Qualitative Risk Assessment:

The process of freeze-drying was invented in 1906 by Jacques-Arsène d’Arsonval and his assistant Frédéric Bordas at the laboratory of biophysics of Collège de France in Paris.[1][2] In 1911 Downey Harris and Shackle developed[3] the freeze-drying method of preserving live rabies virus which eventually led to development of the first antirabies vaccine.

Modern freeze-drying was developed during World War IIBlood serum being sent to Europe from the US for medical treatment of the wounded required refrigeration, but because of the lack of simultaneous refrigeration and transport, many serum supplies were spoiling before reaching their intended recipients. The freeze-drying process was developed as a commercial technique that enabled serum to be rendered chemically stable and viable without having to be refrigerated. Shortly thereafter, the freeze-dry process was applied to penicillin and bone, and lyophilization became recognized as an important technique for preservation of biologicals. Since that time, freeze-drying has been used as a preservation or processing technique for a wide variety of products. These applications include the following but are not limited to: the processing of food,[4] pharmaceuticals,[5] and diagnostic kits; the restoration of water damaged documents;[6] the preparation of river-bottom sludge for hydrocarbon analysis; the manufacturing of ceramics used in the semiconductor industry; the production of synthetic skin; the manufacture of sulfur-coated vials; and the restoration of historic/reclaimed boat hulls.[citation needed]

Stages[edit]

In a typical phase diagram, the boundary between gas and liquid runs from the triple point to the critical point. Freeze-drying (blue arrow) brings the system around the triple point, avoiding the direct liquid-gas transition seen in ordinary drying time (green arrow).

There are four stages in the complete drying process: pretreatment, freezing, primary drying, and secondary drying.

Pretreatment[edit]

Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability, preserve appearance, and/or improve processing), decreasing a high-vapor-pressure solvent, or increasing the surface area. Food pieces are often IQF treated to make it free flowing prior to freeze drying. In many instances the decision to pretreat a product is based on theoretical knowledge of freeze-drying and its requirements, or is demanded by cycle time or product quality considerations.[7]

Freezing[edit]

In a lab, this is often done by placing the material in a freeze-drying flask and rotating the flask in a bath, called a shell freezer, which is cooled by mechanical refrigeration, dry ice in aqueous methanol, or liquid nitrogen. On a larger scale, freezing is usually done using a freeze-drying machine. In this step, it is important to cool the material below its triple point, the lowest temperature at which the solid, liquid and gas phases of the material can coexist. This ensures that sublimation rather than melting will occur in the following steps. Larger crystals are easier to freeze-dry. To produce larger crystals, the product should be frozen slowly or can be cycled up and down in temperature. This cycling process is called annealing. However, in the case of food, or objects with formerly-living cells, large ice crystals will break the cell walls (a problem discovered, and solved, by Clarence Birdseye), resulting in the destruction of more cells, which can result in increasingly poor texture and nutritive content. In this case, the freezing is done rapidly, in order to lower the material to below its eutectic point quickly, thus avoiding the formation of ice crystals. Usually, the freezing temperatures are between −50 °C and −80 °C (-58 °F and -112 °F) . The freezing phase is the most critical in the whole freeze-drying process, because the product can be spoiled if improperly done.

Amorphous materials do not have a eutectic point, but they do have a critical point, below which the product must be maintained to prevent melt-back or collapse during primary and secondary drying.

Primary drying[edit]

During the primary drying phase, the pressure is lowered (to the range of a few millibars), and enough heat is supplied to the material for the ice to sublime. The amount of heat necessary can be calculated using the sublimating molecules’ latent heat of sublimation. In this initial drying phase, about 95% of the water in the material is sublimated. This phase may be slow (can be several days in the industry), because, if too much heat is added, the material’s structure could be altered.

In this phase, pressure is controlled through the application of partial vacuum. The vacuum speeds up the sublimation, making it useful as a deliberate drying process. Furthermore, a cold condenser chamber and/or condenser plates provide a surface(s) for the water vapour to re-solidify on. This condenser plays no role in keeping the material frozen; rather, it prevents water vapor from reaching the vacuum pump, which could degrade the pump’s performance. Condenser temperatures are typically below −50 °C (−58 °F).

It is important to note that, in this range of pressure, the heat is brought mainly by conduction or radiation; the convection effect is negligible, due to the low air density.

Secondary drying[edit]

Miniature quadrupole mass spectrometer used for accurate secondary endpoint detection in aseptic lyophilization application

The secondary drying phase aims to remove unfrozen water molecules, since the ice was removed in the primary drying phase. This part of the freeze-drying process is governed by the material’s adsorption isotherms. In this phase, the temperature is raised higher than in the primary drying phase, and can even be above 0 °C, to break any physico-chemical interactions that have formed between the water molecules and the frozen material. Usually the pressure is also lowered in this stage to encourage desorption (typically in the range of microbars, or fractions of a pascal). However, there are products that benefit from increased pressure as well.

After the freeze-drying process is complete, the vacuum is usually broken with an inert gas, such as nitrogen, before the material is sealed.

At the end of the operation, the final residual water content in the product is extremely low, around 1% to 4%.

