The U.S. FDA is very specific about defining an "adulterated drug." Chapter V of the Federal Food, Drug, and Cosmetic Act states that a drug is adulterated if the facilities or controls used for the manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current Good Manufacturing Practices (cGMP). "Holding of a drug" occurs when the drug is being distributed, transported, or warehoused. Additionally, Chapter III states that it is prohibited to introduce, deliver, or receive a drug that is adulterated.
The World Health Organization (WHO) Guidelines for the international packaging and shipping of vaccines is one of the most widely used manuals in the field. United Nations Children's Fund (UNICEF), Pan American Health Organization (PAHO), and countries that directly procure their vaccines refer to it in their invitations to bid for vaccine supplies. The 2005 edition of the guidelines includes information about stability, temperature monitoring, temperature limits for international shipments, transport-box bulking factors where insulated packages are used for storage, insulated packaging standards, storage volume standards, labeling, standard shipping and arrival procedures, guidance to confirm that packaging complies with WHO recommendation, shake-test protocol, and arrival report. The WHO "Good Distribution Practices for Pharmaceutical Products" states that "where special storage conditions (e.g., temperature and relative humidity) are required during transit, these should be provided, checked, monitored, and recorded." Additionally, "Temperature mapping of vehicles (where applicable) should support uniformity of the temperature across the vehicle. Recorded temperature-monitoring data should be available for review. Containers used for the storage and distribution of pharmaceutical products should not have an adverse effect on the quality of the products and should offer adequate protection from external influences, including bacterial contamination."
The temperature and humidity variations during shipping of drugs and vaccines have been demonstrated in studies conducted by the United States Pharmacopeia. Temperature excursions, humidity, light, and oxygen represent some of the risks associated with the complex distribution process of medicinal products. Establishing temperature profiles, defining controlled room temperature, storage at cool, cold, refrigerator, and freezing conditions are all presented in USP general Chapter <1079>, Good Storage and Shipping Practices. Thus, the complexities of the drug distribution chain and the regulations covering each section have been reviewed.
Canada's "Guidelines for Temperature Control of Drug Products during Storage and Transportation, Guide 0069," states: "Every activity in the distribution of drugs should be carried out according to requirements of the Food and Drug Act, the principles of Good Manufacturing Practice (GMP), good storage practice and good distribution practice."
The European Union's "Guidelines on Good Distribution Practice of Medicinal Products for Human Use, (94/C63/03)," indicate that "When specific temperature storage conditions are required, storage areas should be equipped with temperature recorders or other devices that will indicate when the specific temperature rate has not been maintained. Control should be adequate to maintain all parts of the relevant storage area within the specific temperature range." According to the Medicines and Health Care Products Regulatory Agency (MHRA), United Kingdom, 43% of all critical and major deficiencies recorded by the agency's Good Distribution Practice (GDP) inspectors during 2004–2005 related to the control and monitoring of storage and transportation temperatures. This is an increase from 36% from the time period of 2003–2004.
The Irish Medicines Board's "Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances," requires that "special storage conditions for active substances should be based on results from stability studies." In addition, "monitoring temperatures in storage facilities and during transportation using calibrated measuring devices is necessary in order to provide assurance that conditions are under control."
The "Australian Code of Good Wholesaling Practice for Therapeutic Goods for Human Use" states that "Controlled storage environments, e.g., deep freeze, refrigeration, should be monitored, using suitable temperature recording devices and the records reviewed and filed." The scope of the Australian standard, "Thermal Performance of Refrigerated Transport Equipment–Specification and Testing," covers the performance of insulated equipment fitted with any type of refrigeration system and intended for the transport of perishable products by road, whether as individual packages or as unit loads (e.g., palletized).
The "Good Wholesaling Practice for Wholesalers, Distributors and Bonded Warehouses, Medicines Control Council, Department of Health, Republic of South Africa," states that "Goods labeled or requiring refrigerated storage, where appropriate, are to be transported in insulating containers with ice or other cooling agents. Where appropriate, the transport packaging should be fitted with devices to detect exposure to conditions outside specific limits."
The imported medicines to be registered or authorized by the Bolivarian Republic of Venezuela, Ministry of Health and Social Development must follow several documents, including the specifications for the storage, handling, transport, and distribution of each product that must be kept in special conditions of humidity, temperature, protection from light, storage under nitrogen, cold chain, and other conditions, as the case may be.
The Brazilian National Sanitary Surveillance Agency states that "the registration owner must have a validated transport chain according to the stability characteristics of each product. The temperature records proving that imported lots have been kept under the conditions recommended in the product registration, so as to assure quality efficacy and safety, must be evaluated as part of the Lot Release Certificate."
The "Guidance Notes on Good Distribution Practices, Health Science Authority, Singapore," indicate that manufacturers, agents, traders, brokers, or distributors share important and distinctive roles and responsibilities to ensure that medicinal products are of the required quality for the intended use.
Austrian authorities require medicinal products that have to be stored under controlled temperature to be transported with appropriately validated means, according to the 479 th Decree of the Federal Minister for Health and Women Concerning Companies which Manufacture Medicinal Products, Control them, or Put Them into Circulation."
The PDA Technical Report No.39, Cold Chain Guidance for Medicinal Product: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment, is another attempt to address these regulatory issues.
