Time and Temperature Sensitive Pharmaceutical Products

The breakthrough in the pharmaceutical field has enabled us to test & develop some innovative drug types, such as vaccines and biotechnology.  These technologies offer medicines for critical diseases at  affordable prices, with more enhanced therapeutic effects  as compared to traditional medicines. However, this also comes at an extra cost of maintenance , compliance , and commitment.  

One of the major requirements is environmental control, and such  medicines are known as Time- and Temperature-Sensitive products. 

These types of products require specialized environmental conditions during manufacturing and after they leave the manufacturer's facility. If proper conditions are not provided, their therapeutic effects can be compromised.  

What are Time and Temperature Sensitive Pharmaceutical Products

Time- and Temperature-Sensitive products require predefined environmental conditions and adhere to specific time limits for storage and transportation to preserve their chemical effectiveness, therapeutic effects, quality, and safety. It is due to the nature of the raw materials used, which are only effective at a specific low temperature, and the drug's stability also depends on that specific temperature. 

If appropriate temperature conditions are not provided, the product will degrade, fail to exhibit the required stability characteristics and become ineffective. In some cases, it will also impact the physical appearance of drugs, such as changes in colour. 

In addition to product safety and quality requirements, Time- and temperature-sensitive products are also regulated by relevant guidelines and must be followed. Failure to do so will result in a warning, a fine, or the shutdown of the manufacturing operation. 

What are the risks associated with Time and temperature-sensitive pharmaceutical Products?

TTSPs are more vulnerable to risks than traditional medicines because of the delicacy of the products. Since they cannot sustain a typical environment, normal conditions also  become risky for these products. 

Some common risks to TTSPs include, but are not limited to, the following.

· Problems with temperature control system - If there is an issue with the temperature control system, particularly when the products are in transit, the product or item will no longer receive low temperatures,  permanently damaging  the product. The problem can become worse, if the problem arises in remote areas, where there are less chances of repairing & fault rectification.

· Delays in transportation & times - Longer-than-anticipated transportation routes and times, resulting in delays in reaching the shipment. This, in turn, increases the time factor more than the acceptable limits. As a result, it decreases the product's ability to maintain its quality, safety, and efficacy.

· Insufficient infrastructure - Lack of sufficient infrastructure in remote areas or low-income countries can make it difficult for these product types to sustain. 

· Failure to deploy sufficient monitoring systems - Since TTSPs are more susceptible to temperature fluctuations, a lack of monitoring data will make it challenging to identify the root cause of any issues. Temperature monitoring is also a regulatory requirement, and will also result in non-compliance

Which products fall in the category of Time and Temperature Sensitive Pharmaceutical Products

It is common that manufacturers maintain the required variables as part of their facility design by utilising relevant technologies, such as HVAC. 

However, storage and transportation require dedicated facilities, and are arranged according to the products being stored and transported. 

There are two main categories regarding temperature values, Refrigerated and Frozen.

Let's discuss each category of product. 

Refrigerated temperature Products

These are the products that require a temperature storage range of between 2°C and 8°C. 

Insulin 

Insulin is a hormone naturally produced in the pancreas that regulates blood sugar levels. People with diabetes lose the ability to naturally control sugar levels and use insulin products to manage their condition. 

Insulin is a time and temperature sensitive product, and its effectiveness can be hampered if the appropriate temperature and duration are not provided. Unopened insulin containers must be stored at 2°C to 8°C, and when opened, 15°C to 3°C at room temperatures. 

Antibiotics

Some categories of antibiotics, such as Amoxicillin and clavulanate, are also classified as time- and temperature-sensitive temperature-sensitive products. An inappropriate temperature value can degrade their chemical and physical characteristics and, subsequently, their ability to cure diseases. 

Biological Products 

Biological products are manufactured from living organisms through biological methods and require specific temperature ranges to retain their effectiveness and therapeutic effects. If specific temperatures are not provided during storage and transportation, it can affect the stability of the product, making it useless and unsafe for patients.

Since there are a variety of biological products, each type has its specific temperature range.  Some products require a standard range, such as 2°C to 8°C, while other products require frozen temperatures of range  -20°C to  -120°C.