Silicone oil contamination challenge[edit]

The majority of commercial freeze-dryers uses Silicone oil as a heat transfer fluid to cool-down and/or heat-up the freeze-dryer shelves. However, due to the repeated heat/cool cycle stress that the hose-to-shelf joints experience, a potential Silicone oil leak can occur within the weakened joints. Silicone oil leaks will compromise the quality and safety of the lyophilized pharmaceutical products and will result in a major economic loss of the spoiled pharmaceutical batch in question. Miniaturized mass spectrometers can detect the presence of minute amounts of the leaking Silicone oil vapor within the freeze-dryer product chamber and allow for action to be taken to save the pharmaceutical batch being processed.

Properties of freeze-dried products[edit]

If a freeze-dried substance is sealed to prevent the reabsorption of moisture, the substance may be stored at room temperature without refrigeration, and be protected against spoilage for many years. Preservation is possible because the greatly reduced water content inhibits the action of microorganisms and enzymes that would normally spoil or degrade the substance.

Freeze-drying also causes less damage to the substance than other dehydration methods using higher temperatures. Freeze-drying does not usually cause shrinkage or toughening of the material being dried. In addition, flavours, smells and nutritional content generally remain unchanged, making the process popular for preserving food. However, water is not the only chemical capable of sublimation, and the loss of other volatile compounds such as acetic acid (vinegar) and alcohols can yield undesirable results.

Freeze-dried products can be rehydrated (reconstituted) much more quickly and easily because the process leaves microscopic pores. The pores are created by the ice crystals that sublimate, leaving gaps or pores in their place. This is especially important when it comes to pharmaceutical uses. Freeze-drying can also be used to increase the shelf life of some pharmaceuticals for many years.

Protectants[edit]

Similar to cryoprotectants, some molecules protect freeze-dried material. Known as lyoprotectants, these molecules are typically polyhydroxy compounds such as sugars (mono-di-, and polysaccharides), polyalcohols, and their derivatives. Trehalose and sucrose are natural lyoprotectants. Trehalose is produced by a variety of plant (for example selaginella and arabidopsis thaliana), fungi, and invertebrate animals that remain in a state of suspended animation during periods of drought (also known as anhydrobiosis).

Applications[edit]

Pharmaceutical and biotechnology[edit]

Lyophilized 5% w/v sucrose cake in a pharmaceutical glass vial

Pharmaceutical companies often use freeze-drying to increase the shelf life of the products, such as live virus vaccines,[8] biologics[9] and other injectables. By removing the water from the material and sealing the material in a glass vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection. Another example from the pharmaceutical industry is the use of freeze drying to produce tablets or wafers, the advantage of which is less excipient as well as a rapidly absorbed and easily administered dosage form.

Freeze-dried pharmaceutical products are produced as lyophilized powders for reconstitution in vials and more recently in prefilled syringes for self-administration by a patient.

Examples of lyophilized biological products include many vaccines such as Measles Virus Vaccine Live, Typhoid Vaccine, Meningococcal Polysaccharide Vaccine Groups A and C Combined. Other freeze-dried biological products include Antihemophilic Factor VIIIInterferon alfa, anti-blood clot medicine Streptokinase and Wasp Venom Allergenic Extract.[10]

Many biopharmaceutical products based on therapeutic proteins such as monoclonal antibodies require lyophilization for stability. Examples of lyophilized biopharmaceuticals include blockbuster drugs such as Etanercept (Enbrel by Amgen), Infliximab (Remicade by Janssen Biotech), Rituximab and Trastuzumab (Herceptin by Genentech).

Freeze-drying is also used in manufacturing of raw materials for pharmaceutical products. Active Pharmaceutical Product Ingredients (APIs) are lyophilized to achieve chemical stability under room temperature storage. Bulk lyophilization of APIs is typically conducted using trays instead of glass vials.

Dry powders of probiotics are often produced by bulk freeze-drying of live microorganisms such as Lactic acid bacteria and Bifidobacteria.[11]

Food and agriculture-based industries[edit]

Freeze dried bacon bars

Freeze-dried coffee, a form of instant coffee

Freeze dried icecream and chocolate, and spaghetti with bacon

Although freeze-drying is used to preserve food, its earliest use in agriculturally based industries was in processing of crops such as peanuts/groundnuts and tobacco in the early 1970s. Because heat, commonly used in crop and food processing, invariably alters the structure and chemistry of the product, the main objective of freeze-drying is to avoid heat and thus preserve the structural and chemical integrity/composition with little or no alteration.[12] Therefore, freeze-dried crops and foods are closest to the natural composition with respect to structure and chemistry. The process came to wide public attention when it was used to create freeze-dried ice cream, an example of astronaut food. It is also widely used to produce essences or flavourings to add to food.

Because of its light weight per volume of reconstituted food, freeze-dried products are popular and convenient for hikers. More dried food can be carried per the same weight of wet food, and remains in good condition for longer than wet food, which tends to spoil quickly. Hikers reconstitute the food with water available at point of use.

Instant coffee is sometimes freeze-dried, despite the high costs of the freeze-driers used. The coffee is often dried by vaporization in a hot air flow, or by projection onto hot metallic plates. Freeze-dried fruits are used in some breakfast cereal or sold as a snack, and are a popular snack choice, especially among toddlerspreschoolershikers and dieters, as well as being used by some pet owners as a treat for pet birds. Most commercial freezing is done either in cold air kept in motion by fans (blast freezing) or by placing the foodstuffs in packages or metal trays on refrigerated surfaces (contact freezing).

