Introduction

Principles and practices of cold chain management involves manufacturing, warehousing, and distribution products in a controlled-environment such that the temperature might require ultra-deep freezing (cryogenic) of -80° Celsius of antibodies, nucleic acid probes, or frozen bull semen as used in agriculture; alternatively many pharmaceuticals and frozen foods must be deep frozen, usually around -32° Celsius. Other temperature-sensitive products should be packaged, stored and distributed at cold (2°-4° Celsius) or at standard temperature (23° Celsius). This article will review preparation, warehousing, and distribution of products to be presented to their customers at cryogenic freezing or deep freezing temperatures.

The purpose of cold chain management is multifaceted: it may be a method of preservation of easily spoiled food items intended for sale in worldwide markets; it may be a method to buffer against variable supply and demand, such as warehousing of turkeys before Thanksgiving season; it may allow the distribution and long-term storage of antibodies, RNA probes, DNA probes and lectins used in biomedical research or by medical diagnostic laboratories; it can allow the collection of semen from rare or endangered animals for worldwide transport and conservation; likewise it may allow transport of semen, eggs or zygotes of highly prized livestock worldwide.

A recent example of challenges to cold chain supply comes from a small biotech company, Translate Bio., Inc., in development of a vaccine against Covid-19. Their novel mRNA technology is one anticipated solution to the Covid-19 pandemic (Sherley and Prentice, 2020), but it comes with a very significant disadvantage: the delicacy of RNA and inactivated virus remnants requires freezing to -80° Celsius and maintaining this temperature until it is utilized by a medical practitioner.

As demonstrated by the extreme example of Translate Bio.’s vaccine, the principles of Hazard Analysis and Critical Control Points (HACCP) are applied when distributing medical and food goods throughout the cold chain. The United States Food and Drug Administration (FDA, 1997) endorses HACCP as a rational and effective safety measure to deliver goods from manufacture/harvest to the final consumer. There are seven elements to any HACCP plan that intend to meet its stated goal:

• Analysis of the hazards inherent in the manufacturing/harvesting and distribution environment
• Establishing which processes will be Critical Control Points (CCPs) in the distribution chain
• Establishing critical upper, and perhaps lower limits the product can tolerate (temperature, salinity, time, pH, etc. and for how long)
• Establish written critical limits
• Establishing a validated monitoring procedure
• Have in place in a system for corrective and preventive actions
• Be able to verify that your distribution system delivers the product in the form as intended

Ultimately having a successful HACCP program that is properly implemented and managed means employees and management must be committed to the HACCP approach. In the long run an effective HACPP program will be less costly than a poorly managed one or not having one at all as the cost of one recall of vaccines, a lot of frozen food or degraded active pharmaceutical ingredient could be more expensive than implementing a sound HACPP program before product launch.

1. Analysis of the hazards inherent in the manufacturing/harvesting and distribution environment

A. Primary Freezing

The process of freezing any article containing an aqueous colloidal system common in animals and plants or an aqueous solution is the first hurdle to overcome in any successful cold chain management system. Ice crystals nucleate and grow with atomically sharp tips which could destroy pharmaceuticals, vaccines or food products, rendering them either ineffective or unpalatable. Simple freezing at low temperature in static air is not practical as warm air envelopes the products, insulating them from cold. Slower cooling allows the formation of large air bubbles as gas falls from solution. To overcome such obstacles, various mechanical measures quickly chill various products with little ice crystal damage and bubble formation, as shown below:

i. Fluidized Bed Freezers:

Food particles of a uniform size are placed on a mesh conveyor that can optionally act as a vibrating platform. The freezing airstream travels in an upward direction from underneath the mesh conveyor and the products to be frozen. Air velocity is adjusted such that the product is just lifted a short distance off the belt.

This method is called “fluidized bed freezing” because the solid particles begin to behave as a fluid. Due to lifting of the products to be frozen into air there is an excellent transfer of heat from the product to the freezing air. Heat transfer can be as high as 30-60 Watts/m2Kelvin, quickly enough to preserve the cellular structure of food and therefore its texture (Vazquez and Calvelo, 1983).

Lifting also serves to keep the individual pieces of food or other product from coming in contact with one another; hence they do not stick together and remain separated as they freeze. This is one form of individual quick freezing (IQF). This is particularly important when freezing small food items such as beans, peas, blueberries and the like.

Normally the belt is fed at a rate of 2-5 meters per second with a loading height of 2-13 cm. When the articles to be frozen are of an irregular shape such as cuts of meat or French fries (Cloudy, 1977) they are placed on a vibrating platform.

ii. Individual Quick Freezers or IQF:

Often smaller food particles such as berries, diced meats, shrimp and small fish are rapidly frozen using individual quick freezers (IQF). The principal advantage of this process is its speed, only taking a few minutes, which depends on the type of IQF freezer and the product (Wilson and Singh, 1987). Rapidly freezing food inhibits large ice crystals from forming and damaging cell membranes and thus preventing the frozen food from having a “mushy” consistency. Therefore once the food is defrosted it keeps its original shape, smell, taste, color and texture.

