Handling Temperature Excursions and the Role of Stability Data

Pharmaceutical companies have an obligation to deliver their medical products in pristine condition in order to be effective for the patients. That means keeping them in controlled temperature storage areas to preserve them. Maintaining that temperature condition is one of the big challenges the pharma industry faces today. A product is a revenue loss to the company if it becomes useless or cannot be administered.

In pharmaceutical manufacturing and warehouse areas, prescribed temperatures are maintained with the help of air handling units (AHU). The design and capacity of AHU are based on the volume of the work area or manufacturing stations.

What are Temperature Excursions?

Temperature excursion are a divergence from the prescribed procedures. As defined by the WHO Model Guidance as “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; they are determined by the product manufacturer, based on stability data.”

Temperature excursions during transport can happen anytime. According to information gathered by logistics providers, excursions happen at a frequency of 1 – 5 % during transportation of the products. This puts transport as one of the most vulnerable elements in pharmaceutical distribution processes.

What makes temperature excursions hard to manage is that there is no true method to predict the next condition that the product will be exposed to. Unexpected natural disasters or manmade events could delay the transport route.

There is a growing demand to reduce temperature excursions during pharmaceutical operations and their effect on the quality of products. In an era of Quality by Design (QbD) for pharmaceutical products, the focus is on the inbuilt quality instead of inspected quantity.

With manufacturers having expertise on critical product and process parameters and quality attributes, impact reviews must include temperature excursions. These reviews will form the theoretical basis for the pharmaceutical guidelines to provide recommendations for long-term, intermediate, and accelerated storage conditions and for establishing shelf-life periods or expiry dates of products.

What Should the Temperature Excursion Procedure Cover?

The temperature excursion procedure should include studies in which a batch can be released and those where it cannot. It should include a decision chart conducting the reader beginning from the incoming temperature excursion information, through the different questions that are relevant to making the final decision.

Temperature excursions in the workplace can be caused due to the following factors:

a. An insufficient number of air handling units (AHU) to maintain the prescribed temperature conditions inside the manufacturing work area.

b. Leakage or drips from air ducts, resulting in fluctuating cooling effects.

c. Mechanical breakdowns in AHU.

d. Power failures making the AHU inoperative.

e. Lack of protocols and non-compliance of Good Manufacturing Practices (GMP) on the production line.

f. Lack of knowledge about the consequences of improper temperature settings and uncaring attitudes toward preventing power consumption.

g. Extreme weather changes and obsolete plans to solve temperature fluctuations.

In the transport of these medical products, the following situations could cause temperature excursion:

a. Unscheduled delays in transportation in which the temperature control cannot be set properly. For example, staying too long in unrefrigerated storage facilities

b. Product pallets being put out in the sun unprotected in hot zones of airports or shipping yards.

c. Lack of Reefer containers or refrigerated control vans for transportation.

d. Logistics agency failure to adhere to the planned transport procedures.

e. High cost of maintaining constant temperatures within the prescribed parameters, or failed business endeavors.

f. Power outages due to short battery life during extended travel time or generator failures.

g. Lack of orientation to Good Distribution Practices (GDP) for the people working on the supply chain.

Impact of temperature excursion

The storage conditions for the medical product have been prescribed and set by experts to preserve product efficacy during its life cycle. If the settings are not right, the following negative effects may result:

a. Loss of assay. This means the chemical composition of the product could lose its effectiveness to cure the patient.

b. Presence of impurity. The chemicals in the product could be compromised when exposed and can lead to their impurity.

c. Dissolution of layers of liquid products. The protective linings of the product separating the ingredients could tear and inadvertently mix them together, making them useless.

d. Reduction of solid dosage. Temperature excursions can lower the strength of the dosage required to make it effective. Reduction of active ingredients through the degradation of components (oxidative, hydrolyzed, and others), may result in some of them becoming toxic. The more time and higher temperatures materials are exposed to the degrading conditions, the more likely the deterioration.

e. Discoloration of products. Depreciate formulation properties, for example, coloration of some components, dissolution rate modification, or separation of emulsions.