Culinary herbs, vegetables (such as vitamin-rich spinach and watercress), the temperature sensitive baker`s yeast suspension and the nutrient-rich pre-boiled rice can also be freeze-dried. During three hours of drying the spinach and watercress has lost over 98% of its water content, followed by the yeast suspension with 96% and the pre-boiled rice by 75%.[13] The air-dried herbs are far more common and less expensive. Freeze dried tofu is a popular foodstuff in Japan (“Koya-dofu” or “shimi-dofu” in Japanese).

Technological industry[edit]

In chemical synthesis, products are often freeze-dried to make them more stable, or easier to dissolve in water for subsequent use.

In bioseparations, freeze-drying can be used also as a late-stage purification procedure, because it can effectively remove solvents. Furthermore, it is capable of concentrating substances with low molecular weights that are too small to be removed by a filtration membrane. Freeze-drying is a relatively expensive process. The equipment is about three times as expensive as the equipment used for other separation processes, and the high energy demands lead to high energy costs. Furthermore, freeze-drying also has a long process time, because the addition of too much heat to the material can cause melting or structural deformations. Therefore, freeze-drying is often reserved for materials that are heat-sensitive, such as proteinsenzymesmicroorganisms, and blood plasma. The low operating temperature of the process leads to minimal damage of these heat-sensitive products.

In nanotechnology, freeze-drying is used for nanotube purification[14] to avoid aggregation due to capillary forces during regular thermal vaporization drying.

Other uses[edit]

Organizations such as the Document Conservation Laboratory at the United States National Archives and Records Administration (NARA) have done studies on freeze-drying as a recovery method of water-damaged books and documents. While recovery is possible, restoration quality depends on the material of the documents. If a document is made of a variety of materials, which have different absorption properties, expansion will occur at a non-uniform rate, which could lead to deformations. Water can also cause mold to grow or make inks bleed. In these cases, freeze-drying may not be an effective restoration method.

In bacteriology freeze-drying is used to conserve special strains.

In high-altitude environments, the low temperatures and pressures can sometimes produce natural mummies by a process of freeze-drying.

Advanced ceramics processes sometimes use freeze-drying to create a formable powder from a sprayed slurry mist. Freeze-drying creates softer particles with a more homogeneous chemical composition than traditional hot spray drying, but it is also more expensive.

A new form of burial which previously freeze-dries the body with liquid nitrogen has been developed by the Swedish company Promessa Organic AB, which puts it forward as an environmentally friendly alternative to traditional casket and cremation burials.

Equipment[edit]

Unloading trays of freeze-dried material from a small cabinet-type freeze-dryer

There are essentially three categories of freeze-dryers: the manifold freeze-dryer, the rotary freeze-dryer and the tray style freeze-dryer. Two components are common to all types of freeze-dryers: a vacuum pump to reduce the ambient gas pressure in a vessel containing the substance to be dried and a condenser to remove the moisture by condensation on a surface cooled to −40 to −80 °C (−40 to −112 °F). The manifold, rotary and tray type freeze-dryers differ in the method by which the dried substance is interfaced with a condenser. In manifold freeze-dryers a short usually circular tube is used to connect multiple containers with the dried product to a condenser. The rotary and tray freeze-dryers have a single large reservoir for the dried substance.

Rotary freeze-dryers are usually used for drying pellets, cubes and other pourable substances. The rotary dryers have a cylindrical reservoir that is rotated during drying to achieve a more uniform drying throughout the substance. Tray style freeze-dryers usually have rectangular reservoir with shelves on which products, such as pharmaceutical solutions and tissue extracts, can be placed in trays, vials and other containers.

Manifold freeze-dryers are usually used in a laboratory setting when drying liquid substances in small containers and when the product will be used in a short period of time. A manifold dryer will dry the product to less than 5% moisture content. Without heat, only primary drying (removal of the unbound water) can be achieved. A heater must be added for secondary drying, which will remove the bound water and will produce a lower moisture content.

Tray style freeze-dryers are typically larger than the manifold dryers and are more sophisticated. Tray style freeze-dryers are used to dry a variety of materials. A tray freeze-dryer is used to produce the driest product for long-term storage. A tray freeze-dryer allows the product to be frozen in place and performs both primary (unbound water removal) and secondary (bound water removal) freeze-drying, thus producing the driest possible end-product. Tray freeze-dryers can dry products in bulk or in vials or other containers. When drying in vials, the freeze-dryer is supplied with a stoppering mechanism that allows a stopper to be pressed into place, sealing the vial before it is exposed to the atmosphere. This is used for long-term storage, such as vaccines.

Improved freeze-drying techniques are being developed to extend the range of products that can be freeze-dried, to improve the quality of the product, and to produce the product faster with less labor.

The process of freeze-drying was invented in 1906 by Jacques-Arsène d’Arsonval and his assistant Frédéric Bordas at the laboratory of biophysics of Collège de France in Paris.[1][2] In 1911 Downey Harris and Shackle developed[3] the freeze-drying method of preserving live rabies virus which eventually led to development of the first antirabies vaccine.