Like fluidized bed freezers it keeps the food particles separated, preventing them from sticking together as they would if frozen in one container. This is important because the consumer can select a given quantity of food to be thawed and consumed, leaving the remainder frozen.

There are two main types of IQFs on the market: mechanical freezers and cryogenic freezers. Mechanical freezers use conveyors to move the product through rapidly moving air which envelopes the line in a circular motion.

Cryogenic freezers move food on the conveyor through liquid nitrogen (Figure 1), often supplied as a spray, continuously moving the product to prevent clumping or block formation (Horbaniuc, Ioan, and Dumitrascu, 2012). These freezer types are generally higher in cost due to the need to liquefy nitrogen, an energy intensive process. An alternative name for this type of freezer is a nitrogen tunnel freezer.

IQFs can be used for cold chain management distribution of food or they can be the first step in making freeze dried food. Pre-freezing is preferred over static freezing in traditional lyophilizers as ice crystal damage is minimized due to much faster cooling rates than can be obtained on lyophilizer shelves.

iii. Blast Freezing:

Blast freezing was initially developed by Clarence Birdseye in the 1930s after observing native peoples of the Canadian arctic in Labrador freezing fish and other food on racks when the wind was particularly strong (Karwatka, 2016). From them he learned that the fish could be very rapidly frozen and then safely consumed months later.

He later popularized this technique using mechanical refrigeration and rapidly circulating air driven by powerful fans in chambers loaded on truck beds (a modern example is given in Figure 2). The trucks would be moved to farms where produce was being harvested. After washing, the food would be separated on racks and very cold, fast moving air would freeze the produce in less than half an hour.

Currently this technique is used on fishing vessels soon after a catch is made and fish are cleaned. In this way the fishing vessel can remain at sea for longer periods of time until the hold is full and the catch delivered to market. Due to the cold temperature psychrophilic (cold-dwelling) bacteria can be prevented from spoiling the catch. For example, adaptation of blast freezing technology has allowed sushi to be readily available to consumers thousands of miles from the fishing grounds and expanded the industry’s market to areas far inland (Ishino and Kadoya, 1999).

As was mentioned above rapid freezing prevents the disruption of cellular membranes and blast freezing was later adapted to storage of fresh frozen plasma as it was found to be a safe method of delivering intact platelets to patients (Isaacs, Scheuermaier, and Levy 2004). It has since broadened its market share to include freezing of a variety of biological products such as antibodies, RNA and DNA probes, and vaccines (Bezawada, Thompson, and Cui, 2011).

Blast freezing units can be small (Kleist, 1952) and suitable for laboratories and restaurants. For example, during the large-scale production of antibodies used in research and medical laboratories freshly isolated antibodies can be subjected to blast freezing (Hauptmann, Hoelzl, and Loerting, 2019). They can then be safely placed into a -80° Celsius freezer without adversely affecting freezer temperature. This is especially important when freezing large amounts of material.

Large blast freezing operations for food export can be found at most US ship ports, for example New Orleans Cold Storage, now part of Emergent Cold of Dallas, TX, which has 142,000 feet of available space for blast freezing and cold storage operations (Figure 3). Much of the food processed at facilities of this type will be packaged for export on Reefer ships designed specifically for cold chain management (Thanopoulou, 2012).

B. Primary, Carrier and Customer Freezer Management

Primary producers, carrier and vendors of agricultural and pharmaceutical products must be able to maintain their stock in a frozen condition after primary freezing. This normally entails manual circular chart recorders, which usually give month-duration logs, as a minimum requirement to maintain a cold chain at the point of production. Said devices require annual calibration and manual change every 30-31 days, which may be easily overlooked by production personnel. 5 More sophisticated methods of temperature recording are now available (Wample, 1990) which allow temperatures to be recorded and charted via connections to computer systems, alleviating the need for changing and storage of circular chart recorder graphs. Alarms and back-up generators are common in industries which supply food or scientific/medical reagents using cold chain management (Mvere and Vinelli, 2005).

i. Hazards in the Distribution Environment

The primary hazards arising in cold chain distribution are described as follows: improper initial freezing, faulty freezer equipment arising from mechanical failure or failure to maintain appropriate maintenance and calibration, transfer times of materials to one freezer environment to the next, and improper packaging and/or palletizing a unit load and failure of distribution from one refrigerated area to the next. These issues will be addressed in order.

ii. Initial Freezing

Once the final pharmaceutical or food item is ready to be frozen it must be done so very quickly to avoid damage from growth of large ice crystals. Rapid cooling allows for multiple nucleation sites for ice such that the entire product is rapidly frozen with little to no damage to either biological or chemical structures.

Given all rapid freezing devices are calibrated and in good working order the most likely mode of freezing failure is arrangement of product within the freezing space. This could include an overly thick layer of food product on a fluidized bed reactor or products placed in a blast freezer such that little or no area is available for cold air to quickly encircle and freeze the product.