Medical products that are prone damage from low temperatures are destroyed by losing their therapeutic properties after they have been frozen, causing the structures of the active components to change permanently.

Some products are sensitive not only to the absolute temperature, but also to temperature change itself, such as some creams or biologicals that lose their properties after freeze-thaw or temperature change cycles.

Setting the stability by design for solid dosage pharmaceutical products requires that the implementation of storage temperature (T) and relative humidity (RH) are controlled within limits. Within these prescribed temperatures (T) and relative humidity (RH) limits, the probability of degradation of a pharmaceutical product can be estimated using an extended Arrhenius model (Porter, 2013).

Temperature excursions can have significant effects on the quality of products, which can be examined as a part tracking therapeutic drug properties. As a consequence of excursion, the several possible impacts can be observed.

The trend of Environment Condition (EC) monitoring practices during manufacturing and distribution operations.

Review of the sensitivity of drug products towards temperature excursions

Control of temperature excursions is often complex because there is no fixed method to predict the outcome of the product once it is exposed to conditions outside of specifications. Managing temperature excursions is imperative for drug products, which are vulnerable to temperature conditions. Due diligence against potential excursions is a must during drug manufacturing and during the delivery process.

Product sensitivity to high temperature

Drug products that are vulnerable to higher temperature excursions can be rendered useless by the breakdown of their therapeutic properties.

Product sensitive towards lower temperature

It is not only higher temperature that must be observed but also lower temperatures. Drug products can be compromised by temperatures that fall below recommended settings, which can result in losing the structural lattice of the chemicals and transformation of the biological properties of the drug.

The need for government regulations

Pharmaceutical regulatory agencies expect the pharmaceutical companies will have strict adherence to Good Manufacturing Practices (GMP) and Good Distribution Practices (GDP) during plant manufacturing and product distribution processes.

GMP and GDP are deemed as synonyms for Quality systems in the pharmaceutical business. Since there is the possibility of temperature excursions during raw material receipt, manufacturing operation, and distribution of pharmaceutical products, there is a great need to follow quality systems based on both GMP and GDP.

Regulatory Requirements

Pharmaceutical manufacturers should be clearly aware that they are responsible for a product’s quality until it reaches the user. Thus, guarantees for product safety, efficacy, and quality must be stated within the registration files. When temperature excursions occur, it is the manufacturer’s duty to take responsive steps.

Manufacturers must file documents to track temperature maintenance and excursions:

As a part of the Quality Management System (QMS), the pharmaceutical industry has listed a number of core quality elements at the manufacturing site level. A few of the core elements of plant quality system are listed as:

a. Documents and Record Control: Observe good documentation practices in the company to ensure that document and online records are maintained properly.

b. Deviation Control:  Any departure from the approved procedures shall be recorded and evaluated for potential effects on product quality.

c. Change Control: The revisions to an approved design, equipment, or system in a pharmaceutical facility shall be reviewed and validated.

d. Validation Master Plan: The master plan shall show management practices, strategy, and aims of the company towards validations of processes and qualification of equipment.

e. Quality Risk Management: Quality risk to the medical goods shall be shown and evaluations made to estimate the severity, occurrence, and detectability. There must be a vigorous quality risk management system.

f. Training and Awareness: The Company will implement an active training program for personnel connected to GMP operations.

g. Market Complaint Center system: A well-placed program to receive, log, and investigate each market complaint to take necessary corrective and preventive actions.

h. Recall Management: There shall be an established procedure to handle the recall or marketing of returned goods.

It’s been shown that inadequate QMS guidelines have a direct impact on the status of storage conditions in regards to temperature and humidity. Temperature excursions are signs of other general environmental excursions.

The need for Stability studies for responsive actions.

Stability studies to uphold storage conditions

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has created guidelines to combine testing conditions and methods to determine storage conditions and shelf-lives. The standard program initializes stress tests to find degradation routes and stability methods for long-term and accelerated conditions testing. Most manufacturers use these conditions.

