It is important that each entity define their appropriate storage locations to ensure that adequate controls are in place. These locations include buildings and facilities for drug product storage (e.g., warehouse, storage or hold area, the original manufacturer’s warehouses, contractor warehouses, wholesale distribution warehouses, mail order or retail pharmacy storage area, hospital or nursing home pharmacy storage areas; and border Customs storage areas).

In these locations, two basic processes can occur. First, receiving for storage is the act of bringing a drug product into a facility, while transferring refers to the moving of a drug product internally within a facility or into or out of a vehicle. Second, storing and holding refers to the act of maintaining temporary possession of a drug product in the supply chain process, during which no movement of the product will occur.

Drug product storage areas are required to maintain the product temperature between the limits as defined on the product label. Buildings and facilities used for the warehousing, storage, and/or holding of drug products should be of adequate size for their intended use. These facilities should be adequate to prevent overcrowding. The building and facility should be designed to control environmental conditions where necessary and should be made of readily or easily cleanable materials. Sanitation and pest control procedures should be written, indicating frequency of cleaning and the materials and methods used. The pest-control program should ensure the prevention of contamination as well as the safe use of pesticides. Records of all cleaning and pest-control activities should be maintained.

Storage should be orderly and should provide for the segregation of approved, quarantined, rejected, returned, or recalled drug product. If computerized systems are used for the control of storage conditions, the software should be appropriately qualified for its intended purposes. Facilities should have controls that mitigate risks such as fire, water, or explosion. Certain drug products may cause these risks and should be stored accordingly. Storage areas, when not computerized, should be appropriately visually labeled.

Storage facilities themselves, unless thermostatically controlled, cannot be validated; however, they can be qualified via a mapping process. The generator back-up power supply should be qualified.

Storage of a drug product includes not only the period during which the drug product is held in the manufacturer’s storage areas but also time spent at the receiving bay area. When drug products arrive at warehouse loading docks and other arrival areas, they should be transferred as quickly as possible to a designated storage or within a time period that is consistent with the risk and exposure of the product in the receiving area to a designated storage environment to ensure minimal time outside specified storage conditions as described in a written procedure.

Relative to the incoming receipt of drug product, it is recognized that the process of product reaction to ambient conditions begins immediately and may occur quickly (e.g., reach temperature equilibrium within minutes to a few hours depending on details such as the product mass, volume, and packaging density taking into account secondary and tertiary packaging)1. Time spent in a transport vehicle is considered to be part of the distribution process and is not a storage location.

Receiving docks should protect drug product deliveries from inclement weather during unloading. Any storage area, including loading and unloading docks for receipt and distribution of drug products, should be clean, cleanable, and free from pests. The incoming receiving area should limit access to authorized persons. Where appropriate, the delivery vehicle/container should be examined before unloading to ensure that adequate protection from contamination was maintained during transit. Deliveries should be examined at receipt in order to check that containers are not damaged and that the consignment corresponds to the order. The results of this examination should be documented.

Areas should be designated to provide an adequate space in which containers of drug products can be cleaned and opened for sampling. If sampling is performed in the receiving area, it should be done in a manner that prevents contamination and cross-contamination and ensures that environmental requirements for the drug product are not breached.

Adequate precautions should be taken to prevent theft and diversion of drug products. Drug products that have been identified as counterfeit should be quarantined to prevent further distribution. The appropriate regulatory agencies should be contacted according to established procedures.

Appropriate delivery records (e.g., as applicable, transport vehicle movement papers, receiving/delivery records, data logging records, temperature recorders and similar devices, bill of lading, house air waybill, master air waybill, etc.) should be reviewed by each receiving entity in the supply chain to determine if the product has been subjected to any transportation delays or other events that could have exposed the product to undesirable conditions. Each entity should ensure that their respective Service Level Agreement documents and supporting documents such as SOPs cover delivery and receiving responsibilities of the transactional parties.

Smoking, eating, and drinking should not be permitted in any storage/hold areas.