For example, with blast freezers pallet stacking must be planned and laid out uniformly to allow the high velocity, cold air to move even around each box in the pallet. Spacers should always be included to allow for air space on the top, sides and bottom of each box. Loading of the pallets is also important. In rack-style blast freezers designed for one or more layer of pallets, under loading by using under-sized pallet loads and empty spaces can create pockets of dead air where cold air does not circulate efficiently.

Therefore it is important to know the requirements of any freezing machine before it is used and follow the manufacturer’s directions for proper load requirements (Dempsey and Bansal, 2012).

iii. Freezing Equipment and Material Transfer

Freezers in a cGxP environment require all equipment to pass installation, operational and performance qualifications according to a written plan generated by the manufacturer or the user of the equipment. The qualifications ensure the freezers are operating at a specified level and for a defined time.

Temperature measurements for all freezing systems in the distribution chain should be manually or electronically monitored as described above. In addition, entry and exit into and out of large freezers should be monitored so as to minimize the time the freezer is open and possible exposure of product to ambient temperatures.

This point illustrates the importance of transfer of goods from one frozen container, for example, at the producer, to the environmentally controlled shipping trailer and finally to the vendor. These three time points should be closely monitored as they may be CCPs on one’s HACCP plan.

Finally, freezers should always have some sort of back-up power system in case municipal utilities are interrupted. For large producers this will entail the use of generators which automatically sense power loss and return power to the facility (Fesha, 2016).

iv. Cold Chain Packaging

Cold chain packaging requires specialized knowledge by all employees from warehouse personnel to the final vendor. The producer and its packaging engineers, warehouse employees and warehouse supervisors are ultimately responsible for correctly packaging product for cold chain distribution.

As mentioned above initial freezing may have very different packaging configurations than shipped product—one would not wish to initially freeze any product in an insulated container as freezing times would be greatly extended and products contained therein could be subject to ice crystal damage. Therefore one must first freeze and then place and sort frozen products in insulated containers for distribution; for other products the primary shipping container is identical to the freezing vessel, as shown by the following example.

Some products such a semen and embryos must be shipped in cryogenic temperatures using liquid nitrogen as a refrigerant. Therefore even though it is a Class 3 substance according to the United States Department of Transportation it has special container requirements which specify that it must be stored in a medium with porous insulated walls. (Electronic Code of Federal Regulations, 2020). This permits liquid nitrogen to be easily stored and excess pressure vented from a storage Dewar tank.

Typical cold-frozen (c.a. 23° Celsius) items packaged in walk-in freezers empty space must be minimized to more easily control thermal conditions during distribution. First the primary packages are placed into secondary packaging and sealed in tertiary packaging—most often a corrugated regular slotted container (RSC). The tertiary packaging is placed into an insulated liner and filled on all sides with frozen cold packs wrapped in plastic bags. The insulated container is then placed in the final packaging or “tote”, covered with an insulated lid and finally capped with the “tote” lid (Soroka, 2014). The tote is sealed, palletized and remains in frozen storage until it is to be picked up by a distributor for delivery.

Often as part of product development or quality assurance a thermocouple is place inside the insulated container and paired with another thermocouple on the outside of the transport pallet. Readings from these thermocouples allows the producer and distributor important information about the CPPs in the cycle and how best to address any problems which might arise (Moureh et al., 2002)

2. Establishing which processes will be Critical Control Points (CCPs) in the distribution chain

In the above description of cold chain management there are several areas which could be regarded as critical points in the distribution chain, the first of which is a manufacturing issue and can be treated as both a distribution and preparation issue.

A. Initial freezing

B. Frozen storage at the production facility

C. Packaging at the production facility and transfer to the distributor

D. Frozen storage and shipping by the distributor, including delivery

duration

E. Transfer by the distributor to the vendor

A. Initial Freezing

Initial freezing using fluidized bed, IQF, blast freezing or (uncommonly) immersion in liquid nitrogen cooled iso-pentane can be assessed by several methods. A protocol to assess proper freezing normally begins with an initial visual inspection of the product at cold temperature to assess whether ice crystals have damaged the product beyond company-defined acceptance criteria. This may also include a thaw to above freezing to ensure the product, especially food, is palatable.

Pharmaceuticals, biologics and foods may be assessed by several different techniques common in microscopy laboratories. Cryo-stage Scanning Electron Microscopes allow any material to be sputter-coated for electrical conductivity and then viewed all in cryogenic conditions (Conway et al., 1997). This allows the operator to assess damage to any frozen specimen as cell walls and organelle are visible as are any ice crystals present in the sample. A company could use this technique to establish and meet acceptance criterial for foods, pharmaceuticals and vaccines.

Similar light microscopy techniques using a cryotome (an instrument which sections frozen tissue into 5-12 micrometer thick slices) and mounting sections on a conventional microscope slide (Lan et al., 2011). Ice in this instance cannot be seen directly but can be inferred if it caused damage to the biological tissues.

