Professionals who design and qualify insulated packaging for temperature-sensitive medicinal products continually face the challenge of developing solutions that suit the environmental hazards within the actual distribution system. Exposure to extremes in temperature poses a significant environmental hazard. Without the proper thermal protection for the duration of distribution, product exposure to repeated variations in temperature could result in excursions to temperatures within the package that could compromise drug quality and efficacy.
There has been a significant increase in regulatory oversight and pharmacopeial standards for medicinal products that have broadened to include proper handling, storage, and distribution as an extension of their manufacturing. Global regulators appear to expect that supply-chain integrity must be maintained from the drug manufacturer through to, and including, the end-user.
Given the importance of good pharmaceutical cold-chain management and the plethora of regulatory requirements for storage and distribution, industry needs guidance for establishing meaningful temperature profiles for medicinal products in distribution.
This article is intended to provide a comprehensive, systematic approach to monitoring the distribution environment, formatting a protocol for environmental data collection, and converting data into a representative, risk-assessed distribution temperature profile with multiple confidence intervals. This information can be applied as part of an overall validation process for the development and qualification of packaging for temperature-sensitive medicinal products consistent with current regulatory expectations.
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 (cGMPs). “Holding of a drug” occurs when the drug is being distributed, transported, or warehoused.1 Additionally, Chapter III states that it is prohibited to introduce, deliver, or receive a drug that is adulterated.2
The World Health Organization (WHO) Guidelines on the International Packaging and Shipping of Vaccines is one of the most widely used manuals in the field. United Nations Children’s Fund, Pan American Health Organization, 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 recommendations, the shake-test protocol, and the arrival report.3
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.”4
The temperature and humidity variations during shipping of drugs and vaccines have been demonstrated in studies conducted by the United States Pharmacopeia (USP).5,6,7,8 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, and storage at cool, cold, refrigerator, and freezing conditions are all presented in USP General Chapter <1079>, Good Storage and Shipping Practices.9 Thus, the complexities of the drug distribution chain and the regulations covering each section have been reviewed.10
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.11
For additional regulations on maintaining product efficacy during storage and distribution from around the world, please visit http://www.pmpnews.com/article/supply-chain-management-supplement-appendix for the Supply-Chain Management Supplement Appendix.
PROPERLY ENGINEERED COLD-CHAIN PACKAGING
A properly engineered package must meet multiple requirements that include the following essential criteria:
- Transport packaging must contain the product in such a manner as to effectively protect it from distribution hazards. This is highly influenced by the products’ nature and its physical characteristics.
- The primary and secondary packaging can have an aggregate effect on its resistance to repetitive shock, rotary motion and vertical vibration, light, humidity, mechanical handling, and temperature.
- Packaging configurations should optimize all available space and dimensional limitations and provide for efficient assembly, handling, storage, shipping, and disposal.
- Packaging should elegantly utilize the most-efficient materials and be sensitive to raw material and transportation costs and availability, so as not to interrupt the time-sensitive nature of pharmaceutical product deliveries.
- In the case of temperature-sensitive-product transport packaging, there is one additional important consideration. The package must contain a performance component. It must be engineered in such a way as to capture the aforementioned design elements with the addition of regulating a specified temperature range for the duration of transport.
“General Principles of Process Validation” from FDA’s Center for Drug Evaluation and Research (CDER) is the process most commonly applied to developing packaging.12 Unfortunately, packaging and distribution do not fall neatly into CDER’s Installation Qualification/Operating Qualification/Performance Qualification (IQ/OQ/PQ) definition, as they were not intended to be elements of that process. Since no other process has been established, the industry and PDA’s Pharmaceutical Cold-Chain Discussion Group Technical Report No. 39 use it as current best practice, although slightly modified to a CQ/OQ/PQ process.13
CDER’s “General Principles of Process Validation” requires the following:
- Component Qualification (CQ; covers materials and components in controlled manufacturing that meet specifications). Manufacturers must establish “confidence that ancillary components are capable of consistently operating within established limits and tolerances.”
- Operating Qualification (OQ; covers repeatable testing in a controlled environment with limited variability inputs). Manufacturers must establish “confidence that the process is effective and reproducible.”
- Performance Qualification (PQ; covers real-world shipments through an uncontrolled distribution system). Manufacturers must establish “confidence through appropriate testing that the product produced by a specified process meets all release requirements for functionality.”
When the criteria of a CQ/OQ/PQ process are successfully met, the packaging is considered qualified and the entire process is considered validated.13
UNDERSTANDING YOUR DISTRIBUTION CHAIN
You must thoroughly understand the nature and extent of the hazards within the distribution environment through which the product must travel.14 Understanding the distribution process and knowing the limits of environmental exposure will result in designing, developing, and implementing effective and efficient packaging by maximizing performance while minimizing costs.