Modern freeze-drying was developed during World War IIBlood serum being sent to Europe from the US for medical treatment of the wounded required refrigeration, but because of the lack of simultaneous refrigeration and transport, many serum supplies were spoiling before reaching their intended recipients. The freeze-drying process was developed as a commercial technique that enabled serum to be rendered chemically stable and viable without having to be refrigerated. Shortly thereafter, the freeze-dry process was applied to penicillin and bone, and lyophilization became recognized as an important technique for preservation of biologicals. Since that time, freeze-drying has been used as a preservation or processing technique for a wide variety of products. These applications include the following but are not limited to: the processing of food,[4] pharmaceuticals,[5] and diagnostic kits; the restoration of water damaged documents;[6] the preparation of river-bottom sludge for hydrocarbon analysis; the manufacturing of ceramics used in the semiconductor industry; the production of synthetic skin; the manufacture of sulfur-coated vials; and the restoration of historic/reclaimed boat hulls.[citation needed]

Stages[edit]

In a typical phase diagram, the boundary between gas and liquid runs from the triple point to the critical point. Freeze-drying (blue arrow) brings the system around the triple point, avoiding the direct liquid-gas transition seen in ordinary drying time (green arrow).

There are four stages in the complete drying process: pretreatment, freezing, primary drying, and secondary drying.

Pretreatment[edit]

Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability, preserve appearance, and/or improve processing), decreasing a high-vapor-pressure solvent, or increasing the surface area. Food pieces are often IQF treated to make it free flowing prior to freeze drying. In many instances the decision to pretreat a product is based on theoretical knowledge of freeze-drying and its requirements, or is demanded by cycle time or product quality considerations.[7]

Freezing[edit]

In a lab, this is often done by placing the material in a freeze-drying flask and rotating the flask in a bath, called a shell freezer, which is cooled by mechanical refrigeration, dry ice in aqueous methanol, or liquid nitrogen. On a larger scale, freezing is usually done using a freeze-drying machine. In this step, it is important to cool the material below its triple point, the lowest temperature at which the solid, liquid and gas phases of the material can coexist. This ensures that sublimation rather than melting will occur in the following steps. Larger crystals are easier to freeze-dry. To produce larger crystals, the product should be frozen slowly or can be cycled up and down in temperature. This cycling process is called annealing. However, in the case of food, or objects with formerly-living cells, large ice crystals will break the cell walls (a problem discovered, and solved, by Clarence Birdseye), resulting in the destruction of more cells, which can result in increasingly poor texture and nutritive content. In this case, the freezing is done rapidly, in order to lower the material to below its eutectic point quickly, thus avoiding the formation of ice crystals. Usually, the freezing temperatures are between −50 °C and −80 °C (-58 °F and -112 °F) . The freezing phase is the most critical in the whole freeze-drying process, because the product can be spoiled if improperly done.

Amorphous materials do not have a eutectic point, but they do have a critical point, below which the product must be maintained to prevent melt-back or collapse during primary and secondary drying.

Primary drying[edit]

During the primary drying phase, the pressure is lowered (to the range of a few millibars), and enough heat is supplied to the material for the ice to sublime. The amount of heat necessary can be calculated using the sublimating molecules’ latent heat of sublimation. In this initial drying phase, about 95% of the water in the material is sublimated. This phase may be slow (can be several days in the industry), because, if too much heat is added, the material’s structure could be altered.

In this phase, pressure is controlled through the application of partial vacuum. The vacuum speeds up the sublimation, making it useful as a deliberate drying process. Furthermore, a cold condenser chamber and/or condenser plates provide a surface(s) for the water vapour to re-solidify on. This condenser plays no role in keeping the material frozen; rather, it prevents water vapor from reaching the vacuum pump, which could degrade the pump’s performance. Condenser temperatures are typically below −50 °C (−58 °F).

It is important to note that, in this range of pressure, the heat is brought mainly by conduction or radiation; the convection effect is negligible, due to the low air density.

Secondary drying[edit]

Miniature quadrupole mass spectrometer used for accurate secondary endpoint detection in aseptic lyophilization application

The secondary drying phase aims to remove unfrozen water molecules, since the ice was removed in the primary drying phase. This part of the freeze-drying process is governed by the material’s adsorption isotherms. In this phase, the temperature is raised higher than in the primary drying phase, and can even be above 0 °C, to break any physico-chemical interactions that have formed between the water molecules and the frozen material. Usually the pressure is also lowered in this stage to encourage desorption (typically in the range of microbars, or fractions of a pascal). However, there are products that benefit from increased pressure as well.

After the freeze-drying process is complete, the vacuum is usually broken with an inert gas, such as nitrogen, before the material is sealed.

At the end of the operation, the final residual water content in the product is extremely low, around 1% to 4%.

Silicone oil contamination challenge[edit]

The majority of commercial freeze-dryers uses Silicone oil as a heat transfer fluid to cool-down and/or heat-up the freeze-dryer shelves. However, due to the repeated heat/cool cycle stress that the hose-to-shelf joints experience, a potential Silicone oil leak can occur within the weakened joints. Silicone oil leaks will compromise the quality and safety of the lyophilized pharmaceutical products and will result in a major economic loss of the spoiled pharmaceutical batch in question. Miniaturized mass spectrometers can detect the presence of minute amounts of the leaking Silicone oil vapor within the freeze-dryer product chamber and allow for action to be taken to save the pharmaceutical batch being processed.