Finally, many food companies employ food scientist who evaluate the taste and texture of frozen products before a lot is released (Fu and Labuza, 1977).

Should products not pass company-defined acceptance criterial after the initial freezing process primary freezing would be identified as a CCP and machine parameters would need adjusting or a new freezing method adopted.

B. Frozen Storage at the Production Facility

Despite the constant temperatures in production-facility freezers, whether cryogenic or 23° Celsius, frozen medicinal articles and food do have a shelf-life and a manufacturer must keep production levels in line with both freezer capacity and sales volume. Shelf-life can be defined as the time period within which a pharmaceutical agent loses more than 90% of its initial biological activity (Bajaj, Single and Sakhuja, 2012) or the time within which food is safe to eat and attractive to consumers.

As in any other storage condition biological products deteriorate by different modes or mechanisms. Microbial degradation is less of an issue in cold chain management as microbes 8 are not free to move and reproduce at cold temperatures. However, enzymatic activity can cause flavor changes to foods and accelerate the deterioration of meat products.

Over extended times the nutritional quality of foods and pharmaceuticals can be significant with vitamin C oxidation (Smith and MacLeod, 1955) being one of the most common.

Other concerns over prolonged storage are non-enzymatic browning (such as crosslinking of sugars, lysine and arginine) and water sublimation and recrystallization, otherwise known as freezer burn. Some of these effects, especially physical effects such as freezer burn (Figure 4), may be traced to fluctuating freezer temperatures (Fu and Labuza, 1977). Therefore one critical control could be justly defined as maintenance of freezer temperature, which may be a function of number of entries into a freezer or machine limitations. Temperature monitors should help the packaging engineer identify the causes of any failure in CPPs that occur in the producer warehouse.

C. Packaging at the Production Facility and Transfer to the Distributor

As discussed in Section 1.B.iv packaging of the frozen product for distribution packaging of the product through cold chain management is critical to the performance of the delivery system process. A company’s delivery system should be capable of enduring the known shipping environment with the inclusion of extra time limits in case there are delays in the distribution system.

For instance, if one is using Uline® ice packs at 23° Celsius with a density of two packs on all sides of an RSC with a Uline® insulated shipping container of polystyrene wall thickness of 2 inches, one may find the product may easily withstand air distribution worldwide. If one chooses FedEx as their distribution partner they can ensure deep freeze delivery of your packages and will offer inside and outside temperature monitoring throughout the distribution cycle. They will provide real-time temperature data to allow customers to ensure compliance with national and international notified bodies with shipment audit trails. FedEx is capable of shipping at 9 refrigerated (2°-3° Celsius), frozen (23° Celsius) and cryogenic temperatures of -150° to -195° Celsius (FedEx, Inc., 2020). Cryogenic conditions are suitable for semen, embryos, antibodies, RNA and DNA probes and the like.

D. Frozen Storage and Shipping by the Distributor, including Delivery Duration

Once a parcel or pallet has been transferred to the distributor it leaves the production cold facility, thus becoming as critical point in HACCP, for the actual duration of the journey will vary depending, upon other things, amount of time spent in the ground distribution system and, if transported by air conditions of storage in the airline container, weather, tarmac temperature and time spent clearing customs of foreign jurisdictions.

The second mode of distribution, used more commonly for its lower price compared to air transportation, is the Reefer truck. It is important to know one’s distributor and if the Reefer truck fleet is capable of delivery loads below 0° Celsius (Xiao, et al., 2016) as many are capable of only refrigerated temperatures. In this critical case one would use thermocouples on the inside of a representative package and one on the exterior of the pallet load. Acceptable transit times may vary drastically depending on the trailer temperature. A packaging engineer must foresee that now most shipments can maintain freezing conditions, even if only refrigerated distribution trucks are available.

This becomes yet another CCP. Does thermal packaging which works for air and frozen Reefer truck travel also perform adequately for refrigeration-only Reefer trucks? Likewise, could the thermal packaging be adequate for summertime delivery in unrefrigerated trucks, such as by local delivery panel vans? By outside temperature monitoring of the palletized load and container inside temperature one could determine travel times allowed in refrigerated Reefer trucks; one may also adjust for any duration in unrefrigerated parcel delivery vehicles. Adjustments to insulation and/or frozen ice packs may have to be made to account for different distribution modes.

Some frozen products, especially ones for export, are carried in climate-controlled railcars and Reefer ships equipped with frozen compartments (as mentioned for fishing vessels in 1.A.iii with flash-freezing and frozen holds) allowing frozen items to be economically shipped worldwide. When considering these two modes of transportation one must keep in mind the associated longer travel times and shelf life of the frozen product. Again, the temperature of the inside of the package and the outside of a palletized load should be monitored with thermocouples for traceability—both these modes of transportation have longer loading times than that which is seen for Reefer trucks and air deliveries . Therefore train and ship loading/unloading become a CCP.

