Documenting Temperature Excursions

It is the responsibility of every pharmaceutical manufacturer to guarantee every medicine they deliver to a patient is of the highest quality. Maintaining the quality of a pharmaceutical product requires adhering to strict precautions, including storing or transporting the medication at specified temperatures.

Temperature Excursions

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Cold Chain Monitoring
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If a shipment is complete, a decision needs to be made to release or quarantine the product. The following data must be available:

• Complete measurement record from a calibrated sensor

• Start flag (clear date and time)

• Stop flag (clear date and time)

• Stability Budget (assessment criteria) with clear conditions of temperature zones/limits and allowed times

Sometimes additional criteria are defined, like number of allowed excursions or number of freeze-thaw cycles. As soon as all the data is available, the assessment can be performed a clear OK (= release) or ALARM (=quarantine) decision can be made. Information between stakeholders usually takes place via email or SMS.

A temperature excursion could result in patients ending up with unsafe products that may cause adverse reactions. Therefore, every pharmaceutical manufacturer must ensure all products are kept in the specified conditions until they reach the patient.

So, what are the right tools to use to guarantee that patients are getting the right quality and, most importantly, safe medicine?

What Are Temperature Excursions and Why Do They Even Matter?

Under the World Health Organization (WHO) Model Guidance, temperature excursion is “an excursion event in which a Time Temperature Sensitive Pharmaceutical Product (TTSPP) is exposed to temperatures outside the range(s) prescribed for storage and/or transport. Temperature ranges for storage and transport may be the same or different, as they are based on individual product stability data.”

Like many products, some medicinal products are sensitive to temperature and need to be stored and/or transported within a limited temperature range until expiration. However, unlike a flower that has lost the vibrancy and aromas, it isn't easy to tell when pharmaceutical products have lost their quality or efficacy.

Whenever temperature-sensitive pharmaceutical products are exposed to temperatures above or below the specified range, they experience temperature excursions. These excursions can affect their potency or result in an adverse reaction to the patient’s health. A temperature excursion may occur at the manufacturing site, in transit, or at the repository.

The Role of Regulators

Both the European and United States Pharmacopeia outline that pharmaceutical manufacturers are accountable for a product’s quality until it reaches the patient. While temperature conditions at manufacturing and packaging sites are usually under strict control (GMP regulation), this control is likely to decrease as soon as the product is dispatched for transportation.

As such, manufacturers should guarantee the safety, efficacy, and quality of the product until its final use. When temperature excursions occur, they have to take the required measures.

5 Examples of False Excursions and How to Correct Them

Temperature alarms may not be a final result. Sometimes there are false/positive excursions that can be corrected by a cold chain database. From the experience of millions of pharma shipments analyzed in our database, we know that less in than 10 percent of all cases, a true temperature alert (excursion outside defined shipping conditions) is found.

Typically, half of the temperature excursion cases are caused by a late stop or other mistakes that happen at destination – which could be considered false excursions.

The following are examples of common causes of false alarms and their interventions:

• Early start, sensor measures too early (before product has been loaded or conditioned)

Intervention: Cold chain database can reassess the data using the correct time stamps.

• No temperature values available due to sensor failure (sensor not started or no sensor added)

Intervention: If the shipment contains more than one device, it might be possible to use this data to release the entire shipment.

• Minor temperature excursion during shipment

Intervention: Cold chain database can reassess the data using the stability data of the product.

• Wrong sensor setting triggers a temperature alarm

Intervention: Cold chain database can reassess the data using the correct stability data.

• Late stop at destination, sensor continues to measure (at room temperature)

Intervention: Cold chain database can reassess the data using the correct time stamps.

In every case, it is important to have a two-level process in place whereby both logistics and quality review excursions before the product is released.

How to Document Temperature Excursions

Manufacturers that wish to follow GDP and GMP regulations are required to have procedures in place to document, investigate, and handle temperature excursions. The approach below outlines best practices for the documentation of temperature excursions at the manufacturing site, during transportation, or in warehouse storage.

Collect the following information:

• Details of the person completing the report

• Date and time of the temperature excursion

• Inventory of affected products

• Storage unit temperature (including minimum/maximum temperatures during the time of the event, if available)

• Room temperature (if available)

• General description of the event (i.e., what happened) • The length of the exposure if using a digital data logger (DDL)

• List of other items in the unit

• Any problems with the storage unit or affected products before the event

• Other relevant information

The distributor and recipient of the affected product(s) should receive a notification should a temperature excursion occur.

7 Components of a Cost-Saving CAPAs for Temperature Excursions

In case of a temperature excursion, GMP and GDP regulations require a Corrective Action & Preventive Action (CAPA). It is a structured process, which investigates and identifies root causes of problems and defines corrective action to prevent recurrences.

To create a useful CAPA, ask these questions:

• Who found the temperature excursion, when, and where?

• What is the scope of the case (shipment number, delivery, handling unit, pallet, product, batch)? • What is the severity of the excursion?

a. What was the label/transport condition?

b. What was the highest (or lowest) temperature measure?

c. What was the number of excursion hours (can the product still be released based on stability budget)?

• What was the root cause of the excursion?

• What are corrective actions to eliminate this specific problem?

• Have similar cases happened before? Are there patterns in the data?

• Can we define preventative actions to make sure similar root causes are eliminated?

For a reliable CAPA process in cold chain management, a database is necessary where all data is available in a structured and well-documented way.

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