Stability studies to analyze product handling during preparation and transport

The manufacturer must record temperature variances during the handling of biologicals, bulk products, and packed products until they are stored in the prescribed storage conditions. For each product, the manufacturer should establish stability testing programs related to the actual preparation and handling of the products. If deterioration is present during the handling operations, actions must be taken to maintain product quality.

Studies to decide on product acceptance after temperature excursions

The Parenteral Drug Association (PDA) has made some proposals for the methods to test product stability during transport. The tests include temperature excursions and temperature cycling.

Temperature Excursion Study Program

The study begins with the determination of global product factors, assesses the risks of the supply chain in relation to factors, establishes the study program and checks the results to modify the transportation conditions, if necessary

Global Product Characteristics: The pharma company can use existing stability studies to investigate the environmental conditions that could be causing product degradation.

What are the external factors that can damage the product?

The external factors can be identified by collecting existing data on the product under investigation, such as stress studies, during which the influence of temperature, as well as air, humidity, light, vibration, and X-Ray radiation have been determined. During transport, most of these parameters are usually under control, with the exception of temperature, vibration, or radiation.

Storage temperature and humidity limits

Specified instructions are written with respect to the temperature and humidity at which products will be stored and distributed (including the shipment of articles to the customer). Instructions will specify procedures for when stability data show any deviation in temperature and humidity that might produce undesired results.

One example of the instructions comes from the United States Pharmacopoeia (USP), which enumerated different labeling terminologies related to temperature conditions. The general chapter of USP listed the various storage labeling conditions.

Measurement devices for temperature and humidity

Data loggers, used in measuring temperature and humidity conditions, are available in the market. They log the temperature at preset intervals. The logs can be downloaded to a database for review, evaluation, investigation, and record keeping. Periodic validation of calibration status of temperature data loggers and upgrades of software is required for uninterrupted and accurate data about product storage conditions.

Calibration and periodic checks of measurement devices are imperative for correct recording. To check the accuracy of the devices, it is best to compare them to a temperature measurement reference device of better accuracy verify that it is recording correctly. The temperature and relative humidity sensors should be placed on the hottest spot, after temperature mapping of the area.

Locations where environmental or temperature excursions may take place

To find where temperature excursions occur, it is important to observe against the temperature limits, not only at the manufacturing line or during transportation, or distribution, but also at the final point of delivery to retail outlets and drug stores.

Developing the storage condition database

To minimize environment excursions, strategic planning, effective packaging, and well-documented procedures must be implemented. The development of a storage database of the pharmaceutical products is also used to assign the standard storage condition.

Storage conditions suitable for the product include:

a. At the product development stage, the semi-finished products and final pharmaceutical product dosages are subjected to testing conditions (e.g., forced conditions), to study the potential effect on quality properties.

b. Time-lapse studies are established to determine allowable time extensions at specified storage conditions without compromising product quality. The studies would include chemical, microbiological, and pharmacological properties at various time points of stability.

Thermal packaging during transportations

Packaging conditions should include thermal packing and a temperature display on the package. Careful vigilance to avoid storage outside the specified conditions will help to supply chain personnel to take precautionary steps to ensure the product quality.

The storage conditions should be labeled on the packaging of the pharmaceutical products. The packaging card must contain the details of data loggers.

Conclusion

Manufacturers should be aware of what happens when temperature excursions occur during product storage and transport from their manufacturing site to patients.

They must review if the available stability data are enough to take responsive actions against potential temperature excursions. If not, they should consider initializing more studies to support the release decision, in case of temperature excursions, and remove product batches which were compromised by insufficient stability knowledge.

Temperature excursions are normally referred to as environmental excursions. There is a need for standard procedures to counter temperature excursions from the raw material manufacturing site to the pharmacies and health centers to protect the quality of the products.

Temperature excursions in any stage of cold chain operation must be reported as soon as possible and acted upon immediately.