E. Transfer by the Distributor to the Vendor

A well-qualified cold chain management distributor will have the proper equipment to handle cryogenic and cold frozen products, depending upon their target market. Medical and commercial medical research laboratories must adhere by cGLP (current Good Laboratory Guidelines), including lot traceability and strict adherence to storage temperatures. The hazard in such an environment would become delivery, receiving inspection and time from receiving to laboratory personnel. For this reason products that come under cold chain management should be received rapidly and turned over to qualified personnel, as they are much more time-sensitive than commodity goods such as metals and ceramics. It would be wise for the product 10 producer, the material distributor and management of the final customer to check temperature logs for both inside and outside the load to ensure product reaches laboratories in functional, non-spoiled conditions (FedEx, 2020).

Likewise, grocery stores and restaurants are regulated by USDA and FDA current Good Manufacturing Practices (cGMP) (Bucknavage and Campbell, 2020) as well as county health departments. As good managers of grocery stores and restaurants are well trained in food hygiene they will be knowledgeable about the importance of proper cold chain management. Again, the major time limitation is from unloading of the parcel or unit load, receiving, and delivery into cold storage facilities. Producers, distributors, and restaurant/grocery managers should have the outside and inside (frozen) temperature logs available to them; just as with a cGLP laboratory loss claims could be made against parties responsible for failing to follow prescribed cold chain management principles.

3. Establishing critical upper, and perhaps lower limits the product can tolerate and for how long

Operational qualification of a cold chain management system should identify the CCPs to determine the limits one’s product, primary packaging and secondary packaging can sustain and still maintain functionality (McLean, 2009). For medical and laboratory qualifications this often entails, at minimum, sterility assurance. For food items it may ensure against freezer “burn”, overly tough, hard textures or microbial spoilage.

Therefore one reviews the Cold Chain Supply from initial freezing until final delivery to create a Hazard Analysis and CCPs plan which will include operational “high” points (in this case maximum allowable temperature at a given time point) and “low” points (which may identify the lowest operation temperature of, for instance, a particular packaging material). Production of these data can be performed through actual field testing (by example, quality checks at different temperature for initial freezing) or by use of environmental conditioning chambers, testing the product to a specific control point and using ASTM standards, among others, to test for package integrity, moisture content and the like. Each time the package is opened after being subjected to a critical “high” or “low” limit the test must begin on a fresh package; otherwise the simulation will not reflect real-world conditions.

Often the United States Food and Drug Administration will allow use of accelerated data such as that from an environmental chamber as an initial check on how a product performs within specified temperature, humidity, and pressure. Real time data is often required for clearance of sensitive medicines and biologic materials. In such cases the product must be shipped through its actual distribution channel and data such as temperature, atmospheric pressure and humidity measured on the inside of the package, and if applicable, on the inside and outside of a palletized load. Data gathered is then compared to that obtained by laboratory testing.

Once the upper and lower atmospheric tolerances for the product and its packaging is determined then actual performance qualifications can be planned as part of product pre-release testing (Ayers, 2006).

4. Establish written critical limits

In the first steps of cold chain management systems analysis of the hazards in the manufacturing/harvesting and distribution environment, establishing which may be CCPs in the 11 distribution chain. One must use data to establish what values may be allowed for fulfill acceptance criteria when monitoring CCPs.

After completion of qualification and all of the CCPs identified, limits must be ascertained for each of the CCPs (Moberg, 1992). One calculates maximum or minimum limits for temperature, time, salt level, pH, chlorine level or other processing parameter which may exert influence on the hazard. These data establish critical limits for the CCP. When these limits are exceeded corrective and preventive actions must be taken, even if quarantining of the product is necessary.

The resolving of critical limits is based on data a producer or distributor has produced within the laboratory and confirmed under field conditions. Companies with more limited resources and have no personnel trained in cold chain management principles will often have to hire outside consultants or use the expertise of their contract distributor to develop a plan with proper operational limits.

Each CCP and its critical limit must be entered into a written HACCP plan. Operational limits for the process can then be prepared and documented taking all critical limits into consideration. Limits determined from qualification lots would be defined more strictly than the operational limits to assure critical limits are never exceeded.

When a critical limit is exceeded there is a possible safety hazard and possibly altered product will need to be controlled. This would likely lead to a shutting of production lines and quarantining or even scrapping of the affected product. By allowing limits for processing to be stricter than those determined during CCP identification one may possibly bring the process back into conformity before a critical limit is reached.

The producer thus uses data generated by the process and any potential hazard to identify each step in manufacturing that is a CCP.

5. Establishing a validated monitoring procedure

Monitoring is prepared surveillance of a CCP which creates an accurate record for further use in verification (Badia-Melis et al., 2018). Monitoring has three principle goals:

A. Monitoring is a prerequisite to pharmaceutical, biologic and food safety as it allows lot traceability of products delivered. If the monitoring system works correctly improperly performed procedures or malfunction of critical systems is detected, then steps must then be taken to bring the process back into specifications before there is a deviation in critical controls.

