Sharing Stability Data and Shipping Outside of Label Claim

Manufacturers and distributors should work together to establish proper distribution and product-handling requirements for the purpose of ensuring appropriate product maintenance in transit.¹

Sensitech’s TagAlert
“Manufacturers and distributors should work together to establish proper distribution and product-handling requirements for the purpose of ensuring appropriate product maintenance in transit.”   

The increased regulatory focus on the drug distribution environment is expected to draw attention and to help clarify regulatory and standards-based expectations for temperature-sensitive products. It will also likely drive manufacturers and their supply-chain partners to work closely together in defining product-quality related expectations and required documentation.

While U.S. Pharmacopeia <1079> Good Storage and Shipping Practices states and regulatory authorities support the argument that supply-chain partners work together to protect product quality and ensure patient safety, the practice of sharing stability data is generally not an accepted protocol.

Through a process of managing temperature excursions in later stages of distribution, there is an opportunity to increase downstream partner compliance, reduce costs, and improve patient safety.

Primary Concern
The primary concern for managing cold-chain excursions is that no comprehensive temperature log typically exists to accompany a product from the manufacturer to the final point of dispensation. Without a full temperature log history, serial downstream distribution partners cannot determine if temperature excursions exceed cumulative limits determined by stability data. In this scenario, multiple agents could erroneously conclude the product was maintained within limits and acceptable for use. Ian Holloway, manager, Defective Medicines Report Centre and Unlicensed Imports, United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) supported this position at the 2009 IQPC Cool Chain conference held in Brussels. Holloway raised concerns for these issues related to parallel imports, however, the theme is the same. There is a legitimate concern that more than one supply-chain partner will use the same allowable excursion.

Regulatory Expectations
The regulatory expectation is that medicinal products will be shipped at label claim unless sufficient data is available to support expanded temperature exposure. However, one of the greatest challenges the pharmaceutical supply chain faces when considering distribution of drugs outside of label claim, is that regulations differ dramatically by country and in some cases, by region within a country. Even individual expectations can vary by auditor. Countries like Mexico, Brazil, Taiwan, and others have a reputation for strictly holding product to label claim during distribution. There are other countries, however, that are open to a reasoned position supported by science. The MHRA and the U.S. Food and Drug Administration (FDA) are often viewed as taking this latter approach. The MHRA has repeatedly stated that “The Qualified Person should not release the product unless it complies with the marketing authorization and he/she is convinced that it has not been damaged during transportation. Supporting data would normally have been filed in the regulatory package and been formally approved by the regulator”

Furthermore, from a regulatory perspective not only do excursions beyond label claim need to be substantiated by drug stability data but documentation must also support the potential effects on the container, closure, and label. Regulatory agencies have expressed concern that thermal and humidity variability can negatively impact these items.

Regulatory Trends—A Closer Look at the Drug Distribution Environment
The U.S. Federal Food and Drug Cosmetic Act Chapter V section 501 subchapter A Drugs and Devices, (a)(2)(B) states:  A drug or device shall be deemed adulterated, “if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with CGMP." Because "holding of the drug occurs when the drug is being distributed, transported [or] warehoused for distribution or transfer,”  CGMPs apply in the pharmaceutical supply chain.

This clear regulatory expectation and concerns for how drugs are being stored, handled, and transported in later stages of the pharmaceutical supply chain has led to FDA’s increased focus on the supply chain. Rosa Motta, compliance officer, division of manufacturing and product quality, Center for Drug Evaluation and Research (CDER) at FDA, stated at the Parenteral Drug Association’s (PDA) Pharmaceutical Cold Chain Interest Group (PCCIG) meeting held in Berlin, Germany, in late 2008 that FDA would begin auditing the distribution environment. This is significant because to date FDA has left the auditing of the distribution environment to the individual State Boards of Pharmacy. This will likely drive manufacturers and their supply-chain partners to work closely together in defining product-quality related expectations.

Sharing of Stability Data—Challenges
The sharing of stability data raises a number of concerns for pharmaceutical manufacturers and regulators. First, most manufacturers feel that few of their downstream supply-chain partners are able to accurately interpret and utilize detailed stability data. Second, sharing stability data could enable quality-related decisions to be made without consulting the manufacturer. And, lastly the industry is concerned that if a manufacturer were to publish expanded shipping temperatures, this information could be used multiple times or not documented in a cumulative temperature log.

