a cleaning verification method for the API if the sponsor does not already have a procedure in place that can be transferred by the sponsor's analytical department to the contractor. There may be an extra cost to perform equipment cleaning verification at the conclusion of the batch. A one-time cost may be required to develop a microbial validation procedure for the finished product.

The cost quotation also should include a statement that additional supplies, including reference standards, excipients, and other materials required for the project, will be charged to the sponsor. Additional charges may also be appropriate in unique circumstances such as the handling of potent compounds. If the clinical study will be conducted in Europe, there may be an additional cost for EP testing of the raw materials. The quote also should include a statement for the cost incurred in the event that the sponsor must cancel or postpone the date of manufacture.

The clinical manufacturing representative is responsibile for reviewing the cost quotation to ensure that the services to be provided are accurate. The contractor may ask the sponsor for a signature to confirm agreement of the manufacturing cost.

Purchase requisition

The clinical manufacturing representative may prepare the purchase requisition for the manufacture. It is a good idea to attach the cost quotation, the manufacturing protocol from the contractor, and the contract manufacturing request to the purchase requisition (see Table VIII). The purchase requisition and attachments are then forwarded to the purchasing department for execution.

Table VIII: Purchase requisition.

Some contractors require payment as the operations are completed. Others require one full payment after the product is manufactured. Final payment should only be made after the product and all the batch-record documentation have been received and approved by the sponsor and all product-related investigations have been completed.

Batch manufacturing record

The BMR is the final document and is affected by all previous documents. Typically, the BMR is generated electronically by the contractor's documentation and technical groups. The clinical manufacturing representative is responsibile for reviewing the draft record and ensuring that the sponsor's requests per the contract manufacturing request and the manufacturing protocol are included in the record. In addition to this review, the representative should request that the formulator and the sponsor's QA representative review the draft record and forward their comments (see Table IX). The clinical manufacturing representative compiles these comments and questions on the record and returns them to the contractor at one time. Review of the draft record by all parties at the sponsor's facility should expedite the review and approval of the final BMR.

Table IX: Batch manufacturing record.

The BMR is signed by the contractor's technical representative who prepared the record and one or more approvers at the contract facility. The BMR also is signed by the clinical manufacturing representative as the sponsor's approval and by the sponsor's QA department. The last signature to approve the record is typically the contractor's QA department.


Figure 1 summarizes areas described in this article. Working with a third-party contract facility requires learning how another company operates. The more a sponsor learns about the contractor, the easier it will be to achieve a successful manufacture. Therefore, it is important to get to know a contractor by obtaining background information through visiting the site for the technical assessment and the QA audit after the confidentiality agreement has been signed.

Figure 1: Overview of documentation and responsibilities of contractor and sponsor company.

The goal in preparing the quality agreement, manufacturing protocol, and contract manufacturing request is to specify everything that the sponsor company wants the contractor to provide. Requirements and special requests will be reflected in the cost quotation and purchase requisition. The preparation of these documents influences the final document which is the writing and execution of the batch manufacturing record.

There will always be issues that are inadvertently overlooked, but through discussions with the contractor and experience working with contractors, these issues should occur less frequently. The more information that is discussed before the manufacture of clinical batches, the smoother the operation will later be. These discussions and documents can avoid delays, save time and money, and organize the manufacturing operation for both companies to result in a win–win operation.

Peggy A. Krotzer is a scientist responsible for contract manufacturing clinical supplies at Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, tel. 203.798.5260, fax 203.837.5260,


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