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Temperature fluctuations during mail order shipment of pharmaceutical articles using mean kinetic temperature approach
Abstract
The objective of this study was to determine, during one summer, the extent of temperature and humidity variations to which drugs moving through mail-order distribution may be subjected. In order to record temperatures and humidities experienced by packages during mail-order distribution, indicator-assisted temperature and humidity monitoring devices were packaged and shipped to different parts of the country. Upon .return of the packages, the mean kinetic temperature (MKT) was calculated. Results of the study show that only 8.4% of the packages experienced temperature variations within the excursions allowable under the USP definition of controlled room temperature. The remaining packages were exposed to temperatures above the accepted excursion range. Results obtained also show that, while 65.5% of the packages experienced warm (30° to 40°) conditions during shipment, the remaining 26.1% experienced excessive heat (above 40°) conditions. Additionally, MKT calculations show that 31.1% of the packages had MKT values above 25.0° for periods of 19 to 21 days. Significant spikes in relative humidity also were experienced. The study demonstrates the need for a standard definition of "spike" for cautionary labeling, and a possible need for requiring that temperature devices accompany selected medications. © 1997 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
... This issue can be solved only if the kinetics of the deterioration or inactivation process can be merged with the time/temperature profiles recorded by data loggers. Application of the MKT concept for more complicated temperature profiles is described in the papers of Okeke at al. [33,34]. ...
The evaluation of the shelf life of, for example, food, pharmaceutical materials, polymers, and energetic materials at room or daily climate fluctuation temperatures requires kinetic analysis in temperature ranges which are as similar as possible to those at which the products will be stored or transported in. A comparison of the results of the evaluation of the shelf life of a propellant and a vaccine calculated by advanced kinetics and simplified 0th and 1st order kinetic models is presented. The obtained simulations show that the application of simplified kinetics or the commonly used mean kinetic temperature approach may result in an imprecise estimation of the shelf life. The implementation of the kinetic parameters obtained from advanced kinetic analyses into programmable data loggers allows the continuous online evaluation and display on a smartphone of the current extent of the deterioration of materials. The proposed approach is universal and can be used for any goods, any methods of shelf life determination, and any type of data loggers. Presented in this study, the continuous evaluation of the shelf life of perishable goods based on the Internet of Things (IoT) paradigm helps in the optimal storage/shipment and results in a significant decrease of waste.
Temperature, humidity, and motion can affect the stability of pharmaceutical products during transportation and storage. The authors propose that manufacturers and distributors study the environmental conditions that a product is likely to encounter and use these measurements to determine acceptable temperature ranges for shipping and to select temperature-appropriate packaging for the product.
This paper describes a model for a systematic process to address the growing needs for the transparent control of high quality distribution of life science products which require special handling.
Current global regulatory and compendial guidances indicate the need for pharmaceutical manufacturers and all of their partners such as distributors, carriers, and wholesalers to monitor, document, and confirm with data that the quality and integrity of temperature-sensitive product has not been compromised in any part of the supply chain. This article will assess the regulatory environment, monitoring devices, collection and management of data, and a proposed quality system for Good Cold Chain Management Practices (GCCMP).
This article describes the product distribution pathway utilized when a drug product is shipped from the manufacturer to the end user or patient. This pathway outlines the critical control points during distribution, and these points create the basis for certain risks encountered by drug products. The USP Project Team has identified the critical points and risks associated with each point. The risks were analyzed using Hazard Analysis and Critical Control Point (HACCP) tools adopted by FDA's Center for Food Science and Nutrition (CFSAN), and these risks were categorized as low, medium, or high. High-risk areas are the subject of this Stimuli article. © 2003 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Members of the pharmaceutical supply chain have various global regulatory requirements to meet while handling, storing, and distributing environmentally sensitive products. Their focus is to provide cold chain management for temperature sensitive pharmaceuticals to ensure that the quality and efficacy of the product will not be compromised. This article reviews the increased importance of pharmaceutical cold chain management as a result of changing product portfolios, the requirements for Good Storage and Distribution Practices, current regulatory trends, quality management, risk assessment factors, and temperature monitoring. Trends include: ? Responsibility for cold chain management ultimately resides with the manufacturer ? Increased oversight, management, and control of environ mental conditions across the entire supply chain (from manufacturer to consumer/patient) ? Increased importance of temperature control and monitoring to mitigate and identify risks ? Heightened priority of patient safety Due to the presence of multiple uncontrolled variables in the distribution process, developing an appropriate temperature and humidity monitoring program is essential to protect the quality of environmentally sensitive pharmaceutical product and ensure patient safety.
USP-NF is in continuous revision and the Packaging, Storage and Distribution Expert Committee welcomes comments in the area of drug packaging, storage, and distribution. USP continuously encourages public participation in its process of establishing public standards. Comments and suggestions can be submitted to USP, Information and Standards Branch, 12601 Twinbrook Parkway, Rockville, MD 20852.
Vaccines are a major contribution to public health, and to preserve their stated potency, proper storage of vaccines and establishment of an effective distribution channel that maintains recommended storage temperatures are essential. Because it is the concern of USP to ensure that the quality, strength, and integrity of all pharmaceutical articles, including vaccines, are maintained, the USP Subcommittee on Packaging, Storage and Distribution, in collaboration with the United States Army Medical Materiel Agency (USAMMA), evaluated data from USAMMA shipments of anthrax vaccines throughout the United States and some selected areas outside the United States for the March to October 1998 period. USAMMA used temperature-monitoring devices or temperature-humidity monitoring devices during shipment. Of 520 shipments with TempTale time-temperature indicators, 393 shipments (about 75.6%) were maintained at average temperatures within the refrigerator temperature range (between 2° and 8°) recommended for anthrax vaccines. The temperature spikes above 15°, that is, outside the refrigerator and cool temperature ranges, were encountered. Results show that while the average temperature per trip did not exceed 25°, temperatures as high as 25° were recorded during some of the trips and 1.15% of the packages experienced temperatures higher than 25.0°. All recorded humidity values were within the allowable range. All shipments in containers with built-in temperature-monitoring devices remained within the allowable temperature range. It is clear from the data that maintenance of recommended storage temperatures during shipment and distribution for most vaccines may be difficult, even under a carefully designed system of shipment and distribution. Therefore, the use of some type of temperature-monitoring device may be necessary. © 2000 The United Stales Pharmacopeia! Convention, Inc. All Rights Reserved.
This article provides information about currently available multiple- unit packaging materials, demonstrates why firms may need to change methods of selecting and qualifying containers to meet new standards, and describes the chemical and physical properties of these components and materials. This information applies to pharmaceuticals and nutritional supplements.
The US Pharmacopeia gives recommendations for the storage of pharmaceuticals in terms of mean kinetic temperature (MKT). This study's goal was to determine if color-changing time-temperature indicator (TTI) labels can reliably monitor the MKTs of medications used in ambulances. TTI labels and miniature electronic temperature recorders were placed into the drug storage boxes in five advanced life support units over 12 summer weeks in 1995 and in three advanced life support units over 4 weeks the following winter. The electronic temperature recorders measured temperatures several times per hour, and the color changes of the TTI labels were analyzed periodically. The MKTs calculated from the TTI labels differed from those calculated from the electronic temperature recorders in all cases by less than 1°C. The authors concluded that TTIs can accurately measure the MKTs of medications used in ambulances. A TTI label on each medication container may help insure that drugs are not damaged by temperature conditions.
Temperature excursions during pharmaceutical product storage and distribution may present a risk to product quality. What if any risk to product quality is associated with relative humidity excursions encountered during storage and distribution? This question was the subject of a 2009 Romanian regulation (since withdrawn) that would have required monitoring of humidity conditions during transport of medicines. This Stimuli article readdresses this question by examining the protective properties provided by various types of primary packaging using a validated moisture-vapor transfer model. The information presented here is relevant to topics discussed in Good Storage and Shipping Practices <1079> , Monitoring Devices-Time, Temperature, and Humidity <1118> , and other general chapters that address pharmaceutical product storage. Future revisions to these chapters may benefit from the information presented in this Stimuli article.
Purpose: This multicenter study was designed to determine whether current Emergency Medical Services (EMS) medication storage practices meet USP controlled room temperature standards and, if not, whether a simple inexpensive intervention adequately addresses the problem. This study represents the first broad-based collaborative effort of USP, multiple EMS agencies, and EMS researchers to evaluate this issue. Methods: Forty-five TempTale®3 temperature monitors were placed on 15 EMS vehicles in 5 geographically and meteorologically diverse U.S. cities. On each ambulance, a monitor was placed in the vehicle's medication storage compartment, in the medication bag, and in a simple insulated cooler. Temperatures were recorded every 32 minutes for 363 days. Analysis included calculation of the mean kinetic temperature (MKT), the occurrence of temperature readings below 15 °C and above 40 °C, and the duration of temperature spikes between 30 °C and 40 °C. Results: The MKT exceeded 25 °C on 4 vehicles, in 6 medication bags, and in 4 coolers. The duration of temperature spikes between 30 °C and 40 °C exceeded 24 hours on 6 vehicles, in 9 medication bags, and in 6 coolers. Temperatures exceeded 40 °C on 6 vehicles, in 5 medication bags, and in 5 coolers. No vehicle, medication bag, or cooler at any site experienced temperatures that were totally consistent with the USP recommendations: 10 (66%) of the ambulances and 4 (80%) of the sites experienced excessive heat, and every TempTale®3 sensor recorded temperatures below 15 °C. Conclusion: EMS medications are not stored in environments consistent with the USP definition of "controlled room temperature," and employing a simple insulating cooler does not adequately attenuate the temperature extremes. ©2003 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
The expansion of distibution pathways by emerging technologies has heightened the expectations of those involved in the area of drug storage and transportation. Medicines are now transported to remote areas of the world. Some of these medicines include HIV medications that may require refrigeration or special handling. Added to this, advances in healthcare treatment have allowed the use of complex biologics and proteins, as well as specialized compounded preparations such as biiodegradable hormone therapy that require special handling and specific storage methods. Because of these factors, the temperature and humidity to which these complex active medicines are exposed need to be critically studied and evluated because damage to these medicines could become irriversible and expensive. This article discusses the past and present activities of United States Pharmacopeia in the area of cold chain management with emphasis on appropriate methods of handling, storing, and shipping of these medicines.