Refrigerators and freezers used to store drug products are required to maintain the product temperature between the limits as defined on the product label. Typically, a refrigeration unit specification would be set to 5 with an allowable range of ±3 to store products labeled 2–8. Freezer temperatures may vary and typically range from 25 to 10. Some frozen drug products, however, require lower temperatures, e.g., dry ice or liquid nitrogen temperatures.

Regular operating procedures and maintenance protocols should be in place along with written contractual agreements for all maintenance and evaluation procedures including the following:

Pharmaceutical manufacturers should consider primary, secondary, and tertiary packaging that best protects the drug product during storage and distribution. Package performance testing should be documented as part of a manufacturer’s QMS. Several standard test procedures are available for evaluating package performance for factors such as shock, vibration, pressure, compression, and other transit events. Organizations with standard test methods include the following: the American Society for Testing and Materials (ASTM) Standard Practice for Performance Testing of Shipping Containers and Systems, and the International Safe Transit Association (ISTA) specifications for various types of transit modes such as less-than-truckload, small package, rail car, and air freight.

It is important to be aware that removal or modification of the original packaging may subject the product to unacceptable conditions.

The packaging (tertiary or thereafter) for the distribution of the drug product should be selected and tested to ensure that product quality is maintained and to protect the contents from the rigors of distribution including environmental or physical damage.

All drug products have storage requirements that may contain specific controls. The container used for transporting the drug product should be qualified on the basis of the labeled conditions of the product as well as anticipated environmental conditions. Consideration should be made for seasonal temperature differences, transportation between hemispheres, and the routes and modes of transport.

The type, size, location, and amount of the temperature stabilizers required to protect the product should be based on documented studies of specific distribution environments including domestic and international lanes, mode(s) of transport, duration, temperature, and other potential environmental exposures or sensitivities that may impact product quality. Transportation container materials such as warm/cold packs and materials used to control temperature conditions should be properly conditioned before use. Barrier protection may be important in helping to determine the position of materials such as gel packs in order to avoid direct contact with the drug product. It should be determined if studies are required to ensure that the dry ice and its vapors do not adversely affect the drug product, including the drug product labeling.

Drug product transport systems should be continuously monitored by calibrated monitoring systems, (continuous verification), or shipping systems should be qualified and based on historical data relative to the process. However, it may be acceptable to use product stability data and supply chain risk assessment to justify shipping without either continuous monitoring or qualification of the shipping system.

Operational and performance shipping studies should on a generic level be part of a formal qualification protocol that may use controlled environments or actual field testing, depending on the projected transport channel. These studies should reflect actual load configurations, conditions, and expected environmental extremes. Testing should be performed on both active and passive thermal packaging systems.

Environmental conditions are important parameters to consider in the storage and distribution of all drug products and may require monitoring depending on the requirements. When specific storage conditions are required and transportation qualification has not been performed, and in the absence of active or passive containers, environmental recorders or devices should be used to confirm that an acceptable range has been properly maintained during each stage in the supply chain.

Temperature is one of the most important conditions to control, and requirements for each drug product should be based on stability data. Temperatures should be tracked using a monitoring system, and the monitoring devices used should be included in a calibration and/or preventive maintenance program. Environmental monitoring devices should be calibrated for their range of operation. The monitoring devices used should provide an alert mechanism if the preset ranges are breached. The following practices and controls are examples of appropriate measures that should be put in place to ensure environmental control (see also Monitoring Devices—Time, Temperature, and Humidity 1118):

The basis of any temperature mapping in a temperature controlled space (e.g., facility, vehicle, shipping containers, refrigerator, freezer) is the identification and documentation of a sound rationale used for a given mapping procedure. The temperature variability associated with mapped locations and the level of thermal risk to the product should be defined, unless another process has been put in place to ensure environmental control.

A temperature mapping study should be designed to assess temperature uniformity and stability over time and across a three-dimensional space. Completing a three-dimensional temperature profile should be achieved by measuring points at not less than three dimensional planes in each direction/axis—top-to-bottom, left-to-right, front-to-back, where product will be present.

When temperature mapping is necessary, it should begin with an inspection of the facility, equipment and/or vehicle and should be re-evaluated as appropriate. Environmental mapping also should be performed after any significant modification to the distribution system that could affect drug product temperature.