Properties of freeze-dried products[edit]

If a freeze-dried substance is sealed to prevent the reabsorption of moisture, the substance may be stored at room temperature without refrigeration, and be protected against spoilage for many years. Preservation is possible because the greatly reduced water content inhibits the action of microorganisms and enzymes that would normally spoil or degrade the substance.

Freeze-drying also causes less damage to the substance than other dehydration methods using higher temperatures. Freeze-drying does not usually cause shrinkage or toughening of the material being dried. In addition, flavours, smells and nutritional content generally remain unchanged, making the process popular for preserving food. However, water is not the only chemical capable of sublimation, and the loss of other volatile compounds such as acetic acid (vinegar) and alcohols can yield undesirable results.

Freeze-dried products can be rehydrated (reconstituted) much more quickly and easily because the process leaves microscopic pores. The pores are created by the ice crystals that sublimate, leaving gaps or pores in their place. This is especially important when it comes to pharmaceutical uses. Freeze-drying can also be used to increase the shelf life of some pharmaceuticals for many years.

Protectants[edit]

Similar to cryoprotectants, some molecules protect freeze-dried material. Known as lyoprotectants, these molecules are typically polyhydroxy compounds such as sugars (mono-di-, and polysaccharides), polyalcohols, and their derivatives. Trehalose and sucrose are natural lyoprotectants. Trehalose is produced by a variety of plant (for example selaginella and arabidopsis thaliana), fungi, and invertebrate animals that remain in a state of suspended animation during periods of drought (also known as anhydrobiosis).

Applications[edit]

Pharmaceutical and biotechnology[edit]

Lyophilized 5% w/v sucrose cake in a pharmaceutical glass vial

Pharmaceutical companies often use freeze-drying to increase the shelf life of the products, such as live virus vaccines,[8] biologics[9] and other injectables. By removing the water from the material and sealing the material in a glass vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection. Another example from the pharmaceutical industry is the use of freeze drying to produce tablets or wafers, the advantage of which is less excipient as well as a rapidly absorbed and easily administered dosage form.

Freeze-dried pharmaceutical products are produced as lyophilized powders for reconstitution in vials and more recently in prefilled syringes for self-administration by a patient.

Examples of lyophilized biological products include many vaccines such as Measles Virus Vaccine Live, Typhoid Vaccine, Meningococcal Polysaccharide Vaccine Groups A and C Combined. Other freeze-dried biological products include Antihemophilic Factor VIIIInterferon alfa, anti-blood clot medicine Streptokinase and Wasp Venom Allergenic Extract.[10]

Many biopharmaceutical products based on therapeutic proteins such as monoclonal antibodies require lyophilization for stability. Examples of lyophilized biopharmaceuticals include blockbuster drugs such as Etanercept (Enbrel by Amgen), Infliximab (Remicade by Janssen Biotech), Rituximab and Trastuzumab (Herceptin by Genentech).

Freeze-drying is also used in manufacturing of raw materials for pharmaceutical products. Active Pharmaceutical Product Ingredients (APIs) are lyophilized to achieve chemical stability under room temperature storage. Bulk lyophilization of APIs is typically conducted using trays instead of glass vials.

Dry powders of probiotics are often produced by bulk freeze-drying of live microorganisms such as Lactic acid bacteria and Bifidobacteria.[11]

Food and agriculture-based industries[edit]

Freeze dried bacon bars

Freeze-dried coffee, a form of instant coffee

Freeze dried icecream and chocolate, and spaghetti with bacon

Although freeze-drying is used to preserve food, its earliest use in agriculturally based industries was in processing of crops such as peanuts/groundnuts and tobacco in the early 1970s. Because heat, commonly used in crop and food processing, invariably alters the structure and chemistry of the product, the main objective of freeze-drying is to avoid heat and thus preserve the structural and chemical integrity/composition with little or no alteration.[12] Therefore, freeze-dried crops and foods are closest to the natural composition with respect to structure and chemistry. The process came to wide public attention when it was used to create freeze-dried ice cream, an example of astronaut food. It is also widely used to produce essences or flavourings to add to food.

Because of its light weight per volume of reconstituted food, freeze-dried products are popular and convenient for hikers. More dried food can be carried per the same weight of wet food, and remains in good condition for longer than wet food, which tends to spoil quickly. Hikers reconstitute the food with water available at point of use.

Instant coffee is sometimes freeze-dried, despite the high costs of the freeze-driers used. The coffee is often dried by vaporization in a hot air flow, or by projection onto hot metallic plates. Freeze-dried fruits are used in some breakfast cereal or sold as a snack, and are a popular snack choice, especially among toddlerspreschoolershikers and dieters, as well as being used by some pet owners as a treat for pet birds. Most commercial freezing is done either in cold air kept in motion by fans (blast freezing) or by placing the foodstuffs in packages or metal trays on refrigerated surfaces (contact freezing).

Culinary herbs, vegetables (such as vitamin-rich spinach and watercress), the temperature sensitive baker`s yeast suspension and the nutrient-rich pre-boiled rice can also be freeze-dried. During three hours of drying the spinach and watercress has lost over 98% of its water content, followed by the yeast suspension with 96% and the pre-boiled rice by 75%.[13] The air-dried herbs are far more common and less expensive. Freeze dried tofu is a popular foodstuff in Japan (“Koya-dofu” or “shimi-dofu” in Japanese).

