|Hazard analysis and critical control points (HACCP) • Hazard analysis and risk-based preventive controls (HARPC)|
|Critical control point|
|Water activity (aw)|
A cold chain is a temperature-controlled supply chain. An unbroken cold chain is an uninterrupted series of storage and distribution activities which maintain a given temperature range. It is used to help extend and ensure the shelf life of products such as fresh agricultural produce, seafood, frozen food, photographic film, chemicals, and pharmaceutical drugs. Such products, during transport and when in transient storage, are called cool cargo. Unlike other goods or merchandise, cold chain goods are perishable and always en route towards end use or destination, even when held temporarily in cold stores and hence commonly referred to as cargo during its entire logistics cycle.
Cold chains are common in the food and pharmaceutical industries and also in some chemical shipments. One common temperature range for a cold chain in pharmaceutical industries is 2 to 8 °C (36 to 46 °F). but the specific temperature (and time at temperature) tolerances depend on the actual product being shipped. Unique to fresh produce cargoes, the cold chain requires to additionally maintain product specific environment parameters which include air quality levels (carbon dioxide, oxygen, humidity and others), which makes this the most complicated cold chain to operate.
This is important in the supply of vaccines to distant clinics in hot climates served by poorly developed transport networks. Disruption of a cold chain due to war may produce consequences similar to the smallpox outbreaks in the Philippines during the Spanish–American War.
There have been numerous events where vaccines have been shipped to third world countries with little to no cold chain infrastructure (Sub-Sahara Africa) where the vaccines were inactivated due to excess exposure to heat. Patients that thought they were being immunized, in reality were put at greater risk due to the inactivated vaccines they received. Thus great attention is now being paid to the entire cold chain distribution process to ensure that simple diseases can eventually be eradicated from society.
Traditionally all historical stability data developed for vaccines was based on the temperature range of 2–8 °C (36–46 °F). With recent development of biological products by former vaccine developers, biologics has fallen into the same category of storage at 2–8 °C (36–46 °F) due to the nature of the products and the lack of testing these products at wider storage conditions.
The cold chain distribution process is an extension of the good manufacturing practice (GMP) environment that all drugs and biological products are required to adhere to, enforced by the various health regulatory bodies. As such, the distribution process must be validated to ensure that there is no negative impact to the safety, efficacy or quality of the drug substance. The GMP environment requires that all processes that might impact the safety, efficacy or quality of the drug substance must be validated, including storage and distribution of the drug substance.
The overall approach to validation of a distribution process is by building more and more qualifications on top of each other to get to a validated state. This is done by executing a Component Qualification on the packaging components, an Operational Qualification to demonstrate that the process performs at the operational extremes and finally a Performance Qualification that demonstrates that what happens in the real world is within the limits of what was demonstrated in the Operational Qualification limits.
Performing thermal testing can also help with validating the cold chain. Certified test labs use environmental chambers to simulate ambient profiles that a package may encounter in the distribution cycle. Thermocouple probes and separate temperature dataloggers measure temperatures within the product load to determine the response of the package to the test conditions. Replicate testing based on a qualification protocols is used to create a final qualification report that can be used to defend the configuration when audited by regulators. It is normally best to have an individual that understands the principles of Validation, when defending such processes to a Federal Regulatory body of any nation.
Cold chains need to be evaluated and controlled:
- Carriers and logistics providers can assist shippers. These providers have the technical ability to link with airlines for real time status, generate web-based export documentation and provide electronic tracking.
- The use of refrigerator trucks, refrigerator cars, reefer ships, reefer containers, and refrigerated warehouses is common.
- Shipment in insulated shipping containers or other specialised packaging.
- Temperature data loggers and RFID tags help monitor the temperature history of the truck, warehouse, etc. and the temperature history of the product being shipped. They also can help determine the remaining shelf life.
- Temperature sensors may need to be National Institute of Standards and Technology (NIST) traceable depending on the body monitoring the cold chain. 
- Documentation is critical. Each step of the custody chain needs to follow established protocols and to maintain proper records. Customs delays occur due to inaccurate or incomplete customs paperwork, so basic guidelines for creating a commercial invoice should be followed to ensure the proper verbiage, number of copies, and other details.
During the distribution process one should monitor that process until one builds a sufficient data set that clearly demonstrates the process is in compliance and in a state of control. Each time the process does not conform to the process, the event should be properly documented, investigated and corrected so that the temperature excursion do not occur on future shipments. Any anomaly is thus considered to be a Non Conformance and should be assigned as a trackable event. The event must be reported immediately when it is identified and it is the expectation of the FDA that all adverse events to documented and investigated. The investigation should be completed in a timely manner and must come to some form of a "root cause" and also some form of "corrective action". The system may potentially stay in a Validated state if the root cause identifies that a Standard Operating Procedure (SOP) was not followed or followed incorrectly. If however a SOP needs to be changed or modified, then the system must be re-validated to demonstrate that the change to the SOP maintains the integrity of the process/system. A Non-Conformance may also generate a Corrective Action Preventative Action (CAPA), again, a documented process to make corrective or preventative actions to SOP's and other documents.
Non Conformances and CAPA's are an essential part of the overall Quality System in the cGMP environment. Tracking and trending of these events will also allow businesses to monitor the overall "health" of the systems in place. Excessive Non Conformances can quickly identify areas of concern for management and allow for corrective actions to be takes. During regulatory inspections of quality systems, inspectors will frequently ask to review a list of all "open" Non Conformances" so that they can quickly assess how an organization is processing these events and ensuring they are dealt with in a timely manner.
Thus the process is continually evolving and correcting for anomalies that occur in the process. Eventually the process can evolve into periodic monitoring once sufficient data demonstrates that the process is in a state of control. Any anomaly that occurs once a process is in a state of control may result in the process being invalidated and not in control and could potentially result in product withdraw from the market to ensure patient safety. A formal product withdraw is only done when the quality, safety or efficacy of a product is questionable. A single anomaly would not necessarily require a product withdraw if there is sufficient stability data that demonstrates that excursions will not affect product quality.
It is necessary to develop an internal documentation system as well as multi-party communication standards and protocols to transfer or create a central repository or hub to track information across the supply chain. These systems would monitor equipment status, product temperature history, and custody chain, etc. These help ensure that a food, pharmaceutical, or vaccine is safe and effective when reaching its intended consumer. It is also important to have a complete chain of custody for the entire life cycle of a product, so there is documented evidence as to whom had control of the product throughout the lifecycle of the product, up to the final users consumption of the product.
- Bacterial growth
- Cool Chain Quality Indicator (CCQI)
- Insulated shipping container
- Shelf life
- Temperature control
- Time temperature indicator
- Thermal decomposition
- Thermal insulation
- Tolerance (engineering)
- Transportation management system
- United States Pharmacopeia
- Validation (drug manufacture)
- Verification and validation
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