B. Monitoring also allows operators to ascertain if there is loss of operational control and a deviation occurs at a CCP, i.e., whether one CCP is of improper temperature, humidity, pressure, etc. If a deviation occurs, corrective and preventive actions must be taken to prevent the occurrence in future lots.

C. Monitoring is an important written document—“If you did not document it then it was never done” is a popular phrase to emphasize written documentations must be used to record deviations, actions used to correct for deviations and how the problem was resolved and verified for future use.

Spoilage or microbial degradation may create unsafe, biologic, and pharmaceutical and food products if a process is not under strict control and one or more deviations occur. Products used in medical laboratories may be rendered ineffective and yield false negatives. Due to the severe consequences which may rise if there is a deviation in every one CCP, monitoring of all CCPs should be done in a consistent and continuous manner. The US FDA recommends both physical and biological monitoring should be done on a routine basis. For example temperatures throughout the manufacturing, distribution, laboratory, point-of-sale or clinic should be monitored by regularly by, at a minimum, annually calibrated charts or electronic monitors. Physical monitoring of a CCP could include laboratory measurements such as pH, moisture level, FTIR, sterility testing, endotoxin testing or functional testing using positive controls (as may be done in cGLP compliant laboratories). Where feasible continuous monitoring is desirable even if it is only a check of temperatures, pH and moisture are performed or, if necessary, more sophisticated techniques such as sterility testing is implemented. As emphasized for temperature all equipment used in an ongoing cold chain management program should be calibrated at least annually, with an ID number and calibrated date always noted as part of the record.

Personnel responsible for CCP monitoring must be qualified to perform a task according to governing bodies. For example, environmental monitoring can be conducted by an ISTA Thermal Laboratory Technician whereas microbiology and endotoxin may require a board-certified Medical Laboratory Assistant (MLA) overseen by a state-licensed Clinical Chemist. Laboratory professionals such as these can provide accurate reporting on the CCP monitoring program to ensure loss control by ensuring timely process adjustments.

Proper HACCP monitoring programs are ultimately the responsibility of the producer and vendor of the product to be used in laboratories, consumed as food or used as medicines.

6. Have in place in a system for corrective and preventive actions

The US FDA states that corrective and preventive actions are intended to collect and analyze information during an investigation that identifies quality problems in food, biologic, medical device and pharmaceutical industries (United States Food and Drug Administration, 2014). Specific corrective measures must be then identified to prevent quality issues from reoccurring.

Corrective and preventive actions that deviate from standard operating procedures must then be either verified or validated to ensure quality products are correctly made in further production runs and that those involved in the processes affected are made fully aware of any changes made (Varzakas and Arvanitoyannis, 2007). This includes upper management, shift managers and technicians or other workers directly involved in producing the corrected product.

All changes must be thoroughly documented and provide all necessary information for management review to ensure quality issues are eliminated. Therefore corrective and preventive actions represent one of the most critical parts of any quality system.

A. Corrective Actions

First one must define what a corrective action is. When there is a deviation above or below predetermined critical limits, corrective actions are required (Hulebak and Schlosser, 2002); therefore corrective actions are reactive in nature. One main reason for taking corrective actions is to prevent medicines, biologics or foods which may pose a hazard from reaching either 13 laboratories, hospitals, pharmacists or consumers. Corrective actions will have these items: a) a determination and correction of the problem which led to non-compliance of a product, b) a determination the propensity of non-compliant products to be produced in future production lots and c) documentation of corrective actions that the producer undertook to correct the problem. Distinct corrective actions should be prepared for each CCP and embodied in the HACCP plan. A well written HACCP plan should, at the very least, describe in detail what actions must be taken when a deviation is encountered, which personnel are responsible for completing the corrective actions, and that the responsible person(s) recording the deviation will be develop and maintain actions to prevent CAPAs (corrective and preventive actions) from re-occurring.

B. Preventive Actions

Preventive actions, unlike corrective actions, are not reactive in nature (Mumford, 2013). They are purposeful meant to prevent corrective actions from being taken and may be viewed as one of two types: Preventive Action Process and Preventive Control.

A preventive action process includes a definitive action plan to minimize non-conforming products and also includes the application of controls to assure that all adopted preventive measures work as intended on future production lots. Therefore potential manufacturing or production process difficulties can be identified but solutions for those difficulties can be addressed and improved. Once the changes have been incorporated into a production process validated controls should be updated to ensure there are no further nonconformities.

Preventive controls, the second type of preventive action acts to minimize the chances that nonconformities can occur (Schlessinger and Endres, 2015). Preventive controls comprise a significant part of food preparation quality control. With the introduction of the FDA’s Food Safety Modernization Act (FSMA) certain food producers must have written food safety plans, starting with a hazard analysis and well-defined control points.