Technological industry[edit]

In chemical synthesis, products are often freeze-dried to make them more stable, or easier to dissolve in water for subsequent use.

In bioseparations, freeze-drying can be used also as a late-stage purification procedure, because it can effectively remove solvents. Furthermore, it is capable of concentrating substances with low molecular weights that are too small to be removed by a filtration membrane. Freeze-drying is a relatively expensive process. The equipment is about three times as expensive as the equipment used for other separation processes, and the high energy demands lead to high energy costs. Furthermore, freeze-drying also has a long process time, because the addition of too much heat to the material can cause melting or structural deformations. Therefore, freeze-drying is often reserved for materials that are heat-sensitive, such as proteinsenzymesmicroorganisms, and blood plasma. The low operating temperature of the process leads to minimal damage of these heat-sensitive products.

In nanotechnology, freeze-drying is used for nanotube purification[14] to avoid aggregation due to capillary forces during regular thermal vaporization drying.

Other uses[edit]

Organizations such as the Document Conservation Laboratory at the United States National Archives and Records Administration (NARA) have done studies on freeze-drying as a recovery method of water-damaged books and documents. While recovery is possible, restoration quality depends on the material of the documents. If a document is made of a variety of materials, which have different absorption properties, expansion will occur at a non-uniform rate, which could lead to deformations. Water can also cause mold to grow or make inks bleed. In these cases, freeze-drying may not be an effective restoration method.

In bacteriology freeze-drying is used to conserve special strains.

In high-altitude environments, the low temperatures and pressures can sometimes produce natural mummies by a process of freeze-drying.

Advanced ceramics processes sometimes use freeze-drying to create a formable powder from a sprayed slurry mist. Freeze-drying creates softer particles with a more homogeneous chemical composition than traditional hot spray drying, but it is also more expensive.

A new form of burial which previously freeze-dries the body with liquid nitrogen has been developed by the Swedish company Promessa Organic AB, which puts it forward as an environmentally friendly alternative to traditional casket and cremation burials.

Equipment[edit]

Unloading trays of freeze-dried material from a small cabinet-type freeze-dryer

There are essentially three categories of freeze-dryers: the manifold freeze-dryer, the rotary freeze-dryer and the tray style freeze-dryer. Two components are common to all types of freeze-dryers: a vacuum pump to reduce the ambient gas pressure in a vessel containing the substance to be dried and a condenser to remove the moisture by condensation on a surface cooled to −40 to −80 °C (−40 to −112 °F). The manifold, rotary and tray type freeze-dryers differ in the method by which the dried substance is interfaced with a condenser. In manifold freeze-dryers a short usually circular tube is used to connect multiple containers with the dried product to a condenser. The rotary and tray freeze-dryers have a single large reservoir for the dried substance.

Rotary freeze-dryers are usually used for drying pellets, cubes and other pourable substances. The rotary dryers have a cylindrical reservoir that is rotated during drying to achieve a more uniform drying throughout the substance. Tray style freeze-dryers usually have rectangular reservoir with shelves on which products, such as pharmaceutical solutions and tissue extracts, can be placed in trays, vials and other containers.

Manifold freeze-dryers are usually used in a laboratory setting when drying liquid substances in small containers and when the product will be used in a short period of time. A manifold dryer will dry the product to less than 5% moisture content. Without heat, only primary drying (removal of the unbound water) can be achieved. A heater must be added for secondary drying, which will remove the bound water and will produce a lower moisture content.

Tray style freeze-dryers are typically larger than the manifold dryers and are more sophisticated. Tray style freeze-dryers are used to dry a variety of materials. A tray freeze-dryer is used to produce the driest product for long-term storage. A tray freeze-dryer allows the product to be frozen in place and performs both primary (unbound water removal) and secondary (bound water removal) freeze-drying, thus producing the driest possible end-product. Tray freeze-dryers can dry products in bulk or in vials or other containers. When drying in vials, the freeze-dryer is supplied with a stoppering mechanism that allows a stopper to be pressed into place, sealing the vial before it is exposed to the atmosphere. This is used for long-term storage, such as vaccines.

Improved freeze-drying techniques are being developed to extend the range of products that can be freeze-dried, to improve the quality of the product, and to produce the product faster with less labor.

