This general information chapter is intended to provide general guidance concerning storing, distributing, and shipping of Pharmacopeial preparations. It describes procedures to maintain proper storage environments for individual articles and to ensure a preparation's integrity, including its appearance, until it reaches the user. There is no change to any applicable requirements under Current Good Manufacturing Practices, approved labeling, state laws governing pharmacies, the USP General Notices and Requirements, or monographs. The section Preservation, Packaging, Storage, and Labeling under General Notices and Requirements provides definitions for storage conditions. All equipment used for recording, monitoring, and maintaining temperatures and humidity conditions should be calibrated on a regular basis. This calibration should be based on NIST or international standards (see Monitoring Devices—Time, Temperature, and Humidity 1118). A Pharmacopeial preparation may follow several potential routes from the original manufacturer to the patient. Figure 1 documents present-day routes and the associated risks. These risks include exposure to temperature excursions, humidity, light, and oxygen. For a discussion of climates, stability, and mean kinetic temperature, see Pharmaceutical Stability 1150. Temperature- or humidity-sensitive articles are to be handled in accordance with General Notices.

Most articles have storage conditions identified by their labeling. Otherwise, it is expected that the conditions for storing the article are specified in the monograph according to definitions provided by the General Notices and Requirements in the section Storage Temperature, and Humidity under Preservation, Packaging, Storage, and Labeling. In cases where additional information on packaging and storage is desired, a specific statement can be provided in the Packaging and storage or the Labeling section of the individual monograph.

Pharmacopeial articles are to be stored in locations that adhere to conditions established by the manufacturer. Where the desired conditions are not established, use storage conditions described in the General Notices and Requirements or in the applicable monograph.

Warehouses

establishing temperature profiles

controlled room temperature

storage at “cool,” “cold,” “refrigerator,” and “freezing” conditions

personnel training

qualification of “cold” equipment or stores

As indicated in Figure 1, a drug can take a variety of paths from the manufacturer to the patient. In the simplest form of the distribution system, the manufacturer ships directly to the customer, such as a doctor's office, clinic, or hospital. However, more often, the article leaves the manufacturer's chain of control and enters a complex system of handoffs that involve the distribution chain to the patient.

Figure 1. Drug product distribution.

Shippers and distributors are to follow the proper storage and shipping requirements as indicated by the manufacturer. For particular cases, such as shipment of vaccines or other special care products, manufacturers may require special shipping and storage conditions generally referred to as “cold-chain management”. For example, manufacturers may attach temperature-monitoring devices and/or ship under specified controlled conditions to ensure that the desired temperature is maintained during distribution (see Monitoring Devices—Time, Temperature, and Humidity 1118). Validated, available temperature- and/or humidity-monitoring technologies can be used to monitor the overall environmental effect on compendial articles during shipment and distribution. In these cases, the shipping conditions of the package are recorded. In general, extreme temperature conditions (i.e., excessive heat, freezing) should be avoided. Distribution systems chosen to deliver pharmaceutical products from the manufacturer to the consumer should take into account basic operational parameters, including timeliness and accountability. The manufacturer's FDA-approved storage conditions, printed in the labeling of the product, should be observed carefully at each destination of the distribution chain (see Figure 1), unless specifically instructed otherwise in the immediate label of a shipping container. This may be the case for certain pallet-sized shipping containers where the amount of refrigerant contained (e.g., dry ice, gel packs) is based on an anticipated exterior condition approximating controlled room temperature. In such cases, placing the shipping container in a refrigerator could lead to the product inside freezing, potentially affecting its quality. Items requiring special handling conditions will have those conditions clearly indicated in the labeling for the product. The Prescription Drug Marketing Act of 1987 and the ensuing regulations in 21 CFR Part 203, Prescription Drug Marketing, and Part 205, Guidelines for State Licensing of Wholesale Prescription Drug Distributors, provide the necessary regulations and guidance for several legs of the distribution chain for the prescription drug. The manufacturers and distributors should work together to establish proper distribution and product-handling requirements for the purpose of ensuring appropriate product maintenance in transit. Pharmacists and physicians should educate patients regarding proper storage of products to ensure product integrity at the patient level. Information that may be considered in determining the ability of pharmaceutical articles to maintain their Pharmacopeial requirements of identity, strength, quality, and purity through the distribution channel may include, but is not limited to the following: ICH stability studies, temperature cycling studies, stability shipping studies, ongoing regulatory stability commitment studies, market experience portfolio (i.e., product complaint files, historical product performance data, product development data), and product labeling commitments.

Qualification Protocol

Physical Challenges

Temperature Challenges

Materials

Certain classes of Pharmacopeial articles may require special handling. Such articles include products classified as dangerous goods under the Department of Transportation (DOT), state, local, or carrier rules; or products classified as controlled substances by the Drug Enforcement Administration (DEA) or by individual states.

