Chapter 39: Shipping and Distribution

A finished pharmaceutical’s labeling and/or pharmacopeia monograph provide specific directions for the temperature and humidity conditions of storage and shipment to the consumer, which is ultimately based on stability data. The United States Pharmacopeia (USP) General Notices section on preservation, packaging, storage, and labeling provides working definitions for the temperature ranges/storage devices designated as freezer, cold, cool, controlled cold temperature, room temperature, controlled room temperature, warm, excessive heat, and protection from freezing.

Warehousing/storage temperatures should be controlled and monitored using calibrated monitoring devices and records of temperature, and alarms, where applicable, should be maintained. Refrigerators and freezers used to store drugs should:

• Be well maintained

• Be equipped with alarms

• Be free from frost buildup

• When combined, be a two-door unit with separate freezer compartment and door

• Allow for adequate air distribution and orderly storage within the chamber; storage practices and loading configurations should not lead to the obstruction of air distribution

• Have sensors for continuous monitoring, and alarms located at the points representing the temperature extremes

If an alarm is associated with the refrigerator or freezer, the functionality of the alarm should be checked periodically at the upper and lower set points. Warehouses must undergo temperature profiling using a suitable number of temperature-recording instruments placed strategically (for example, based on sun-facing walls, ceiling height). Temperature profiles should occur at least over three consecutive 24-hour periods and during days of extreme outdoor winter cold and summer heat. Products should not be stored in areas shown by temperature mapping to present a risk.

The calculation of a mean kinetic temperature (MKT) is necessary for compliance with 21 CFR 203.32 “Drug Sample Storage and Handling Requirements” (part of 21 CFR 203 “Prescription Drug Marketing”). MKT is a single derived temperature that, 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. In other words, MKT is a calculated, fixed temperature that simulates the effects of temperature variations over a period of time. It expresses the cumulative thermal stress experienced by a product at varying temperatures during storage and distribution. The calculation of MKT is given in USP <1150> and usually requires 52 weeks of continual temperature monitoring or weekly high-temperature and weekly low-temperature recordings.

The formula for MKT is:

MKT = (–DH/R)/Ln{(SUM(exp(–DH/R × Tn)))/n}

Where

DH = Activation energy

R = The universal gas constant (0.0083144 kJ/molK)

T = The temperature in degrees K

n = The total number of (equal) time periods over which data are collected

Ln = The natural log

exp = The natural log base

Various temperature measurement technologies exist that are distinguished by their fragility and their measurement precision. USP <1118> describes several temperature measuring devices: alcohol or mercury thermometer, infrared (IR) device, resistance temperature detector (RTD), thermistor, thermocouple, data loggers, and time-temperature integrators (typically single use). Temperature and humidity monitoring devices should be calibrated at predetermined intervals. Single-use monitoring devices should be qualified.

Selection of a shipping container and/or box should be based on:

• Storage and transportation requirements of the drugs

• Space required for the amount of drugs to be transported

• Anticipated external temperature extremes

• Estimated maximum length of time required for transportation of the drugs, including any in-transit storage

Measures should be in place to prevent unauthorized persons from entering and/or tampering with vehicles and/or equipment and to prevent the theft or misappropriation thereof. Monitoring data recorded during vehicular transport should be reviewed upon receipt of the pharmaceutical products to assess maintenance of any special storage conditions. Any deviations from storage conditions that are considered to be acceptable (that is, small, brief excursions) should be determined in consultation with the marketing authorization holder and/or manufacturer.

At a port of entry into a country, consignments of pharmaceutical products should be stored under suitable conditions for as short a time as possible. All reasonable steps should be taken by importers to ensure that products are not mishandled or exposed to adverse storage conditions at wharves or airports. Where necessary, persons with pharmaceutical training should be involved with the customs procedures, or should be readily contactable.

Any counterfeit or suspected drugs found in the pharmaceutical supply chain should be segregated immediately from other pharmaceutical product. The marketing authorization holder and relevant competent authorities should be informed immediately.

21 CFR 211.132 requires over-the-counter (OTC) retail drug products sold in the United States (except a dermatological, dentifrice, insulin, or lozenge product) to have a tamper-evident (primary and/or secondary) package. Such a package has one or more indicators or barriers to entry that, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. Each retail package of a drug product having a tamper-evident feature(s) must bear a statement that identifies all tamper-evident feature(s) and any capsule sealing technologies, is prominently placed on the package, and is so placed that it will be unaffected if the tamper-evident feature of the package is breached or missing.