The mapping process will help determine when excursions could occur and are useful when pharmaceutical manufacturers develop a plan for dealing with them. Alarms should be used to reveal environmental excursions during operations. Temperature excursions for brief periods outside of respective storage label conditions may be acceptable provided stability data and scientific/technical justification exists demonstrating that product quality is not affected (see Health Canada’s GUI 0069 entitled, Guidelines for Temperature Control of Drug Products During Storage and Transportation, 2011).

The MKT is the single calculated temperature at which the total amount of degradation over a particular period is equal to the sum of the individual degradations that would occur at various temperatures. MKT may be considered as an isothermal storage temperature that simulates the non-isothermal effects of storage temperature variation. It is not a simple arithmetic mean.

The temperatures used for calculating MKT can be conveniently collected using electronic devices that measure temperatures at frequent intervals (e.g., every 15 minutes). MKT can be calculated directly or the data can be downloaded to a computer for processing. Software to compute the MKT is available commercially.

For dispensing sites, such as pharmacies and hospitals, where the use of such instruments may not be feasible, devices such as high-low thermometers capable of indicating weekly high and low temperatures may be employed. The arithmetic mean of the weekly high and low temperatures is then used in the calculation of MKT. MKT is calculated by the following equation (derived from the Arrhenius equation):

where Tk is the mean kinetic temperature; DH is the heat of activation, 83.144 kJ·mole–1 (unless more accurate information is available from experimental studies); R is the universal gas constant, 8.3144 × 10–3 kJ·mole–1·degree–1; T1 is the value for the temperature recorded during the first time period, e.g., the first week; T2 is the value for the temperature recorded during the second time period, e.g., second week; and Tn is the value for the temperature recorded during the nth time period, e.g., nth week, n being the total number of storage temperatures recorded during the observation period. [Note—All temperatures, T, are absolute temperatures in degrees Kelvin (K). ]

The holding of a drug may occur as part of storage and distribution practices. Drug products in the distribution supply chain may be held at temperatures outside their labeled storage requirements as determined by an appropriate stability study. Drug products stored either in warehouse conditions or in transportation modes may experience excursions from their acceptable temperature ranges. Each product excursion must be evaluated to determine the final product effect. The means of evaluation must be scientifically sound with documented technical justification that the integrity of the drug product has not been affected. One method of analysis for drug product stored outside its respective label storage conditions is the use of an MKT calculation.

Because MKT expresses the cumulative thermal stress a drug product experiences, it is considered an acceptable practice for storage, and it follows that it should be considered for transit excursions in the process of distribution. The calculation must be justified for use with distribution excursions by confirming that the stability limiting characteristic of the product follows first order kinetics over the temperature range encountered. The ICH stability-testing guidelines define MKT as a “single” derived temperature, which, if maintained over a defined period, would afford the same thermal challenge to a pharmaceutical product as would have been experienced over a range of both higher and lower temperatures for an equivalent defined period.

The MKT analysis must be based on good science and should take into account the integrity of the product. The calculated MKT is not sensitive to the impact of excursions that may occur if the baseline is a long period of time such as a storage segment or the entire lifetime of the drug product. For shorter baseline periods of time, such as transport segments, an excursion can have a significant impact on the resulting MKT for that segment; however, this would not necessarily have a significant impact on product quality.

The MKT analysis may be used for storage conditions that have exceeded the acceptable parameters for a drug product, for a short period of time and is not intended to be a measure for long-term storage.

Knowing the MKT for an excursion is useful for evaluating the potential impact on product quality. However, it is also essential to know the upper and lower temperature limits of any excursion. If these extreme temperatures are outside available stability data, it may not be possible to predict the quality impact of the excursion with any confidence regardless of the MKT. Although higher temperatures are given greater weight in the calculation, the calculation of MKT for nonfrozen product that becomes frozen for any amount of time may not result in an acceptable temperature although the product may not be adulterated. At higher temperatures the kinetics of degradation may change or new degradation reactions may occur; at lower temperatures (near freezing) a phase change may occur that is known to have a negative impact on the quality of some drug products (e.g., some proteins and vaccines). For an example of a calculation, see Pharmaceutical Calculations in Prescription Compounding 1160.