Process controls are comprised of procedures that assure all control parameters are met. Process controls include many operations such as heating, rapid freezing, sterile filtration, etc. They should encompass an entire set of critical limits, as necessary to ensure the final product satisfies the manufacturers’ safety systems.

Biological contaminant controls are written procedures the manufacturer must have and implement to control cross-contamination and ensure allergens, mycotoxins and bacterial endotoxins are either excluded or are addressed with appropriately placed as warnings on product labels.

Sanitation controls are simply procedures, processes and practices to ensure that production facilities remain free from outside contamination including but not limited to those listed in the previous paragraph. These include proper washing and gowning techniques. These may be as elaborate as those used in aseptic production of vaccines and biological agents to simpler, food production sanitary controls. All personnel entering production facilities should be trained with written documentation testifying to their training supervisors and date.

Monitoring of all above safety precautions allows assurance levels to be defined that ensure preventive controls are regularly met. All monitoring must be recorded and records retained.

7. Be able to verify that your distribution system delivers the product in the form as intended

Verification concerns making satisfactory measures to assure that the operations outlined in an HACCP plan are operating in practice and specifically that the defined critical limits are satisfactory for ensuring all identified hazards are tightly controlled at CPPs (Kvenberg and Schwalm, 2000). When applied in cryogenic and deep freeze operation this can include the following:

A. Making measurements at critical points for freeze rate, air flow rate, pH temperature, microbial, allergen, mycotoxin and endotoxin, among others to ensure that the process is proceeding as expected at every CCP.

B. Targeted microbiological and/or chemical sampling of intermediate and final products to ensure that the pharmaceutical, biologic or food is meeting expected standards.

C. Documentation should be produced and audited at all CCPs in the production line to be confident that the entirety of correct information is recorded, reviewed and utilized to generate any non-conformance report or CAPA as described in the HACCP plan.

D. Suppliers of raw goods, machines and machine component should be periodically audited to ensure all raw materials entering the production line meet acceptance criteria.

E. Periodic retraining and retesting of production staff should be scheduled to make sure those individuals involved in production are aware of all operating procedures and are capable of performing their assigned tasks.

F. A program of trend analysis to monitor recorded data from a production line needs to be established to determine if one or more CCPs strays from its tolerances or is adequate for generating the required data.

G. Customer complaints should be addressed, especially if representative examples of spoiled product are returned. Third party audits may be useful for analyzing the HACCP and recognizing any potential flaws or oversights in the plan.

H. Ongoing collection of data about product waste during production or time spent reworking items needs to be carefully monitored to assure they follow any records of preventive and corrective actions.

Conclusions

Establishment of an effective Hazard Analysis and CCPs (HACCP) program for cryogenic and deep frozen products hinges on seven critical items listed above, from initial freezing of the product to its final distribution through a cold chain environment.

A wide variety of new products such as uncooked seafood, frozen tissue products and unique medical adhesives are now available due to improvements the use HACCP for cold chain management, both by manufacturers and distributors.

Well-established principles of temperature control during storage and distribution allow a supplier and/or shipper to create protocols to ship goods world-wide under cryogenic, freezing or refrigerated conditions. A well-written and validated plan is expensive to create and implement but does serve to prevent even greater financial losses incurred by spoiled or possibly infectious products when consumed by the end user.

References:

Ayers, James B. Handbook of supply chain management. CRC Press, 2006.

Badia-Melis, Ricardo, et al. "New trends in cold chain monitoring applications-A review." Food Control 86 (2018): 170-182.

Bajaj, Sanjay, Dinesh Singla, and Neha Sakhuja. "Stability testing of pharmaceutical products." J App Pharm Sci 2.3 (2012): 129-138.

Bezawada, Ashish, Mark Thompson, and Weidong Cui. "Use of blast freezers in vaccine manufacture." BioProcess Int 9.9 (2011).

Bucknavage, Martin, and Jonathan A. Campbell. "Good Manufacturing Practices and Other Programs in Support of the Food Safety System." Food Safety Engineering. Springer, Cham, 2020. 159-173.

Cloudy, Westley Ray. "Vibratory weir assembly and method for separating foods being frozen during fluidization in a food freezing tunnel." U.S. Patent No. 4,062,202. 13 Dec. 1977.

Conway, James F., et al. "Visualization of a 4-helix bundle in the hepatitis B virus capsid by cryo-electron microscopy." Nature 386.6620 (1997): 91-94.

Dempsey, Patrick, and Pradeep Bansal. "The art of air blast freezing: Design and efficiency considerations." Applied Thermal Engineering 41 (2012): 71-83.

Electronic Code of Federal Regulations. “Part 172—Hazardous Materials Table, Special Provisions, Hazardous Materials Communications, Emergency Response Information, Training Requirements, and Security Plans”. https://www.ecfr.gov/cgi-bin/text-idx?node=49:2.1.1.3.9.2.25.2&rgn=div8, 2020.