Receipt of Pharmacopeial Articles

Distribution or Shipping Vehicles

Vehicle Qualification

Pharmaceutical Delivery Staff

Wholesaler

Compromised Temperature Conditions

Pharmacy

Compromised Temperature Conditions

The pharmacy should provide an appropriate label on the package sent through air or surface routes so that the deliverer does not place the package in a mailbox exposed to extremes in temperature. In the event that no one is available to receive the package, the deliverer should return the package to the post office or service office, and store it in a cool or air-conditioned area until the patient can receive the medication. In the event that the package has not been delivered for more than 2 days, the package may be returned to the pharmacy. For temperature-sensitive articles, it is important that proper arrangements be made to protect the drug from exposure to high temperatures, or in some cases, from freezing conditions. Such arrangements may include the following: insulating the packaging, or packaging with coolant included; overnight shipping; and pre-arranged pick-up. In such cases, the pharmacy should provide on the external package a statement of an acceptable period of delay for delivery. The patient or customer should examine the delivery documentation to ensure that the package has not been subjected to any unacceptable delays during shipping and distribution. The patient or customer receiving the pharmaceutical articles, either by mail, delivery vehicle from the pharmacy, or directly from the physician or pharmacy, should be advised that upon receipt the articles are to be transferred to appropriate storage conditions without delay, as directed by the pharmacy, ideally within 2 hours of receipt. The vehicle used for air or surface shipping and distribution of pharmaceutical packages to the patient or customer, especially those requiring low temperatures, should contain the article suitably packaged in containers that maintain the desired storage conditions until the article reaches the patient or customer. The vehicles used for shipping and distribution of pharmaceutical articles to patient or customer, especially those requiring storage at room or controlled room temperatures, should be suitably equipped during extreme temperature conditions such that the packages are not exposed to extremes of temperature either in winter or summer months. In the event that the vehicle is not adequately equipped with air conditioning or heating to protect the product, the time that the article is exposed to ambient conditions should be strictly limited, ideally not more than 2 hours. Where appropriate, a monitoring device may be used to ensure that required temperatures are maintained until the package reaches the patient or customer. If stability studies for the Pharmacopeial preparation indicate that it is particularly sensitive to environmental insults or if appropriate shipping safeguards described in this section are not feasible, then the preparation should be shipped by a different method whereby environmental control can be maintained.

Compromised Temperature Conditions

The wholesaler, manufacturer, and pharmacy personnel should evaluate the validity of the request for return, and maintain an auditable account of the return receipt. For products in unopened manufacturer's containers that have been at variance during shipment, arrangement may be made to return the products to the manufacturer, wholesaler, or pharmacy preferably within 3 working days of receipt. The supplier may request records or written confirmation by the patient to show that the product was stored properly while in possession of the customer.

Storage of physician samples by sales representatives is regulated under 21CFR 203.34(b)(4); each manufacturer or distributor is to have appropriate policies in place to ensure that proper storage is maintained. The following suggestions may be considered in response to this need and are of interest to practitioners who may observe actual practices. Automobile trunks or passenger cabins used for the storage and distribution of physician samples should be monitored to determine the temperature profile of the trunk or passenger cabin. Suitable monitoring devices as determined by the sales representative may be placed in different areas of the trunk or passenger cabin on a hot summer and a cold winter day. Measurements should also be made during typical 24-hour periods, and the derived temperature should be used for calculation of the mean kinetic temperature at which the sample is stored (see Pharmaceutical Calculations in Prescription Compounding 1160 for examples of MKT calculations). If the Pharmacopeial article designated for storage requires storage at controlled room temperature, then suitable measures should be taken to maintain the sample within the allowable limits of the storage parameters. Environmentally-sensitive preparations should not be stored in automobile trunks or passenger cabins. Medications stored in automobile trunks or passenger cabins should be removed at the end of 3 days. Sales representatives should consider parking automobiles in shaded areas to avoid extreme heat during the summer and in garages to avoid freezing temperatures during the winter. The use of vouchers from the manufacturer that patients could use to obtain medication samples from participating pharmacies is an alternative way of providing drug samples.

The design of stability studies of Pharmacopeial articles is based on knowledge of the behavior, properties, and stability of the drug substance and experience gained from clinical formulation studies.1 The length of the studies and the storage conditions for a Pharmacopeial article should be sufficient to cover storage, shipment, distribution, and subsequent use of a Pharmacopeial article. The data gathered from ICH accelerated testing or from testing at an ICH intermediate condition may be used to evaluate the effect of short-term excursions outside the label storage conditions such as those that might occur during shipping. See Pharmaceutical Stability 1150.

Storage statements should be based on the stability evaluations of the Pharmacopeial drug substances and in accordance with national and international requirements.