There is no hard-and fast-rule or universally accepted guidance on how to develop temperature test profiles. The methodology and subsequent profiles developed from those methods vary widely throughout the pharmaceutical industry.
The International Safe Transit Association (ISTA), a multimodal transportation industry advocacy group, has published numerous performance tests for packaged products. These include two that address thermal performance: Procedure 5B—Focused Simulation Guide for Thermal Performance Testing of Temperature Controlled Transport Packaging, and: Procedure 7D—Thermal Controlled Transport Packaging for Parcel Delivery System Shipment.
Both of these procedures provide valuable and detailed testing methodology for the effects of transportation on packaged product (repetitive shock, rotary motion vibration, and drop). However, only general guidance for individual and comparative analysis of insulated transport packages is provided. The tests are, by ISTA’s own admission, “a general starting point” and not intended to represent anticipated extremes to thermal exposure.15 These procedures are limited in their scope in that they are used to establish acceptable performance parameters in the expedited small-parcel delivery environment common in U.S. distribution. They are not detailed enough to address specific circumstances and concerns inherent in the global distribution of medicinal products. For example, the profiles are limited to 24-, 48-, and 72-hour cycles, those most common in expedited freight delivery. The ambient-temperature-profile examples represent “some generally recognized ambient temperatures and time ranges that occur.”16
There has been a proliferation of temperature data generated in recent years by various pharmaceutical manufacturers, resulting from the change in drug manufacturing, which has largely gone from intraplant to international. It is not uncommon for a drug to go from active pharmaceutical ingredient to finished product in multiple steps through multiple countries. In addition, with temperature data loggers becoming far more precise and reliable, not to mention necessary, most pharmaceutical companies employ frequent use of them to monitor the movement of temperaturesensitive cargo as a means of documenting control throughout manufacturing and distribution. Here again, the data collected in international distribution differ from the U.S. small-parcel distribution system as the distribution models can be quite different. For these reasons, ISTA strongly recommends “that the user determine the applicability of any temperature cycle or ramp prior to use.”15
In order to design an appropriate cold-chain system and to minimize the risk of damaging product during transit, distributors of temperature-sensitive materials must develop a temperature profile that adequately challenges their designed shipping container and process. Temperature profiles need to encompass not only the distribution process, but also the different types of containers and products.
IDENTIFYING DISTRIBUTION VARIABILITY
Often overlooked or not considered is distribution variability. It includes (but is not limited to) delays in delivery, differences in handling practices, various global distribution models, seasonal and hemispheric variation, varying modes of transport, ship-to and ship-from locations, and time-of-day pack-outs. These are necessary elements to consider when performing a gap analysis on a distribution environment. They have a direct influence on the development of a temperature profile.
The longer the product is stored at uncontrolled conditions, the greater the risk to the product. In order to mitigate the risk, pharmaceutical organizations need to understand the complexity of the pharmaceutical distribution chain. In order to fully understand how specific distribution and storage segments operate, there are a multitude of people and processes to factor—from the number of contractors and subcontractors involved in handling the products to the wide range of storage times. For instance, European regulators are now defining storage times above 36 hours as long-term storage.17 When carriers do not follow or are not aware of specific handling requirements, the shipments run a high risk of exposure to adverse conditions. One manager of logistics stated, “Our experience with carriers includes highlights such as carriers leaving temperature-sensitive materials outside at –20°C when they were told to avoid freezing and when the containers said to avoid freezing.”18
Because of the cold chain’s complicated situations, no two temperature profiles are ever alike. “Shipping of temperature-sensitive articles requiring thermally controlled packaging presents a special challenge. Unlike shock, vibration, and other physical hazards, thermal hazards tend to be unique to a given system,” as mentioned in USP General Chapter <1079>.9 Thus, with continuous temperature monitoring, organizations have the ability to know exactly the temperatures across the cold chain and receive undisputed data of the environments through which the products have traveled. Furthermore, continuous monitoring provides information on the actual conditions and quality of the transported pharmaceutical articles.