Executive Summary
The Food and Drug Administration (FDA) has conducted a qualitative risk assessment (RA) related
to manufacturing, processing, packing, and holding activities for human food when such activities
are conducted on farms. The purpose of the RA is to provide a science-based risk analysis of those
activity/food combinations that would be considered low risk. FDA conducted this RA to satisfy
requirements of the FDA Food Safety Modernization Act (FSMA) to conduct a science-based risk
analysis and to consider the results of that analysis in determining whether to exempt small or very
small businesses that are engaged only in specific types of on-farm manufacturing, processing,
packing, or holding activities involving specific foods that FDA determines to be low risk from the
requirements of sections 418 and 421 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), or
whether to modify such requirements for such facilities.
The RA identified the following as low-risk activity/food combinations:
• Boiling gums, latexes, and resins;
• Chopping/coring/cutting/peeling/pitting/shredding/slicing acid fruits and vegetables with
pH<4.2 (e.g., cutting lemons, limes), baked goods (e.g., slicing bread), dried fruit and
vegetable products (e.g., pitting dried plums), dried herbs and other spices (e.g., chopping
intact dried basil, intact dried mint), game meat jerky, gums/ latexes/ resins, other grain
products (e.g., shredding dried cereal), peanuts and tree nuts, and peanut and tree nut
products (e.g., chopping roasted peanuts)
• Coating dried fruit and vegetable products (e.g., coating raisins with chocolate), other fruit
and vegetable products except for non-dried, non-intact fruits and vegetables (e.g., coating
dried plum pieces, dried pitted cherries, and dried pitted apricots with chocolate are low-risk
activity/food combinations but coating apples on a stick with caramel is not a low-risk
activity food combination), other grain products (e.g., adding caramel to popcorn or adding
seasonings to popcorn provided that the seasonings have been treated to significantly
minimize pathogens), peanuts and tree nuts (e.g., adding seasonings provided that the
seasonings have been treated to significantly minimize pathogens), and peanut and tree nut
products (e.g., adding seasonings provided that the seasonings have been treated to
significantly minimize pathogens);
• Dehydration/drying (that includes additional manufacturing or is performed on processed
foods) of other fruit and vegetable products with pH<4.2 (e.g., cut fruit and vegetables with
pH<4.2), and other herb and spice products (e.g., chopped fresh herbs, including tea);
• Extracting (including by pressing, by distilling, by solvent extraction) dried herbs and other
spices (e.g., dried mint), fresh herbs (e.g., mint), fruits and vegetables (e.g., olives,
avocados), grains (e.g., oilseeds), and other herb and spice products (e.g., chopped, fresh
mint);
• Freezing acid fruits and vegetables with pH<4.2 and other fruit and vegetable products with
pH <4.2 (e.g., cut fruits and vegetables);
• Grinding/milling/cracking/crushing baked goods (e.g., crackers), cocoa beans (roasted),
coffee beans (roasted), dried fruit and vegetable products (e.g., raisins, dried legumes), dried
herbs and other spices (e.g., intact dried basil), grains (e.g., oats, rice, rye, wheat), other fruit
and vegetable products that are processed foods (e.g., dried, pitted dates), other grain
products that are processed foods (e.g., dried cereal), other herb and spice products (e.g.,
chopped dried herbs), peanuts and tree nuts, and peanut and tree nut products (e.g., roasted
peanuts);
4
• Labeling baked goods that do not contain food allergens (e.g., crackers that do not contain
wheat, milk, egg, or nuts), candy that does not contain food allergens (e.g., maple candy and
maple cream), cocoa beans (roasted), cocoa products that do not contain food allergens,
coffee beans (roasted), game meat jerky, gums/ latexes/ resins that are processed foods,
honey (pasteurized), jams/ jellies/ preserves, milled grain products that do not contain food
allergens (e.g. corn meal) or that are single ingredient foods (e.g., wheat flour, wheat bran),
molasses and treacle, oils, other fruit and vegetable products that do not contain food
allergens (e.g., snack chips made from potatoes or plantains), other grain products that do not
contain food allergens (e.g., popcorn), other herb and spice products (e.g., chopped or
ground dried herbs), peanut and tree nut products that are single ingredient, are in forms in
which the consumer can reasonably be expected to recognize the allergen(s) without label
declaration, or both (e.g., roasted or seasoned whole nuts, single-ingredient peanut or tree nut
flours), processed seeds (e.g., roasted pumpkin or roasted sunflower seeds), soft drinks and
carbonated water, sugar/syrups, trail mix and granola (other than those containing milk
chocolate and provided that peanuts and/or tree nuts are in forms in which the consumer can
reasonably be expected to recognize the allergen(s) without label declaration), vinegar, any
other processed food that does not require time/temperature control for safety and that does
not contain food allergens (e.g., vitamins, minerals, and dietary ingredients (e.g., bone meal)
in powdered, granular, or other solid form);
• Making baked goods from milled grain products (e.g., breads and cookies);
• Making candy (including boiling, evaporation, mixing) from peanuts and tree nuts (e.g., nut
brittles), sugar/syrups (e.g., taffy, toffee), and saps (e.g., maple candy, maple cream);
• Making cocoa products (including grinding, mixing, conching, tempering) from roasted
cocoa beans;
• Making dried pasta from grains;
• Making jams, jellies and preserves (including cutting/mashing, boiling, mixing, canning)
from acid fruits and vegetables with a pH < 4.6 (e.g., rhubarb, strawberries) ;