This paper describes two calculation methods for estimating the amount of refrigerant required to maintain the temperature inside a small insulating container within a desired range under cyclic temperature conditions. The first calculation method is for a phase change material (PCM) that absorbs and releases heat by melting and solidifying. The PCM used in this study had a phase change temperature of 23.5°C (74.3°F). An equation for estimating the amount of the PCM required under cyclic conditions is shown. Test packages were constructed to meet USP Controlled Room Temperature (CRT) requirements. Several cyclic tests were conducted with the calculated amount of PCM in the test packages. The results showed that the calculated amount of PCM did maintain the inside temperature within the range 21.4–25.8°C (70.5–78.4°F) throughout the tests. This range met the USP CRT requirement. The second calculation method is for unfrozen gel packs that absorb and release heat by changing temperature. The amount of unfrozen gel pack required to maintain temperature within the USP range was calculated. Several cyclic tests were conducted with the calculated amount of gel packs. The calculated amount was enough to meet the USP requirement. Good agreement between the experimental and calculated temperature profiles was also found. Copyright © 2006 John Wiley & Sons, Ltd.
Although these recommendations have been produced by the Medicines Control Agency in response to interest from the pharmaceutical industry and wholesalers, they are relevant to the storage of medicines in community pharmacies, hospitals and clinics M edicinal products and starting materials used in the manu-facture of medicinal products should be stored and trans-ported under conditions which ensure that their quality is maintained. Manufacturers' recommendations concerning storage tem-peratures should be observed and this may involve the use of specialised storage and transport facilities. Temperature-monitor-ing devices should be used to demonstrate compliance with the designated tempera-ture ranges. The distribution chain is seldom simple and distribution systems can vary enor-mously. In its simplest form, the chain in-volves shipment direct from the manufacturer to the customer or end user. In its more complex form, the distribution chain may involve a number of storage and transit locations, including airports and docks, and a variety of transport facilities, including aircraft. Good warehousing and distribution practices 1 require that storage areas for medicines should be maintained within ac-ceptable temperature limits and that, where special storage conditions are specified by the manufacturer, these should be provided, checked and monitored. Measuring and monitoring equipment should be calibrated and checked at defined intervals. Medicinal products should be transported in such a way that they are not subjected to unaccept-able degrees of heat and cold, and spe-cialised means of transportation should be used where necessary. There have been a number of open sem-inars and conferences on this subject in re-cent years. The Medicines Control Agency (MCA) has published guidelines for the pharmaceutical industry 2 and the British As-sociation of Pharmaceutical Wholesalers has introduced a protocol for its members. 3 This article provides additional advice for the control and monitoring of temperatures during the storage, shipping and distribu-tion of medicinal products. CONTROLLED LOW TEMPERATURE STORAGE The cold chain The cold chain encompasses all the storage and transport facilities neces-sary to ship a product requiring controlled low-temperature storage from the manufac-turer to the end user. In some circumstances (such as the manufacture of a product con-taining a temperature-sensitive active ingre-dient), the cold chain may also include the storage and shipping of active pharmaceuti-cal ingredients used in the manufacture of the product. At every point in the chain pre-cautions should be taken to minimise the ef-fect of adverse external conditions on the quality and stability of that product. Where relevant, records should be maintained to provide evidence of compliance with the la-belled storage recommendations for those in whose care the product is at the time and to other interested parties who may seek this assurance, such as the recipient and/or mar-keting authorisation holder. There are an increasing number of medicinal products requiring controlled storage and transit conditions. Among the cold-chain items are high-risk products such as vaccines, insulins, blood products (such as Factor VIII) and other proteinaceous mate-rials, which normally require storage be-tween 2C and 8C. These products must be protected from freezing; even a brief period at sub-zero temperatures can irreversibly denature the protein, leading to a loss of ef-ficacy. There are also products such as emul-sion systems and solutions of sparingly solu-ble components which can become physically unstable at sub-zero tempera-tures. Before setting up a cold storage facility or transport system, or before taking on a new range of products, it may be useful for distributors to carry out a risk analysis to es-tablish a list of high, medium and low risk products and to make apropriate arrange-ments for their handling.