The following factors are critical when working to minimize variability of storage, handling, and distribution:
- Customs. Pharmaceutical products do get held up during inspection at customs. Delays of up to two weeks in shipping to countries outside of North America are experienced. “Even though assurance was given that the material was kept in a refrigerator during this time, at 2°C to 8°C, it was discovered later that the temperatures actually fluctuated as high as 18°C.” 18
- Hemispheric, climatic, and seasonal variations. The time of year shipments are made is critical. Products that are shipped internationally often travel through different hemispheres and climates. For instance, it is highly possible that a pharmaceutical may originally ship out of the warm climate of India, have the product repackaged in the winter frigid weather of Canada, yet end up in the tropical heat of Florida—all within a week’s time (that is, if there are no delays at customs). Thus, the shipment has been exposed to warm and possibly freezing temperatures before it gets to its final hot-weather destination. The product, packaging, and shipments all will need to effectively manage extreme temperature variation.
- Modes of transport. When transporting shipments via van and truck—between distribution centers or to and from the airport—it is important to know what specific temperatures will be experienced. For instance, if shipping from a cold winter climate, such as Canada, temperatures can dip down to –20°C. These same freezing temperatures could be experienced on the back of the truck. If temperatures on the back of the truck are expected to be this extreme, it may be best to transport the pharmaceutical products with a heated trailer, instead of a refrigerated trailer.
A significant problem for transporting product between trailers and airplanes is the staging area. Typically, carriers will need to stage freight outside of the aircraft for a period of several hours before loading onto the aircraft, which can be a problem in extreme climates. Shipments may be staged on a ramp sitting outside in the winter, which often occurs at smaller airports. Manufacturers often assume their shipments are maintained at the courier’s warehouse or hub. These holding areas at airports may not meet the strict standards of pharmaceutical manufacturers.
Besides the temperatures on aircraft, shipping directly means less variation and eliminates additional handling. Shipping with connecting flights not only adds to the transit time but also may expose products to higher temperatures. “Most of the data we have collected show temperatures on an aircraft are typically between 10°C and 15°C. Having said that, we have measured temperatures as high as 50°C. If your package can experience temperatures this extreme, should the design of the system protect at the extreme or the average?”18 The USP in General Chapter <1079> discusses similar factors.9
Also, manufacturers often assume aircraft holds are maintained at a steady temperature during flight. However, variability in temperature is often evidenced and determined by aircraft type, cargo-hold location, and flight duration. Additionally, maintaining a package at a temperature range (such as 2°C to 8°C) under both extreme warm and coldconditions can be a significant challenge on both the upper and lower limits. With most package designs, it is easier to maintain temperatures under cold conditions during the first part of the flight. For instance, on international trips, such as from India to Canada to Florida, the gel-pack cooling elements within the container will gradually lose their ability to effectively maintain the required temperatures.
A package is often most vulnerable to variable temperature exposure when it is static. The nature and extent of this exposure risk varies depending on the distribution model—and that distribution model is a moving target.
Nearly half of the health-insured population in the United States now receives pharmacy care from pharmaceutical benefits managers. As a consequence, the mail-order channel has grown dramatically, with supply-chain requirements differing greatly from those of the hospital or retail store channel.19
THREE METHODS FOR DEVELOPING AN AMBIENT TEMPERATURE PROFILE
Figure 1. The relationship between empirical knowledge, historical data, and actual data.
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A critical component for determining a test profile is to understand what happens within the distribution chain. Capturing expected temperature exposure during shipment could be accomplished in three distinct ways, as shown in Figure 1:
- Through empirical knowledge.
- Through a historical temperature database.
- Through actual data, collected directly from specific distribution environments.
The key is to have the most-accurate data possible. This ensures a more-thorough understanding of your particular distribution chain and lane segments. It also enables you to assess and implement the most-efficient packaging and distribution practices.
Figure 2. An empirical temperature model of four-day international shipments.
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Empirical knowledge. Developing a thermal model by means of empirical data relies heavily on making assumptions about the distribution environment and processes. As illustrated in Figure 2, it is often based solely on when and where the touch points occur in the process. Its inaccuracies often produce a profile that is not truly representative of the distribution process, resulting in packaging that is improperly engineered. This translates directly to higher product risk as well as wasteful packaging and transportation costs.
Historical data. Development of a temperature test profile based on an evaluation of historical data from a governing agency, such as the National Weather Service, allows only for point-to-point daily highs and lows, monthly averages, and extremes. It fails to take into account the nuances and effects of transportation. Packages traveling by a combination of air and ground, for example, are exposed to multiple swings in temperature that are the result of atmospheric changes, road heat, radiant heat, and cross-docking operations, in addition to other variabilities.
The limits of using empirical and historical data. These approaches for determining the limits of the distribution environment are very difficult to defend in an audit, as there is an erroneous understanding of what the distribution process actually looks like and little, if any, documentation to support it.
