Outsourcing Stability Studies

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.

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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

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").

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.

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.

Vendor-qualification program. A CAL may use vendors if it cannot perform a particular function in house. These functions may include calibrations or specialty analyses that are not among the CAL's normal services (e.g., microbial limits, container integrity, or sterility testing). The sponsor should therefore review the qualification program and list of qualified vendors to determine whether the program meets its requirements. An internal policy may require the sponsor to qualify the subcontract laboratory independently of the CAL's vendor-qualification program. If the CAL intends to subcontract analyses and the sponsor requires prior notification, then this requirement should be stated in the quality agreement or master services agreement.

Corrective and preventive action program. During the course of a stability study, procedural deviations, analytical investigations, or other quality-related investigations will inevitably occur. The CAL's corrective and preventive action (CAPA) program should enable deviations and investigations to be evaluated and remedied thoroughly to prevent future occurrence. The root cause, therefore, must be identified, and appropriate performance factors must be categorized and monitored so that trends can be identified and addressed. The sponsor should review the CAL's standard operating procedures for the CAPA program because inadequacies could compromise the study data.

Environmental stability chambers. Environmental stability chambers must be operated to the guidelines established by the International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) if the stability study is for a new drug substance or product (1). Nonrefrigerated products must be maintained within ±2 °C of their specified temperature and at ±5% of the specified RH. Refrigerated products must be maintained within ±3 °C of their specified temperature. The CAL should have procedures for installing, operating, and monitoring its stability chambers. Periodic maintenance and disaster scenario plans are highly recommended.

Performance qualification should include mapping the chambers for temperature and humidity. A chamber's recovery performance and ability to hold its set temperature and humidity conditions should be confirmed so that the chamber can withstand power losses. The chambers should be locked, located in a restricted area, and include door alarms, so that unauthorized personnel cannot access the chambers. An alarm should be activated if the door is open for an extended period. The chambers and monitoring system should be calibrated every every six months.

Stability disaster recovery and sponsor notification. The CAL should have a procedure for occasions when the chambers cannot maintain the setpoints because of malfunction or power loss. The sponsor must be notified if the chambers have been outside of their setpoints for a period longer than that specified by the CAL's internal procedure (24 h is a standard limit). Samples should be relocated if the chambers cannot be restored within this timeframe. The sponsor is typically responsible for determining whether the pull dates require reevaluation if samples are stored outside the intended conditions for a prolonged period.

In addition, the stability chambers and environmental-monitoring system should have a backup power source (i.e., a generator) that automatically activates when power is lost. A backup water supply is also required in case the main water supply is interrupted. Backups prevent the loss of power and subsequent deviation from the temperature and humidity conditions.

Stability-study setup and management. The CAL's shipping and receiving group should be capable of handling large-scale deliveries. Long-term stability studies may involve thousands of samples that may be received in bulk shipments directly from the sponsor, manufacturer, or packaging plant. The CAL should have the physical capacity for such shipments and a means of transferring the samples into the laboratory in an efficient manner.

The procedure for initiating a stability study should demonstrate how the CAL controls the placement of the samples in the chambers and should require all stability studies to be performed according to a sponsor-approved stability protocol. An initial sample inventory should be taken and updated as the samples are removed.

The process for calculating pull dates should be reviewed, and the sponsor should provide specific details if it prefers its own practices to be followed. Various approaches exist, including a sliding pull date that depends on the time point or a fixed time point on a specific date. Weekends, holidays, and other company closures should be taken into account. The CAL should have a procedure for removing and destroying the stability samples when the stability study is complete. The sponsor should inform the CAL in advance if it prefers a process different from that stated in the CAL's procedure so that samples are not removed and destroyed but rather retained or returned to the sponsor.

The CAL should have a procedure for storing the samples after being pulled and before being tested. The typical condition is room temperature, unless they are refrigerated or frozen, in which case they may remain at those conditions until testing. If the sponsor requires specific conditions, they should be included in the stability protocol.

If samples are kept in bottles or blister packs, an entire bottle or strip is typically removed from the chamber at the pull point, except for in-use tests. If a sample is drawn from a bulk container, however, a sponsor's preferred procedure must be described if it differs from that of the CAL. For example, if the bulk material is vacuum packed and the container must be resealed at each interval, this process should be explained in the stability protocol.

Stability-testing windows typically are based on a sliding time window that depends on the time point (e.g., test within 10 days for intervals of three months or less and within one month for intervals of six months or greater) or on a specific timeframe regardless of test interval (e.g., test within one month). If the CAL's procedure does not meet the sponsor's expectations, the latter must be addressed in the protocol or quality assurance agreement.