How Pharmaceutical Manufacturers Manage the Process Today
Most industry leaders would argue that manufactures have taken a conservative approach to managing the supply chain for temperature-sensitive medicinal products.

In general, a manufacturer’s internal quality system defines control limits for thermal variability. The manufacturer’s exception management system is then referenced in managing any thermal excursion. Allowable excursion rates are defined and there is an exception reporting process that captures variability. Deviations that fall outside of the predefined allowable excursion limits, often beyond label claim, trigger a corrective action/preventative action and root cause analysis process. In the case of a temperature excursion falling outside the predefined allowable range, the product impact is researched on a lot basis and compared against stability data. A decision is then made and documented justifying further distribution or destruction of the product.

Expanded Shipping Conditions—An Opportunity for Cost Savings while Ensuring Patient Safety
By not providing broader shipping temperature guidance to their downstream supply-chain partners, pharmaceutical manufacturers have placed a higher level of compliance and cost onto later stages of distribution. In other words, the distribution environment is largely held to label claim while the pharmaceutical manufacturers often rely on their quality system and stability data to allow for predefined excursions. This challenge is significant because it typically results in one of two outcomes: 1) the distributor does not monitor thermal variation in the distribution environment; or 2) the distributor chooses to comply with label claim storage conditions, thereby increasing the packaging and logistics costs.

In the first scenario, medicinal products are often exposed to thermal variability beyond label claim without the support or documentation of allowable excursion data to justify the variability. And, given that few distributors use electronic temperature monitoring devices calibrated to National Institute of Standards and Technology (NIST) standards and compliant with CGMP and USP <1118>, few have data to support their current processes.

In the second scenario, the distributor has very likely taken on higher costs than is potentially necessary in an effort to maintain label claim during the later stages of distribution—arguably the most difficult to control.

If pharmaceutical manufacturers could get comfortable with a process to better manage allowable excursions in later stages of distribution, there is an opportunity to increase compliance while working to ensure patient safety.

Looking Forward:  
Johnson & Johnson’s (J&J) Ortho Biotech division has implemented the use of Sensitech’s TagAlert electronic temperature indicator in each four-vial carton of Procrit (Epoetin Alfa). As indicated in the Prescribing Information for Procrit, the storage conditions are 2˚ to 8˚C (36˚ to 46˚F), do not freeze. The document goes on to explain that Sensitech’s TagAlert device “will be triggered when exposed to temperatures below the recommended storage conditions of 2˚to 8˚C (36˚ to 46˚F).” In this example, the pharmaceutical manufacturer has taken a proactive position to manage later stages of distribution by applying a validated electronic temperature indicator at the point of packaging. This device was designed to monitor the drug all the way to the patient and can be viewed through the packaging by supply-chain partners at any stage of distribution. While the alarm conditions in the monitor are outside the published label storage conditions, they are supported by the company’s quality systems. J&J has gone above and beyond what others in the industry have done by taking responsibility for ensuring product quality and patient safety across the entire supply chain.

Longer term, it is likely that other manufacturers will take a similar approach—monitoring bulk shipments with temperature data loggers with data that support their quality programs while applying cost-effective validated electronic indicators at a more granular level of distribution to ensure compliance with regulatory expectations while protecting patient safety. Alternatively, manufacturers and supply-chain partners may eventually elect to collectively manage some expanded temperature range for the distribution environment. In this case, increased monitoring in later stages of distribution would provide the necessary documentation required to manage expanded storage temperatures as well as provide opportunities for costs savings in the form of reduced packaging and distribution expenses.

1. USP <1079> Good Storage and Shipping Practices, U.S. Pharmacopeia (USP) 28, Suppl. (2) (November 1, 2005).

2. Holloway, I. “Understanding and Complying with MHRA Guidelines” Presentation—Pharma IQ’s IPQC 8th Annual Cool Chain Europe Conference, Brussels—January 28, 2009.

3. Motta, R., “Cold Chain Management: Requirements and Recommendations” Presentation—Parenteral Drug Association (PDA) Pharmaceutical Cold Chain Interest Group (PCCIG) Conference, Bethesda, MD—March 13-14, 2008.

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