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.