FedEx, Inc. “Cold Chain Services”. http://www.fedex.com/pt_english/shipping-services/industry-solutions/supplychain/coldchain.html, 2020.

Fesha, Getahun. A descriptive study into the cold chain management of childhood vaccines by pharmacists at central and regional level in Ethiopia. Diss. St. Mary’s University, 2016.

Fu, Bin, and Theodore P. Labuza. "Shelf-life testing: procedures and prediction methods." Quality in frozen food. Springer, Boston, MA, 1997. 377-415.

Hauptmann, Astrid, Georg Hoelzl, and Thomas Loerting. "Distribution of protein content and number of aggregates in monoclonal antibody formulation after large-scale freezing." AAPS PharmSciTech 20.2 (2019): 72.

Horbaniuc, Carmen Cătălina Ioan, and Gheorghe Dumitraşcu. "Study of individual quick freezing using liquid nitrogen: An ecological foods freezing technique." Agronomy Series of Scientific Research/Lucrari Stiintifice Seria Agronomie 55.2 (2012).

Hulebak, Karen L., and Wayne Schlosser. "Hazard analysis and CCP (HACCP) history and conceptual overview." Risk analysis 22.3 (2002): 547-552.

Isaacs, M. S., et al. "In vitro effects of thawing fresh-frozen plasma at various temperatures." Clinical and applied thrombosis/hemostasis 10.2 (2004): 143-148.

Ishino, Yuji, and Hironobu Kadoya. "Packed and frozen sushi product and process for thawing the same." U.S. Patent No. 5,861,184. 19 Jan. 1999.

Karwatka, Dennis. "Clarence Birdseye and Frozen Food." Tech Directions 75.8 (2016): 8.

Kleist, Herman W. "Blast freezer." U.S. Patent No. 2,607,201. 19 Aug. 1952.

Kvenberg, John E., and Darrell J. Schwalm. "Use of microbial data for hazard analysis and CCP verification—Food and drug administration perspective." Journal of food protection 63.6 (2000): 810-814.

Lan, Xiu-jian, et al. "Shared Management and Troubleshooting for Shandon Cryotome FSE." Research and Exploration in Laboratory 11 (2011).

McLean, Diane. "Cold chain shipping: Protecting temperature sensitive products." Parenteral Drug Association (2009).

Moberg, Lloyd J. "Establishing critical limits for CCPs." HACCP. Springer, Boston, MA, 1992. 50-61.

Moureh, Jean, et al. "Analysis of use of insulating pallet covers for shipping heat-sensitive foodstuffs in ambient conditions." Computers and Electronics in Agriculture 34.1-3 (2002): 89-109.

Mumford, John. "Biosecurity management practices: determining and delivering a response." Biosecurity. Routledge, 2013. 119-134.

Mvere, David, and Elizabeth Vinelli. Manual on the management, maintenance and use of blood cold chain equipment. World Health Organization, 2005.

Schlessinger, Lisa R., and A. Bryan Endres. "FDA's New Rule for Preventive Controls for Human Foods." farmdoc daily 5.70-2016-285 (2015).

Sherley, James L., and David Prentice. "An Ethics Assessment of COVID-19 Vaccine Programs.” 2020.

Smith, A. C., and Patricia MacLeod. "The effect of artificial light on milk in cold storage." Journal of Dairy Science 38.8 (1955): 870-874.

Soroka, Walter. Fundamentals of packaging technology. Inst of Packaging Professionals, 2014.

Thanopoulou, Helen. "Bulk reefer market economics in a product life cycle perspective." Maritime Policy & Management 39.3 (2012): 281-296.

United States Food and Drug Administration. “HACCP Principles & Application Guidelines”. https://www.fda.gov/food/hazard-analysis-critical-control-point-haccp/haccp-principles-application-guidelines, 14 August, 1997”.

United States Food and Drug Administration. “Corrective and Preventive Actions (CAPA)”. https://www.fda.gov/corrective-and-preventive-actions-capa 8 Sept. 2014.

Varzakas, Theodoros H., and Ioannis S. Arvanitoyannis. "Application of Failure Mode and Effect Analysis (FMEA), cause and effect analysis, and Pareto diagram in conjunction with HACCP to a corn curl manufacturing plant." Critical reviews in food science and nutrition 47.4 (2007): 363-387.

Vazquez, A., and A. Calvelo. "Modeling of residence times in continuous fluidized bed freezers." Journal of Food Science 48.4 (1983): 1081-1085.

Wample, Robert L., et al. "Microcomputer-controlled freezing, data acquisition and analysis system for cold hardiness evaluation." HortScience 25.8 (1990): 973-976.

Wilson, H. A., and R. P. Singh. "Numerical simulation of individual quick freezing of spherical foods." International journal of refrigeration 10.3 (1987): 149-155.

Xiao, Xinqing, et al. "Applying CS and WSN methods for improving efficiency of frozen and chilled aquatic products monitoring system in cold chain logistics." Food Control 60 (2016): 656-666.