Actual data. Environmental data collected directly from the distribution chain allows for the most accurate information. It dispels assumptions and allows for a clearer understanding of the realities of a specific distribution environment and can reveal potential risks within the process relative to time, temperature, and location. Long-term data can establish trends and avert potential risks. Ongoing, periodic temperature monitoring is strongly recommended by the USP in General Chapter <1079> as a means of understanding and maintaining control over the distribution process. It also provides an organized and documented method for establishing temperature ranges, thresholds, and durations for product and package development.
EXECUTING ACTUAL DATA COLLECTION
Creating ambient temperature profiles is an essential element in successful packaging designs for temperature-sensitive products. A systematic study to provide actual data on temperature hazards can be used to develop packaging and meet applicable regulatory requirements. As an example, knowing that a product must be kept at 5°C ±3°C only represents half of the design criteria. It is like knowing only what the ingredients are in a recipe without knowing their quantities or what to do with them once you have them. The temperature profile quantifies the ingredients (i.e., the design) by providing a specific mix of challenges to overcome and employing a menu of packaging components. Special care must be taken when developing a profile to ensure that it is both representative and valid.
The information gathered from the data collection will be used to identify the external temperatures experienced throughout various transportation lanes and to provide documentation for temperature thresholds and durations for use in product package design. It is imperative that a preapproved protocol is written and then executed as approved. The protocol should, at a minimum, outline the process’s overall objective, scope, and detail. It should include the expected duration of the study, quantity of samples, lanes, origins, and destinations. As stated in USP General Chapter <1079>:
“Operational and performance testing should be parts of a formal qualification protocol that may use controlled environments or actual field testing based on the projected transportation channel. These should reflect actual load configurations, conditions, and expected environmental extremes. Temperature and humidity monitors should be placed into product or a representative thereof. Testing consists of consecutive replicate field transportation tests using typical loads, according to an established protocol.”9
A written report at the conclusion of the study should, at a minimum, include the preapproved protocol; document and summarize the results; statistically summarize the data; include all raw data, dates, times, and segments; note any deviations to the protocol; include appropriate calibration documentation; objectively state conclusions; and make recommendations.
The sampling plan for data collection for ambient temperature studies should be representative of applicable distribution practices. For example, if 90% of all packages are sent to the same five destinations, the sampling plan should reflect that. The scope of the data collection should not be so large as to make data handling and organizing difficult, confusing, or subject to error.
As a general rule, the ambient temperature should be sampled at least every 15–30 minutes. The interval will vary depending on the time frame of the shipment and the allowable number of data points. The more data points, the higher the quality of the information used in the analysis. The regularity of shipments, or trips, should include as many ship days and routes, methods, and modes as is normal to a specific distribution process.
The sampling size for data collection should capture the range of segment variability in each transportation system. These include carriers, methods of shipment (e.g., overnight, two-day, or international freight), points of origin, and seasonal considerations (e.g., summer or winter). A sampling size of no fewer than 30 (trips) should be applied for each transport system, each method of shipment, each point of origin, and each season. This will help to identify distribution events that might not otherwise be known.
Electronic, battery-powered thermister recorders (data loggers or monitors) used should be consistent throughout the study. They should all be from the same manufacturer and be the same model, with the same tolerance and specifications. The monitors should have a certificate of validation assigned to the serial number of each data logger used and verification that they received a three-point calibration to the National Institute of Standards and Technology traceable standards, thus demonstrating reliable proof of accuracy prior to use.
All data loggers should be identically preprogrammed to the same specifications for frequency, alarms, and duration. This will aid greatly in organizing and performing statistical analysis of the data. The data loggers should be located outside of a package or in such a way that there is no interference with reading ambient air temperatures.
The data should be collected in such a way that all types of segments within a specific distribution system are monitored. Seasonal, origin, and destination; allowed transit time; and carrier variations should be covered.
ORGANIZING THE DATA
The data, at a minimum, should be organized by location, such as each origin to each destination, to determine differences among lane segments. From this, an overall summary can be derived.
Data collection begins with identifying the conditions at a product’s point of origin. After production, temperature-sensitive products are placed into a controlled environment. However, in many cases they are removed from this controlled environment to be placed into distribution packaging. This change is generally consistent, from a refrigerator to an air-conditioned distribution center floor. Because all of the products will undergo this change in a similar manner, the basis for data collection begins here. Even if a product is still at its place of origin, it is still at risk of temperature exposure. Data collection at this point should record the normal temperature of the packing environment as well as the length of time required to pack an entire shipment.
The preferred method for collecting data is tracking live product shipments to the customer. If this is not an option, using small, uninsulated, preferably vented boxes containing a data-logging device may be employed. Depending on specific needs, multiple profiles may need to be generated in order to represent differing distribution channels.
