Outsourcing Stability Studies

The author provides advice about evaluating contract analytical laboratories and establishing an effective procedure for working with them to perform reliable stability studies.
Aug 01, 2009
Volume 2009 Supplement, Issue 4

The decision to outsource stability studies to a contract analytical laboratory (CAL) is a significant commitment for a pharmaceutical business. Stability studies evaluate the change of a material over time when stored at various environmental conditions (e.g., temperature and relative humidity [RH]) and may last as long as five years. A pharmaceutical sponsor may outsource such studies to free internal resources for other research and development activities or simply because it does not have an internal laboratory available. The sponsor company entrusts the CAL to perform studies that may cost millions of dollars, affect a product's course to commercialization, and ultimately contribute to the success or failure of the sponsor's business. This article provides basic guidelines to pharmaceutical businesses that have not previously outsourced stability studies. It highlights practices and procedures that pharmaceutical businesses should review as they select a new contract laboratory.

Choosing a CAL

Choosing a CAL is the first step of a business partnership that often requires much interaction. The sponsor expects to receive stability data at the highest quality standards, with the quickest possible turnaround and at the lowest price. Contract analytical testing is a competitive business, and the sponsor must ensure that its expectations are met. No two CALs are alike, and sponsors have different expectations. A period of acclimation is often required at the early stage of the relationship. The parties' expectations and procedures are crucial to the development of a partnership. Some sponsors are hands-on and expect to be involved in all decisions, but others prefer minimal communication and simply expect to receive an analytical report when the testing is completed. When a collaboration is established and begins to grow, small-scale stability studies should be initiated first so that problems can be addressed easily with minimal impact. Open and honest communication between both parties is a crucial component in the development of the partnership, but such communication may not occur until mutual trust is established.

Historically, the decision to entrust a CAL with a study was based on an evaluation performed by the sponsor's technical managers. In recent years, however, procurement or strategic outsourcing groups have become increasingly involved in selecting CALs. The current process may include price negotiations, including volume discounts, in addition to an evaluation of the CAL's ability to perform stability studies with technical excellence and superior quality. Price negotiations and discount structures may be the products of a competitive market, but they give little indication of the procedures a CAL follows to meet sponsors' expectations.

Before confidentiality agreements, master services agreements, and quality-assurance agreements are drafted, a sponsor might only provide a CAL with example methods and request a quote. After the confidentiality agreement is in place, the sponsor should allow the CAL to evaluate its actual methods. It is essential for the CAL to review the details of specific methods and protocols to determine whether the scope of the work is consistent with the example methods.

Sponsor audit

Auditing a contract analytical laboratory
Sponsors' quality-assurance units generally perform on-site facility audits as part of the selection process or after a CAL has been chosen and confidentiality and quality agreements are in place. Sponsors must examine the CAL's procedures for various tasks (see sidebar, "Auditing a contract analytical laboratory").

Employee-training program. A sponsor should have confidence in the CAL's employee-training program. If personnel are not trained appropriately, sample-preparation or other laboratory errors may occur. Errors lead to laboratory investigations when analytical results do not meet specifications or appear to be out of trend. The additional effort required to determine the root cause of errors may delay the release of the results. Many samples are tested throughout the course of a stability study, and investigations should be anticipated because laboratory errors do occur, although they should be rare. It is therefore worth the sponsor's time to thoroughly review the CAL's training program to determine whether the training process is suitable for its requirements. CALs' training programs differ and may be based on technology such as high-performance liquid chromatography (HPLC) or gas chromatography, on-the-job training, or procedural review and qualification. In addition to its existing training program, the CAL should train employees in its sponsors' specific methods. The sponsor should be confident that the CAL can effectively train its employees so that methods are performed accurately and errors are minimized.

Stability method performance. To gain an understanding of the CAL's processes, it is critical for a sponsor to review the way the CAL performs sample analyses. The review provides valuable information such as data-processing procedures or sample-testing timelines and helps the sponsor assess its confidence in the CAL's ability to manage stability programs and test samples successfully.

The sponsor should determine how the CAL transfers a stability study from its business-development group to its laboratory. The point at which the relevant department manager becomes involved will affect the success of the information transfer. For example, if the CAL's new-business development group is only responsible for providing a price quote, then the technical input such as analysis run times or specifics regarding the purity analysis may not occur until the business contract is signed. A great deal of technical information, including sponsors' special requests, may be created during this time. This information should be transferred to the stability manager and to the personnel working on the project (e.g., the lead chemist and analysts).

The CAL should demonstrate how it manages resources and schedules the work to ensure that the analyses are completed within the expected timelines. For example, large-scale registration stability pulls include many samples. A team of analysts may be required to complete the testing in the required timelines. The CAL should describe how it allocates resources, how it determines that the correct samples are pulled and tested, and how it communicates activities and responsibilities to the team members.

The CAL should demonstrate how it processes and reports analytical data within self-imposed timelines. Data should be generated far enough in advance so that anomalous results can be investigated in a timely manner, preferably before the sample and standard solutions have expired.

The sponsor should review the CAL's conventions for rounding numbers and reporting them to determine whether they are consistent with expectations. For example, does the CAL round up a value of 5 to the nearest digit, follow the American Society for Testing and Materials's convention, or truncate its values? The sponsor will have to accept the CAL's process or impose its own. Sponsors that impose their own rounding process should be aware, however, that they may cause unexpected consequences such as affecting validated spreadsheets.

Data review should occur in a timely manner to ensure the prompt evaluation and confirmation of final results. The frequency depends on the sponsor's policy because no established guidelines have been established. The process should ensure that analytical investigations are initiated when appropriate and allow reinjections to occur before the sample in solution expires. If structured correctly, timely data review can detect errors that occur during reagent preparations before sample analysis is affected.

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