Outsourcing Stability Studies - Pharmaceutical Technology

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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.

Pharmaceutical Technology

Method transfer. If the CAL has not developed and validated analytical methods, then a formal method transfer is required. This transfer determines the CAL's proficiency in performing the methods. Method transfer should be performed sufficiently in advance of the corresponding stability study so that the sponsor can fully review the data. Issues with instrument compatibility, data evaluation, and reporting should be addressed during method transfer. Method transfer precedes and sets the benchmark for the entire stability study. The sponsor should receive a full report of the data generated so that it may conduct a thorough review.

Analytical method transfer may simply mean that the CAL performs the methods. It may include other aspects such as spiking samples with additional impurities or degradation products during purity evaluation, linearity, or other qualification analyses. The analysis should include samples that have higher and lower strength than the product. The originating laboratory and the CAL should test the same lots or batches of samples, and testing should be within a similar time period so that the samples are aged to a similar degree. The sponsor establishes the acceptance criteria and issues a certificate of conformance once it has evaluated the data.

Document review. Before the initiation of the stability study, the lead technical staff from the sponsor and CAL should meet to review the data and results of the analytical method transfer. This review provides the opportunity to evaluate the transfer and address any problems that arose during analysis or reporting. This opportunity should also be used to review the final stability protocol, specification requirements, and anticipated timelines to confirm that both parties' expectations are met. Document review may occur several weeks or months after the original agreement is established, and it is prudent to revisit these items in case subsequent changes have affected the scope of work or timelines. If the scope of work has increased or timelines shortened, then the CAL may negotiate to revise the contractual agreement.

Reporting. The manner in which data are reported is often overlooked, and expectations should be communicated and agreed upon by both parties. A significant volume of data may be generated early in the process, and several stability reports may be created during the first 12 months of the study. If the reporting details are not thoroughly established in advance, the stability reports may need to be reissued, which could potentially compromise the sponsor's ability to evaluate the data properly or submit regulatory filings within the planned timeframe.

The format of the analytical report should be established during the startup meeting. The sponsor may require the data to be presented in a specific report format that it provides (e.g., Excel or Word). The sponsor might prefer the CAL's standard report or require a custom report. If a sponsor's format is to be used, then the CAL's quality-assurance unit may request a review of the template before the study is initiated. This review ensures that all of the information and references that the CAL requires are included in the template.

Specifications. The CAL compares the results it generates with the sponsor's specifications. It may use action limits to highlight results that approach the specification limits. If the sponsor requires an investigation procedure that is different from the CAL's standard procedure, then specific notification and processes should be described in the study protocol, specifications, or quality agreement. CALs' investigation processes are generally specific to investigation notification and review process and typically do not include reanalysis procedures because of sponsors' differing internal policies. Therefore, a sponsor should specify the particular processes it requires so that the CAL can conform to the sponsor's requirements. The process maybe listed in the protocol or specifications. The sponsor may choose to provide its own standard operating procedure for investigation under the confidentiality agreement.

Results that meet specifications but are out of trend should also be considered. For example, suppose the assay specification is 95.0–105.0%, the initial results are 101.0%, and the three-month results are 97.0%. Although the results are within specification, the drop in the assay value may be considered aberrant. This interpretation is subjective, therefore clarification may be required in the specifications.

Document revisions. If the CAL generates and validates the analytical method, then it should ensure that the sponsor is notified of revisions to analytical methods and other relevant documents. Also, the sponsor should provide the CAL with the most recent versions of protocols, methods, specifications, and other pertinent documents. The two parties should agree on a chain of custody or other form of acknowledgement process to ensure that the documents are successfully received and implemented. The sponsor should also release updated documents at appropriate times. For example, a method release that occurs while the CAL is actively testing the associated samples will conflict with the effective period of the method. The CAL will have used a method that is no longer valid, and the sponsor will potentially need to justify how this occurred.


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