Logging intervals link the number of shipments and data points. Such logging must be consistent. This will provide equal weight for temperature bands when the data are analyzed. The interval should provide sufficient resolution of temperature changes without generating superfluous data.
CRUNCHING THE NUMBERS
Using Microsoft Excel (or a similar program), give each trip from each recorder its own column. Start times should be aligned as closely as possible to facilitate development later. Once arranged, it is possible to turn the data into useful information.
Figure 3. The frequency of occurrence versus temperature. Mean 24°C.
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The method illustrated in Figure 3 is based on the frequency of occurrences of a particular temperature. This allows non-normally distributed data to be analyzed with a high degree of confidence. An overall confidence interval should be established based on individual user risk assessment. For purposes of this model of profile development, a confidence interval of three standard deviations will be considered and illustrated. This represents 99.7% of all data on either side of the mean.
DATA ANALYSIS AND THE SCHOENHERR MODEL 20
The data analysis seeks to provide a representative profile from a full range of observed temperatures. While the data analysis includes all events, some temperatures in the observed dataset may not be significant in the overall view of the profile. This nonsignificant data will not be considered in the final profile as it does not make a relevant contribution, even at a very high confidence level. (Further discussion can be found under the section “Nonsignificant Data.”)
Simple statistics can be applied to parse the data into a meaningful profile. Establishing the standard deviation of the data set is a practical way to divide the data set into temperature bands, hereafter referred to as subsets. Each subset will make up a portion of the overall time in the profile. The subsets are formed by grouping the temperatures in standard deviations away from the mean, both above and below.
Figure 4. Data set: mean and standard deviation.
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It is necessary to explore the reasons for not including data from the collected set for consideration in profile development. In Figure 4, outlying data on either side of the frequency distribution beyond three standard deviations are not included as they represent less than 0.1% of the overall observations in terms of occurrences and do not contribute to the profile in a meaningful and representative way. These outliers represent approximately 100 points of the 33,000 points collected in this study. Using the formula in the analysis section, it accounts for 0.2 hours (or 12 minutes) in what will be a 72-hour profile.
As illustrated, the minimum temperature observed was 13.9°C, well within three standard deviations from the mean of 24°C on the low end. On the upper end, observations above 35°C are not included. It is imperative that users each define the appropriate confidence interval for their processes, thus delineating outliers. This decision must be based on a combination of multiple factors, including company quality policies and standards, cost-benefit ratios, engineering factors, and the composition of the dataset, to name a few.
THE SAFETY FACTOR
Qualifying a package to too high of a confidence level, with the insertion of an additional safety factor, does not necessarily provide greater confidence, added value, or improved protection. In the illustration above, the difference between a confidence interval of 3 Sigma (99.7%) and 5 Sigma (99.9%) is a mere 0.2%. The frequency of data within that range represents only 0.1% of all data collected. The difference in temperature, 35°C to 42°C, increases the upper end of the range by 7°C. First, it adds complexity to the design. This adds material, additional components and warehousing, unnecessary weight, increased labor, and all associated costs, as well as elevating the chances of making a mistake during assembly, all in an effort to capture that additional 0.2% probability of exposure. The confidence interval must represent an optimal balance of testing validity and actual observed conditions applicable to a specific distribution process.
Extending the dwell time at an extreme temperature in a temperature profile has similar ramifications on package design.
More importantly, there exists the potential to impact product quality negatively by artificially overengineering the package. If a package is designed to meet the challenges of a profile with an overly conservative safety factor but actual field ambient conditions show no evidence of this occurring, there is potential for the product to experience excursions in temperature below its minimum specified transport temperature.
Given that many products face a requirement of 2°–8°C and that designs are frequently on the edge of remaining in criteria because of the need for long durations, it is more risky to exaggerate temperature extremes. A more-reasonable approach to employing a safety factor is by using elements of design that tighten product temperatures closer to the mean of the design criteria. This type of safety factor helps build confidence in the design, regardless of the level of confidence in the ambient profile.
DATA SUBSET FORMULA
Figure 5. Data subsets.
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Once the confidence interval and subsets are established, the data can be compressed into a more-manageable form, as seen in Figure 5. The number of temperature occurrences for the subset should be summed and a formula of ratios applied. This formula combines the effects of the temperature in the subset to provide a representative, but usable, set of temperatures. Generally, the formula takes the following structure:
X = Hours at temperature in the profile
R = Number of observations in the subset
T = Length of the profile
O = Total number of observations within the confidence interval
The median temperature of the subset will serve as the temperature to be used for the set point in each time interval “X.” Now that set points and durations are established, the profile can be drawn.
CONVERTING THE SUBSETS INTO A PROFILE
Figure 6. Temperature and time of all trips, with the moving average in bold.
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The final step in the Schoenherr Model is graphing each recorded trip into the same graph. Each series of data should be adjusted so that the times of day the shipments were made align. The last series should be the mean across all rows of each column to develop a moving average. In the graph, the moving average trend will determine where each subset falls. The subsets may be divided so as to accommodate similar temperatures in multiple portions of the profile. For example, if in a 24-hour profile 10 hours are spent at a temperature of 22°C, it is acceptable to place four hours at the beginning of the profile and six hours at the end to represent dock staging time after packing and prior to unpacking. The moving average does not show the actual temperatures to be included; it gives an indication of either increasing or decreasing trends. The sharper the change in the curve, the more pronounced the overall temperature difference. Figure 6 illustrates how the profile is reflective of the moving average, which is highlighted in (thick) black.
The graphed example (Figure 7) represents a confidence interval of 3 Sigma of all the data represented in Figure 6. Time at temperature, the area under the curve, equals 99.7% of heat exposure cumulatively, as recorded by the data loggers on all packages sent during the study. The graphs in Figure 6 and Figure 7 cannot be directly overlaid, as Figure 7 has been compressed from 96 hours to 72 hours to meet the limits of a specific distribution model. The assignment of temperatures at the appropriate place in the timeline, the elapsed time during the distribution process, is essential to capture day/night exposure and touch points. Such information can be obtained simultaneously to capturing temperature data during the study by utilizing the automatic tracking capabilities employed by most freight carriers that indicate pickup times, transfer times time at hub, and delivery.
Figure 7. A representation of a confidence interval of 3 Sigma of all the data represented in Figure 6.
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The graph is a meaningful and representative temperature profile for the specific distribution process from which the data were obtained. This profile can be used with a high degree of confidence in the performance of an OQ for package development. It is important to point out that performing an OQ—that portion of FDA’s “CDER General Principals of Process Validation” requirement, which also meets USP’s General Chapter <1079> guidance and Technical Report #39— is not, in and of itself, a validation in the eyes of FDA. It needs to be built on a CQ and followed-up with a PQ.1
The PQ should include two parts: gathering additional ambient data and verifying shipping system performance. During the PQ, a data logger should record ambient temperatures. These temperatures should then be compared to those used in the OQ portion of the validation to verify that the profile captured conditions as expected. An additional data logger should capture internal air temperatures recorded as close to the product as possible. These air temperatures can then be compared to air temperatures in the OQ portion of the validation for correlation to the actual product temperature.
IMPORTANCE OF AUDITABLE DOCUMENTATION
There are many complicated steps and parties involved to bring the drug to the patient. In the pharmaceutical cold chain, complexities are numerous, given the many supply-chain partners: manufacturers, distributors, third-party packagers, primary and secondary wholesalers, retail and online pharmacies, hospitals, and clinics.10 Because of the various exchange and drop-off points, distribution environments often involve several modes of transportation, climate zones, seasonal changes, and other external factors. Manufacturers must show that they can ship their products at the right temperature and condition. They must demonstrate this to global regulators, who have insisted on such information indicating that temperature-sensitive products have been maintained at the defined controlled requirements.
All pharmaceutical products have published storage requirements, which are identified by their labeling. Many of today’s pharmaceutical manufacturers require the 2°C to 8°C standard. However, drugs often experience temperature fluctuations well beyond or below this temperature specification.
According to USP <1079>, “this general information chapter is intended to provide general guidance concerning storing, distributing, and shipping of pharmacopeial preparations.”9 Some of today’s leading pharmaceutical organizations are following good cold-chain management practices by creating auditable documentation of a temperature-sensitive product in both the storage and in-transit segments in case these areas may experience temperature extremes.
An auditable trail of recording time and temperature data of a distribution process by means of a validated monitor is a prudent practice. Pharmaceutical companies can then prove to regulators and their internal quality auditors with documented evidence that even though their products have experienced some form of temperature excursion, the fluctuation was within their required temperature specifications. This will also verify that their pharmaceuticals did not experience product degradation. Thus, the drugs are efficacious and safe to the public.
In this regard, the application of electronic records and data analysis for good cold-chain management practices is advantageous.21
CURRENT BEST PRACTICES FOR AMBIENT PROFILE DEVELOPMENT: RISK ASSESSMENT
Collecting time and temperature data of temperature-sensitive pharmaceuticals helps ensure “identity, strength, quality, and purity of a drug throughout the distribution environment,” which is stipulated in the USP General Chapter <1079> guidance document. It also ensures that pharmaceutical organizations are taking a risk-based approach to safeguard the drug supply chain. By factoring in the environmental conditions—light, humidity, shock, and vibration, along with temperature—manufacturers have tangible input to assess the risks of their individual and unique supply chains.