Monitoring stability chambers. The CAL must monitor the stability chambers' performance on a daily basis. Chart recorders and electronic probes can monitor temperature and humidity. Chart recorders should be monitored every day. They are vulnerable to malfunction when pens run out of ink and other basic errors occur. Electronic probes combined with a commercial environmental-monitoring program constantly evaluate the chambers and provide performance-trending data, so that malfunctions may be predicted before they occur. If a chamber deviates from its setpoint (e.g., it exceeds ±2 °C or 5% RH), the system can be programmed to call an employee to investigate and resolve the problem. If the CAL uses chart recorders, it may not detect the error until the chamber is checked during the daily routine. The sponsor should review the CAL's procedure to determine whether the process is appropriate and adequate. If electronic probes are used, their performance should be confirmed periodically (e.g., every six months).

Sample storage. If the sponsor is storing the stability samples in its own chambers or in a vendor's chambers, it must decide on the timing for pulling samples and shipping them to the CAL. During large studies, the CAL may have a team waiting to receive and test the samples. If a shipment is delayed, it might compromise the CAL's ability to test the samples within the test-window period.

If the CAL is to store the stability samples in its chambers, then the parties should decide in advance whether the CAL or the sponsor will decide how the samples are distributed and how much overage will be placed on station. A recommended overage is a minimum of 25% additional samples in case the study is extended or additional samples are required. The party responsible for labeling the samples should be specified clearly. This decision will help the CAL plan and place the samples on station. Once the samples are on station, the pull dates must be communicated to the sponsor. For large, complex studies, the sponsor may choose to audit the stability setup.

For registration stability studies, it is increasingly common for a secondary set of samples to be maintained at a different facility. This arrangement prevents samples from being compromised if the primary storage facility is shut down. Secondary storage facilities should be in separate regions. Disaster recovery scenarios should always be in place.

Study design

The US Food and Drug Administration accepts lot and packaging matrices for stability studies that are based on ICH guidelines. The guidelines greatly reduce the number of samples to be tested but increase a study design's complexity. Special tests such as in-use tests, which may be triggered by the failure of the corresponding open-dish tests, also contribute to the complexity.

Studies often have contingency conditions for when failures are observed. For example, samples may be stored at long-term conditions of 30 °C and 65% RH and at 25 °C and 60% RH. The latter samples might only be tested if the former samples fail specifications. Ideally the former samples' results should be approved by the quality assurance unit before the latter samples are tested. The two sets of samples should therefore be placed on station at staggered intervals to allow the first set to be evaluated to avoid erroneously testing the contingency samples.

The anticipated time of the beginning of a study should be clearly communicated and mutually decided by both parties. When a CAL commits to a study, its resource allocation is based on the information that the sponsor provides for the start date. The CAL considers resource allocations to determine whether they may conflict with current active studies. If delays such as manufacturing difficulties occur, then the CAL should be notified to ensure that no resource conflicts with the new proposed start date. Open communication also serves the interest of the sponsor because it may require the CAL to report the analyses quickly to meet a filing deadline. Such deadlines should be communicated and mutually agreed upon in advance.

Summary

If the CAL's procedures are not consistent with the sponsor's expectations, then specific details may be addressed in the quality assurance agreement or the study protocol. In addition, the CAL and the sponsor's lead technical staff should meet to evaluate the study. This evaluation should include a comparison of the instrumentation specified in the methods and the CAL's equipment. Items such as the compatibility of available HPLCs may be addressed (e.g., dwell volume comparison), as may questions such as whether a wrist-action or reciprocating shaker is preferred.

The sponsor should evaluate the CAL's departmental structure to determine the necessary resources. The sponsor should be informed about whether the same person will remain the technical lead throughout the study and whether the same resources will be used for each time point. The sponsor should also learn whether temporary employees will be used for large stability pulls, which occur during the first six months and include accelerated conditions and special time points such as photostability. The early time points generate critical data, and the sponsor must be confident that the teams are sufficiently trained. Inexperienced temporary employees can reduce the study's quality.

Conclusion

A sponsor that seeks to hire a CAL to perform stability studies should consider several important factors and take critical steps during its evaluation process. The sponsor should perform a thorough audit of the CAL's procedures, paying attention to the latter's training program, environmental chambers, data processing, and reporting practices and timelines. Timing and study design should be considered so that the appropriate resources are allocated and the sponsor receives analytical reports in a timely manner. The relationship between the sponsor and the CAL should be viewed as a partnership with open communication between both parties. The parties should have the same objective: to perform the stability study within the expected timelines so that the product can get to market successfully.

David C. Browne is a manager of stability and pharmaceutical testing at Intertek QTI, 291 Route 22 East, Whitehouse, NJ, 08888, tel. 908.534.4445, ext. 658, fax 908.534.1054, david.browne@intertek.com

Reference

1. ICH, Q1A Stability Testing of New Drug Substances and Products (Geneva, February 2003).