This paper reviews contemporary trends in the stability testing of pharmaceutical products. In particular, it considers the progress toward globalization and harmonization and indicates stability problems, which probably will be the focus of attention for pharmaceutical scientists and regulators in the near future. Attention is specifically directed to monitoring stability in the channels of distribution.
The United States Pharmacopeia recently published a general chapter specifically addressing on-ambulance storage of medications, including a suggestion for stock rotation. This study describes the effectiveness of a simple stock rotation strategy in mitigating EMS medication exposure to excessive heat and cold. Previously collected on-ambulance temperature data from 5 US cities were randomly resampled to generate model exposures of 2 days to 6 months duration. The temperature measurements for every other 24-hour period were then set at 20 degrees C to model the rotation of medications into a controlled environment. For each model, we then determined consistency with the official United States Pharmacopeia definition of controlled room temperature. Without stock rotation, excessive heat occurred in 39.9% of the model exposures. With stock rotation, exposures to excessive heat occurred in less than 1% of northern city models and in 2.9% of the central US models. Stock rotation did not reduce heat exposures in the models for southern cities.
The purpose of this study was to report methods currently recommended by commercial laboratories for collecting, shipping, and processing of samples for feline herpesvirus type 1 (FHV-1) testing using polymerase chain reaction (PCR) and to determine the effect of temperature and time on the ability of 1 PCR method to detect FHV-1 DNA in experimental and clinical samples. Eleven laboratories offering FHV-1 PCR were surveyed. There was notable variation in sample types and shipping conditions recommended and PCR protocols used by these laboratories. Subsequently, using a single PCR method, FHV-1 DNA was detected in samples exposed to various temperatures within the laboratory. Finally, FHV-1 PCR was performed on paired clinical samples collected from 25 cats and shipped at ambient temperatures via US Postal Service (USPS) or with an ice pack via a courier. Samples sent by USPS were exposed to significantly longer transit time and arrived at significantly higher temperature than did samples sent by courier. Despite this, all sample pairs yielded concordant results when tested for FHV-1 DNA using this PCR method. Although it may not be necessary for samples collected for detection of FHV-1 DNA using this PCR method to be shipped under the most expedient or temperature-controlled conditions, this should be verified for a variety of PCR assays and sample types.
The transit temperature profiles, mean kinetic temperatures (MKTs), and stability of insulin samples in both insulated and noninsulated containers exposed to summer and winter temperatures were evaluated.
Regular insulin, isophane insulin human (NPH) insulin, and 70% isophane-30% regular (70/30) insulin were packaged in the most commonly dispensed quantity of four vials in noninsulated mailers and insulated containers with frozen gel packs. After packaging, sealed containers and mailers were placed in an environmental chamber for 24-120 hours and exposed to summer and winter transit conditions. Temperatures inside the environmental chamber were recorded every 15 minutes and maintained within 3 degrees C of the specified transit temperature. After exposure to the transit conditions, insulin cartons were removed from their packaging, visually inspected for changes in physical appearance, and stored at 4 degrees C until analysis. The MKT of each package was calculated. High-performance liquid chromatography was performed to determine sample stability, and size-exclusion chromatography was conducted to detect aggregate products of insulin.
Regardless of shipping conditions or packaging, all samples met the United States Pharmacopeia's ( USP's) specified limits and retained product stability. Visual inspection of the physical appearance of insulin samples before and after temperature exposure revealed results similar to those described in the product inserts. Microscopic analysis of the injectable suspensions confirmed similar crystal morphologies before and after temperature exposure.
Regular, NPH, and 70/30 insulin maintained potency within USP limits when stored in programmable environmental chambers simulating summer and winter overnight or three- to five-day ground delivery conditions, regardless of packaging material.
The effects of packaging and storage in multiple-unit and unit-dose containers on dissolution rate of model prednisone tablets are reported. USP Prednisone Dissolution Calibrator Tablets were packaged in three multiple-unit and five unit-dose containers. Packaged tablets were stored for three to six months under three conditions: 40 degrees C and 85% relative humidity (R.H.), 37 degrees C and 75% R.H., and 22 degrees C and 75% R.H. Dissolution rate was measured at pre-determined intervals during storage. For each condition tested, two separate runs of six tablets each were performed. Tablets in the least moisture-permeable containers were least affected by storage. The conditions of high heat and humidity caused the greatest change in dissolution rate. When stored at 22 degrees C and 75% R.H., little change in dissolution rate occurred in any packaged tablets. It is concluded that packaging and storage conditions affect tablet dissolution characteristics markedly. The practice of labeling repackaged tablets with the expiration date of the original container is shown to be invalid.