Some manufacturers are not monitoring the quality of their products from end to end of the distribution chain. As a result, they are relying on third-party logistics providers to maintain the quality of their shipments, as indicated by the service-level agreements and standard operating procedures (SOPs). However, manufacturers need documentation to confirm that logistics providers are adhering to their SOPs, such as:
- Were the pharmacopeial articles transferred to their manufacturer-designated storage environment within two hours of receipt, as recommended by the USP?9
- Were the shipments transferred from the loading dock to the distribution center within 60 minutes, as indicated by an SOP stipulation?
- Were the refrigerated trailers properly precooled?
- How do manufacturers know that the logistics providers are doing everything they say they are doing to ensure product quality?
The condition of temperature-sensitive drugs must be ensured throughout the entire distribution chain in order for the products to be efficacious and safe to the public. According to the USP, manufacturers must “ensure a preparation’s integrity, including its appearance, until it reaches the user.”
Manufacturers must cooperate with the various supply-chain partners using a risk-based approach to ensure the quality and safety of their pharmaceuticals until they reach the end user, the patient. In this regard, manufacturers will avoid jeopardizing their brand and losing costly shipments because of temperature excursions, and they will meet customer demand.
MONITORING THE SYSTEM FOR CHANGES
When a drug leaves the manufacturer’s control, the USP states it “enters a complex system of handoffs that involve the distribution chain to the patient.”9,10
The system for monitoring a drug’s temperature throughout the supply chain is not only highly complex, but also highly variable. The distribution environment depends on a range of factors, such as points of origin and destination, article and container sensitivities to cold and heat, accidental freezing, transit mode (e.g., air, truck, ship, or a combination), trade lanes, time, weather, season, carrier type (e.g., small and large package providers), etc.
Additionally, the pharmaceutical delivery staff, which may have high turnover rates, needs appropriate training, especially concerning the SOPs. Training should include the proper placement of pharmacopeial articles in a transport vehicle, the special arrangements of immediately transferring articles to proper storage locations, and the procedure that should be followed in the event of a temperature deviation from the required conditions.
Only with ongoing temperature monitoring can manufacturers know what factors are influencing their unique system. According to USP <1079>, “manufacturers may attach temperature-monitoring devices and/or ship under specified controlled conditions to ensure that the desired temperature is maintained during distribution.”9
Analysis of the time and temperature information can be used to determine why variations are happening in one segment during a set time period or with specific logistics providers. Additionally, manufacturers will have undisputed data to identify the corrective actions to drive process improvement within their pharmaceutical cold chains and demonstrate they are in control of their own unique product and cold-chain routes.
- Documents utilized by FDA, such as the Federal Food, Drug and Cosmetic Act, the Code of Federal Regulations Title 21, USP General Chapter <1079>, and PDA Technical Report No. 39, as well as guidance documents issued by several other countries and governmental agencies, illustrate that regulatory requirements for storage, distribution, and shipping of temperature-sensitive pharmaceutical articles continue to expand globally.
- As expectations for compliance have increased, so have responsibility and liability issues, which no longer end with the drug manufacturer.
- Strict adherence to regulatory requirements has placed increased importance on qualified packaging, qualified distribution systems, and compliant storage practices.
- Qualifying packaging for the transport of temperature-sensitive products provides a high level of assurance that product integrity has not been compromised owing to hazards within the distribution environment and that regulatory requirements have been met.
- Qualified packaging maximizes efficiencies in package design and may help reduce overall shipping expense by minimizing material cost, storage space, and package weight, thereby reducing freight charges.
- Understanding the distribution chain is key to qualifying a properly engineered package.
- Creating temperature profiles that realistically reflect those found within a given distribution system requires a thorough understanding of that environment.
- Monitoring the distribution chain for changes in temperature as a result of environmental change and handling practices is an ongoing necessity in order to establish trends, capture emerging modes, and set realistic limits.
- A key element that must be considered when developing a temperature test profile must include accepting a percentage of risk of exposure to extremes in temperature and determining a confidence interval associated with that risk.
- The Schoenherr Model of Profile Development for temperatures in distribution is a practical, statistically relevant, accurate, and repeatable process for developing a temperature profile based on a specific distribution environment.
- Distribution processes should be monitored to determine trends and identify factors that influence changes to the system. Ongoing monitoring programs also provide supporting documentation for continuous improvement for temperature-sensitive drug distribution.
For the appendix on pharmaceutical distribution regulations, visit
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9. United States Pharmacopeia 28, Supp. 2, General Chapter <1079> Good Storage and Shipping Practices, The U.S. Pharmacopeia Convention (Rockville, MD, 2005).
10. Bishara, R.H., and PSD Project Team, “Drug Product Distribution Chain,” Stimuli to the Revision Process. Pharmacopeial Forum, 29(3), (May-June 2003): 864-875.
11. Bishara, R.H., Chair, Pharmaceutical Cold Chain Discussion Group, Parenteral Drug Association: Cold Chain Guidance for Medicinal Product: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. Technical Report No. 39. PDA Journal of Pharmaceutical Science and Technology, 59(S3), (2005).
12. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food and Drug Administration, “General Principles of Process Validation,” (1987): 3.
13. O’Donnell, K., “Can Transportation Packaging Really Be Validated?” Pharmaceutical and Medical Packaging News, November 2006.
14. Walter Soroka, Fundamentals of Packaging Technology, (Richard Warrington, Herndon, VA, 1995).
15. International Safe Transit Association (ISTA), “Procedure 5B—Focused Simulation Guide for Thermal Performance Testing of Temperature Controlled Transport Packaging,” (2002): 1, 4.
16. International Safe Transit Association (ISTA), “Procedure 7D—Thermal Controlled Transport Packaging for Parcel Delivery System Shipment,” (2002): 5.
17. Hosseiny, A., “Design, Qualification, and Maintenance of a ‘Temperate’ Supply Chain,” American Pharmaceutical Outsourcing, 7(2), (2006): 47–50.
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19. Pharmaceutical Research and Manufacturers of America, “Pharmaceutical Industry Profile 2001,” 2001 (Washington, DC, PhRMA, 2001).
20. Schoenherr, C., O’Donnell, K., “Summer Domestic Ambient Temperature Data Collection and Profile Development,” Abbott Laboratories, internal study (Pharmaceutical Cold-Chain Discussion Group Meeting, Chicago, 2004).
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Acknowledgments: The authors would like to thank Corey Schoenherr of ISC Labs for his development of the ambient profile model and for his contributions in the preparation of this article. Technical review and comments by Henry Ames, Amanda Widell, Mark Maurice, and Chris Leary of Sensitech Inc.; and Rich Ellinger, ThermoSafe Brands, are appreciated.
Rafik H. Bishara, PhD, is the current Chair of the Pharmaceutical Cold Chain Interest Group (PCCIG), PDA. Dr. Bishara retired from his position as Director, Quality Knowledge Management and Technical Support, Eli Lilly and Company, after a 35-year career. During his tenure at Eli Lilly and Company, Dr. Bishara was responsible for the Quality Knowledge Management, Global Compendial Affairs, Stability and Distribution Excellence, Global Product Protection, Special Security Substances and Controlled Substances Administration. Dr. Bishara frequently chairs and presents at industry leading conferences, has authored numerous articles, and has technically advised several organizations on Good Cold Chain and Temperature-Controlled Management Practices. Dr. Bishara received his Ph.D. from Purdue University. He may be reached at: [email protected].
Kevin O’Donnell is Director and Chief Technical Advisor to Industry for Tegrant Corporation, ThermoSafe Brands. He retired in 2005 from Abbott Laboratories, as Principle Packaging Engineer, and was responsible for the design, development, qualification, and implementation of all temperature-controlled distribution packaging for the Abbott Global Pharmaceutical Division. His 26-year career at Abbott included more than 20 years of temperature-assurance packaging experience. Well respected throughout the pharmaceutical industry in the United States and in Europe as a leading advocate for implementing good cold-chain distribution practices, Mr. O’Donnell is active in providing his knowledge and expertise to industry and is heavily involved helping draft guidance. He is an Advisory Board member for the International Air Transport Association (IATA) Live Animals & Perishables Board and coauthor of IATA’s Perishable Goods Manual Chapter 17 “Air Transport Logistics for Temperature-Sensitive Healthcare Products”; a member of the Canadian Association for Pharmacy Distribution Management (CAPDM) Temperature Control Subcommittee; a founding member of the Parenteral Drug Association Pharmaceutical Cold Chain Discussion Group (PDA-PCCDG) and coauthor of the Cold Chain Guidance Document for Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products Through the Transportation Environment, PDA Technical Report #39; Advisory Board Member at Rochester Institute of Technology, Rochester, NY, Masters Thesis Program for Packaging; and host of “Where Cooler Heads Prevail” http://www.coolerheadsblog.com, an open discussion forum on matters related to pharmaceutical cold-chain. Mr. O’Donnell may be reached at [email protected].