Frozen temperature Products

Frozen temperature products have much more reduced temperature requirements, between –25°C to -10°C. These extreme low temperatures reduce the ability of biologic or chemical reactions that results in molecular degradation.  

Additionally, it is also used to preserve medication for the long term, as compared to other forms. Examples of some products that are required frozen temperatures include,

Chickenpox vaccine - This vaccine consists of a  varicella-zoster virus. A frozen temperature is necessary to preserve its integrity and, in turn, to trigger the immune system in the human body.

Zoster vaccine - it is a recombinant that requires frozen temperatures. After opening, it must be administered to the patient immediately.

Requirements for Time and Temperature-Sensitive Pharmaceutical Products

For Time- and temperature-sensitive pharmaceutical products, the manufacturer is responsible for making the required arrangements. Some include the following.

Temperature control

Temperature control systems must be implemented for all equipment or systems that store TTSP, such as freezers, cold storage, and refrigerators. It must 

· Maintain the required temperature values within the limits

· The sensors to monitor temperature must have accuracy up to  ± 0.5 °C and must be calibrated accordingly

· Special emphasis shall be placed on measuring temperatures in the worst areas.

Alarm Systems

It is also necessary and critical that there be a system to alert concerned personnel in case a problem arises with the temperature system or it deviates from standard values. It must be incorporated for all equipment that stores TTSP, such as cold storage, freezers, and refrigerators. Some important points related to alarm include the following

· The sensor must be accurate to acceptable levels and calibrated 

· Sensor must be used to monitor worst-case values

· High / Low temperature set values to trigger visual alarms

· In addition to visual alarms, there must also be audible alarms

· There must be an adequate system of communication to alert on-call personnel, if alarms trigger outside the working hours

In addition to temperature alarms, humidity alarms must also be integrated with appropriate characteristics 

Storage requirements

Pharmaceutical products do not go directly to the distributor or into the hands of patients. Instead, they have a holding period in the warehouse or storage facility for various reasons, such as quality testing, market demands, or arranging cold chains for transportation. Often, every pharma manufacturer maintains its warehouse, and it is necessary that the warehouse must be provided with relevant requirements.

For TTSP products, the storage or warehouse must be developed with relevant requirements. 

The manufacturer should install suitable equipment or machines to produce and maintain low temperatures. Examples of such equipment include cold storage for frozen products and HVAC for regenerated products. 

The facility must also maintain redundant capabilities, so if one system fails, the backup system must be operational to maintain the temperature and prevent product damage or degradation.

The storage must have safety systems to prevent temperature deviations. Additionally, it must be capable of handling the maximum stock levels of these products.

Container  

Time and Temperature Sensitive Products (TTSP) must be shipped in specialized containers, capable of maintaining the required temperatures. These containers must be 

· Comply with relevant standards

· Prevent leakage or spillage of products. 

· It must also be able to protect the product from physical damage.

· Prevents tampering during the product transit

· Use active or passive temperature control vehicles throughout the entire transportation phase.

· The transport system must be able to maintain the required temperature profile throughout the journey.

· Qualify the passive containers, including all relevant components.

· Qualify active containers to ensure they can maintain the required temperature profile throughout the journey. 

Monitoring 

Temperature monitoring is a critical requirement for various areas and processes, including the TTSP. Temperatures must be monitored for all equipment and storage areas that play any part in storing TTSP. Its primary purpose is to ensure that the product has received suitable values and to immediately alert concerned personnel if there is a deviation in temperature values. 

The measuring sensors must be accurate and calibrated to allow accurate monitoring. It must be designed to measure sensors with high variability and minimally affected by the distortions. 

Some options for temperature monitoring include the following.

Data Loggers - to enable temperature monitoring throughout the life cycle. It allows the collection of data at the end of the cycle for analysis.

IIOT - using smart sensors to measure temperature and send them to centralized storage. It allows real-time monitoring and error correction. Additionally, it also helps the manufacturer to monitor individual product units for security purposes, such as anti-tampering and anti-counterfeit

Cloud Storage - using a centralized repository to store all relevant parameters. It enables different systems and technologies to access data and perform analysis.