• Making molasses and treacle (including extracting, boiling, concentrating, evaporating) from
sugar beets, sugarcane;
• Making oat flakes from grains;
• Making popcorn from grains;
• Making snack chips from fruits and vegetables (e.g., plantains, potatoes);
• Making soft drinks and carbonated water (including flavoring, carbonating) from sugar,
syrups, water;
• Making syrups and sugars (including extracting, boiling, concentrating, evaporating,
crystalizing) from fruits and vegetables (e.g., dates), grains (e.g., rice, sorghum), other grain
products (e.g., malted grains such as barley), sap (e.g., agave, birch, maple, palm), sugar
beets, and sugarcane;
• Making trail mix or granola from cocoa products (e.g., chocolate), dried fruit and vegetable
products (e.g., raisins), other fruit and vegetable products (e.g., chopped dried fruits), other
grain products (e.g., oat flakes), peanut and tree nut products, and seeds (processed)
(provided that peanut and tree nut products, and seeds (processed) have been treated to
significantly minimize pathogens);
• Making vinegar (including fermenting) from fruits and vegetables, other fruit and vegetable
products (e.g., fruit wines, apple cider), and other grain products (e.g., malt);
• Mixing/blending baked goods (e.g., cookie types), candy (e.g., varieties of taffy), cocoa
beans (roasted), coffee beans (roasted), dried fruit and vegetable products (e.g., raisins, dried
5
currants and dried blueberries), dried herbs and other spices (e.g., dried intact basil and dried
intact oregano), honey (pasteurized), milled grain products (e.g., flour, bran, corn meal),
other fruit and vegetable products (e.g., dried, sliced apples and dried sliced peaches); other
grain products (e.g., different types of dried pasta), other herb and spice products (e.g.,
chopped or ground dried herbs, dried herb- or spice-infused honey, dried herb- or spiceinfused
oils and/or vinegars), peanut and tree nut products, sugar/syrups, vinegar, any other
processed food that does not require time/temperature control for safety (e.g., vitamins,
minerals, and dietary ingredients (e.g., bone meal) in powdered, granular, or other solid
form);
• Packaging (including modified atmosphere or vacuum packaging) baked goods, candy,
cocoa beans (roasted), cocoa products, coffee beans (roasted), game meat jerky, gums/
latexes/ resins that are processed foods, honey (pasteurized), jams/ jellies/ preserves, milled
grain products (e.g., flour, bran, corn meal), molasses and treacle, oils, other fruit and
vegetable products (e.g., pitted, dried fruits; sliced, dried apples; snack chips), other grain
products (e.g., popcorn), other herb and spice products (e.g., chopped or ground dried herbs),
peanut and tree nut products, processed seeds, soft drinks and carbonated water,
sugar/syrups, trail mix and granola, vinegar, any other processed food that does not require
time/temperature control for safety (e.g., vitamins, minerals, and dietary ingredients (e.g.,
bone meal) in powdered, granular, or other solid form);
• Packing/re-packing baked goods, candy, cocoa beans (roasted), cocoa products, coffee beans
(roasted), game meat jerky, gums/ latexes/ resins that are processed foods, honey
(pasteurized), jams/ jellies/ preserves, milled grain products (e.g., flour, bran, corn meal),
molasses and treacle, oils, other fruit and vegetable products (e.g., flours made from
legumes, pitted, dried fruits; sliced, dried apples; snack chips), other grain products (e.g.,
popcorn), other herb and spice products (e.g., chopped or ground dried herbs and herbal
extracts), peanut and tree nut products, processed seeds, soft drinks and carbonated water,
sugar/syrups, trail mix and granola, vinegar, any other processed food that does not require
time/temperature control for safety (e.g., vitamins, minerals, and dietary ingredients (e.g.,
bone meal) in powdered, granular, or other solid form);
• Pasteurizing honey;
• Roasting/toasting baked goods (e.g., toasting bread for croutons);
• Salting other grain products (e.g., soy nuts), peanut and tree nut products, processed seeds;
• Sifting milled grain products (e.g., flour, bran, corn meal), other fruit and vegetable products
(e.g., chickpea flour), peanut and tree nut products (e.g., peanut flour, almond flour);
• Storing/holding (cold, ambient or controlled atmosphere) baked goods, candy, cocoa beans
(roasted), cocoa products, coffee beans (roasted), game meat jerky, gums/ latexes/ resins that
are processed foods, honey (pasteurized), jam/ jellies/ preserves, milled grain products (e.g.,
flour, bran, corn, meal), molasses and treacle, oils, other fruit and vegetable products (e.g.,
pitted dried fruits, sliced dried apples, snack chips), other grain products (e.g., popcorn),
other herb and spice products, peanut and tree nut products, processed seeds, soft drinks and
carbonated water, sugar/syrups, trail mix and granola, vinegar, any other processed food that
does not require time/temperature control for safety (e.g., vitamins, minerals, and dietary
ingredients (e.g., bone meal) in powdered, granular, or other solid form).

6
Table of Contents
Contributors ………………………………………………………………………………………………………………………… 2
Acknowledgements ……………………………………………………………………………………………………………… 2
Executive Summary ……………………………………………………………………………………………………………… 3
Table of Contents…………………………………………………………………………………………………………………. 6
List of Tables ………………………………………………………………………………………………………………………. 8
I. Background and Purpose ……………………………………………………………………………………………………. 9
A. Statutory and Regulatory Framework of the FDA Food Safety Modernization Act
(FSMA) ……………………………………………………………………………………………………………………. 9
B. Approach to the Qualitative Risk Assessment ………………………………………………………………… 10
C. Food Types That Are Out of Scope of the Qualitative Risk Assessment ……………………………. 11
D. Specific Questions to be Addressed in the RA ……………………………………………………………….. 12
E. Definitions of Low-Risk Activity and Low-Risk Activity/Food Combination ……………………. 12
F. