Pharmaceutical Cold Chain: A Gap in the Last Mile

 

By Sanford Cook, Joseph Villa, and Teri Magennis, RN

Thermal Packaging Solutions LLC

 

According to USP Chapter <1079> Good Storage and Shipping Practices, “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.”

 

In a recent study conducted by Thermal Packaging Solutions (TPS; Ocean, NJ) and Brigham and Women’s Hospital (B&W), shipments from a major wholesaler/distributor (W/D) were delivered to the hospital in a packaging condition that left the drugs highly vulnerable to temperatures below the drugs’ labeled temperature limits. This study revealed an audit gap in the last mile between the manufacturer and the hospital. The same condition exists between the W/D and retail pharmacies.

 

Upon further investigation, audits of this segment appear to lack focus on temperature control as it relates to appropriate protective packaging and procedures. These procedures were scientifically developed and qualified to safeguard the delivered drugs from frozen phase-change material (PCMs) gel packs used to cool the medical products. In fact, in many cases, the gel packs were actually fully in contact with the product, resulting in conduction of freezing temperatures.

 

The challenge for TPS was primarily to develop a reliable procedure to close the gap that protects temperature-sensitive drugs during W/D shipments to the recipient during the last mile while being cost effective. The choices are using qualified containers and/or temperature monitors/indicators.

 

QUALIFIED PACKAGING

In the past 15 to 20 years, there has been a proliferation of companies that manufacture containers to protect temperature-sensitive products during transport. Since packaging systems are normally designed to accommodate specific groups of products for given shipping event times, temperatures, and physical characteristics, it would be difficult to qualify one passive package for the variety of temperature-controlled drugs such as solid dosages, liquids, capsules, filled syringes, etc. In addition, product mass is critical in the calculations for determining package design and varying label temperatures, so various product configurations combined with different lengths of time and temperature exposure further complicate adequate protection.

 

Packaging can be qualified for a specific use case, but quality can’t be ensured without downstream controls. Although packaging manufacturers have made claims for their packaging, we have not seen that they can actually verify that the products will arrive at hospital and retail pharmacy destinations within specified temperatures. During our study with B&W, we found there was little verification of audit existence and appropriate training at the W/D.

 

It should be noted that USP <1079> as well as other support groups such as the Parenteral Drug Association (PDA) identify Mean Kinetic Temperature (MKT) as the aid in the design of packaging and storage using a complicated equation that determines a single value for the various conditions mentioned above.

 

TEMPERATURE MONITORING

Almost all global regulatory agencies and pharmaceutical industry supporting guideline organizations have discussed “The Last Mile” in various work study groups and published or soon-to-be published documents. However, to date there is little guidance that actually ensures medical products are received at their ultimate destinations within the label or stability test verified tolerances.

 

When there are applications that require verification of product temperature exposures as described above, TPS has found that the use of temperature monitors and indicators best serve to fill the information gap.

There are, of course, many devices offered in this market. In a recent study and test of available solutions, TPS sought to determine the various types of monitors and indicators available as well as the best fit for each application. However, we found that although the suppliers published product characteristics, information about why one product is more suitable than another has been lacking. Also, certain claims have been made at industry seminars and to customers, such as that some regulatory agencies—Health Canada among them—would not accept less-expensive chemical indicators in their jurisdictions.

Since we knew there are less-expensive and highly accurate chemical time temperature integrators (TTIs) now available for certain applications that could dramatically reduce our customer’s shipping costs in addition to filling the distribution gap discussed above, TPS investigated these claims and has found them to be inaccurate.

 

In an e-mailed letter from Sarah Skuce of Health Canada on June 29, 2010, to TPS’s Teri Magennis, Skuce wrote: “Health Canada does not prohibit the use of chemical indicators for temperature monitoring nor does it endorse the use of any specific type of temperature monitor. If the temperature monitoring device can be qualified, tested, and proven to meet specification as set by the company and follows the requirements set out in Health Canada’s Guidelines for Temperature Control of Drug Products during Storage and Transportation, (GUI-0069), then the monitoring device should be deemed acceptable at time of inspection.”

 

Given this information, we needed to specify the appropriate device for our client, a leading global pharmaceutical manufacturer that distributes their products mainly through W/Ds. We developed a simple equation: Accuracy + Cost Efficiency = Value (A+CE=V).

 

TYPES OF TTIs

There are at least four major types of chemical TTIs—Chemical/Physical, Polymerization, Diffusion, Enzymatic. (USP <1079>). We selected two freeze indicators that are based on diffusion technology and two indicators that are based on colloid science, a new technology. Our selection was based on our experience for packaging applications and the easiest to read visibly. Chemical indicators are “go/no go” and in some cases add a feature that can indicate the time until alarmed at “no go” temperatures. Simply, “go” meaning the temperatures being monitored are within tolerance and “no go” meaning there are out-of-tolerance temperatures.

 

By definition in USP <1079>, temperature indicators, commonly known as TTIs, change color or physical appearance based on temperature above (or below) a specific threshold for a specific time duration. TTIs are typically single-use disposable devices that change state irreversibly once the color changes. It will not revert to the original color even if the temperature returns to an acceptable range.

 

Conventional Wisdom (CW) has depicted chemical indicators as not as accurate as electronic go/no go devices: +/-1˚C. versus +/-0.5˚C respectively. Reliability was also a complaint that we heard from many of our customers in terms of false positives or alarms, which could create a condition that perfectly good medical materials would be discarded. Yet another complaint was visual clarity of alarms—in other words, whether an indicator did actually alarm or not. In some indicators, particularly colored ones, a color such as red would indicate an alarm. However, in many cases there are shades of pink. Interpretation becomes somewhat subjective.

 

In the industry, CW as well as a reference in USP <1079> also mention difficulty in the validation process, since chemical indicators are generally one-way devices and testing individual devices causes destruction. It should be noted that the vast majority of pharmaceutical shipments use one-way temperature monitors or indicator devices. Unless more information is required than the temperatures encountered during distribution, each shipment’s data can be individually verified and tamper proofed. It simply is not cost effective to use more-expensive multiple-use monitors. For the purpose of this article, the discussion is centered on one way “go/no go” type TTIs. However, the ladder chart (Figure 3) offers added guidance.

 

QUALIFYING TEMPERATURE INDICATORS

In order to establish A+CE=V (the equation above), TPS tested several chemical indicators as well as electronic devices that monitor freeze events. We developed test protocols and physical chamber tests that were consistent with the Summary of Validations and Qualification Standards included in USP 1079 (1118) in addition to the Health Canada guidelines and typical field applications that TPS and their customers have actually encountered.

The parameters of the validation tests included:

1.         Reliability= Level of false positives (alarms) and false negatives.

2.         Accuracy = Overall degree of accuracy and consistency.

3.         Sudden Freeze (Response Time) = The time it takes to alarm when encountering out of tolerance
temperatures.

 

The Sudden Freeze or response time feature has become increasingly important to trigger alert during packaging and repackaging operations. In other words, when frozen gel packs are inserted into a package and the package is sealed, is the product subjected to super freeze conditions? This condition in our experience drops the product temperature below tolerances provided for in manufacturer’s stability tests until the interior of the package reaches equilibrium consistent with the phase material temperatures.

 

Many of our temperature-protective packaging study projects are for vaccines, drugs, diagnostic, and device products that have allowable “excursion” tolerances during shipping events. Most of the products can be exposed to higher than label temperatures for relatively short periods of time specified and are stability test verified. However, most products that are labeled between 2˚C to 8˚C should be kept above zero or spend as little time as possible below freezing. Freezing is, in many cases, destructive and may result in loss of efficacy. Therefore, the response time or sudden freeze indication is critical.

 

CHOOSING A LAB

All of these tests were conducted at Micom Laboratories in Montreal, Canada, an International Safe Transit Association (ISTA) certified lab, under supervision of TPS. Testing was conducted using environmental chambers to a level of precision of +/-0.1˚C, a tighter tolerance than industry standards. Multiple thermocouples were used to verify performance. All calibrations were performed using NIST-traceable Intelligent Resistant Temperature Devices (IRTD) with a tolerance of +/-0.005˚C. TPS tested TempTime’s FREEZEmarker’s D and L as well as two other major chemical manufacturer’s products and two electronic go/no go indicators that are used for the same applications. Twenty samples from each supplier were tested.

 

TESTS RESULTS

FREEZEmarker D, FREEZEmarker L, Freeze Watch, and TagAlert performed as advertised in their published literature. (See test graphs, Figures 1 and 2.) The TempTime FREEZEmarker D chemical indicator performed equal to or better than any of the electronic or chemical indicators in terms of reliability, accuracy, response time, and sudden freeze.

 

CONCLUSION FROM TESTS

TempTime’s samples provided the value noted in the Accuracy + Cost Efficiency = Value equation and therefore the device could be used in our customer’s application for a one-way, “go/no go” indicator at significant cost savings. (Note: The complete test report is available upon request.)

 

WHEN MORE INFO IS NEEDED

When “Qualified/Validated” temperature-protective packaging is being used for shipping events, we recommend that “go/no go” indicators are used internally in strategic locations. On behalf of a major pharmaceutical firm’s requirements, we asked TempTime to use one card to alert both specific low and high temperatures. The result was they achieved building the product to our specifications and were still below the cost of electronic TTIs.

 

However, when more information than merely a “good product or bad product” is required, we have been working with an electronic TTI manufacturer long established for monitoring shock and vibration as well as other conditions encountered during distribution. This product has up to eight information points depicting go/no go indications at tolerances of +/-0.5˚C. The additional information can indicate whether there is an issue with the label, whether high and low excursion temperatures have been exceeded, whether the packaging is over designed, or whether shipping conditions have changed since the package was originally qualified. We worked with ShockWatch Corp. (Dallas) on behalf of a global pharmaceutical to develop this product so that they could have an inexpensive method to verify their shipping materials and procedures. The ShockWatch product is the Temp Mark 8. There are also electronic TTIs available when measurements are required to record temperatures to calculate Mean Kinetic Temperatures (MKT).

 

CW was to use electronic data logger/monitors in most applications where monitoring was desired. However, we analyzed whether we actually needed all of the information provided by the more expensive device in a majority of shipments. By definition, “a more capable device records the temperature at very short intervals and is able to download the temperature history record to a peripheral system, such as a personal computer,” reads USP <1079>.

 

The U.S. and global market provides many data logger suppliers that have various additional features and memory capability. We worked with Marathon Products (San Leandro, CA) several years ago to manufacture and provide an inexpensive, miniature data logger monitor that can also provide MKT data. We specify Marathon’s Micro-DL products when applications require a record of temperatures for archiving and/analyzing specifically when an out-of-temperature tolerance event has occurred.

 

In startup product shipments, we often use data loggers for some period of time to provide shipping data to confirm packaging, handling, and time temperature events assumed in the temperature profile. We often employ Acceptable Quality Level (AQL) in a sampling of shipments. If the AQL is not reached, we will then scrutinize various parameters in the packaging and distribution process to determine the areas causing the defects. After the AQL has been achieved, we often recommend using TTIs for general shipping of temperature-sensitive products to provide safe shipments at reduced costs.

 

However, at random intervals of time and routes, we suggest that data loggers are employed to confirm there have been no changes in distribution assumptions and practices. Shipments requiring special package interior protection for frozen products are also good candidates for low-temperature data loggers. We found Marathon’s low-temperature series of products were very effective at holding alarm tolerances.

 

CONCLUSION

The audit gap between W/D’s deliveries to hospitals and pharmacies can be cost effectively patched by the use of inexpensive chemical TTI indicators efficiently located in each package or tote with every shipment. Inexpensive, highly accurate, chemical TTIs strategically placed can safely assure recipients that the medical products are within intended temperature tolerance in the Last Mile of distribution.

 

Claims and misinformation circulating regarding the regulatory acceptance of chemical TTIs, their accuracy, reliability, and response time are incorrect. Conventional Wisdom regarding indicator accuracy and acceptance is now obsolete. In this article, we have provided a guide to the latest technology and when to use what types of temperature monitors/indicators.

 

 

  

Bibliography
1. <USP 1079> Good Storage and Shipping Practices, and <USP 1118> Monitoring Devices-Time, Temperature and Humidity, United States Pharmacopeia.

2. “Supply Chain Management Pharmaceutical Cold Chain: A Gap in the Last Mile, Part 1,” Teri Magennis, TPS, Michael Cotugno, Brigham and Women’s Hospital, et al, Pharmaceutical & Medical Packaging News, September 2010.

3. “Technical Report No. 46, Last Mile: Guidance,” Parenteral Drug Association (PDA).

4. International Quality and Productivity Center (IQPC) Cold Chain Conference, 2010.

5. Food and Drug Administration (FDA) Code of Federal Regulations CFR, Title 21 cGMP.

6. Code of Federal Regulations 21CFR Part 211.142 Holding and Subpart H—Distribution of Current Good Manufacturing Practices for Finished Pharmaceuticals.

7. “Model Guidance for the Storage and Transportation of Time and Temperature-Sensitive Pharmaceutical Products,” World Health Organization (WHO), WHO/BS/10.2129 Geneva, 2010. Additional reference QAS/.04.068.

8. European Union (EU) Guidance Distribution Practices regarding quality systems operated by distributors (wholesalers) of medical products.

9. E-mailed letter from Health Canada to TPS, Re: Use of chemical indicators for temperature monitoring, June 2010.

10.       Freeze Indicator Test Reports, TempTime Corp./Micom Laboratories, 2010.

 

Thermal Packaging Solutions, (Ocean, NJ) is a consulting group independent of suppliers that develops pharmaceutical packaging, temperature controlled packaging systems, and associated packaging components, and generates test protocols for storage/packaging/distribution, audit procedures, and international regulatory guidance. TPS has over 50 years experience in the field collectively since 1990, and is a multiple patent holder in the healthcare industry (www.thermalpackagingsolutions.com).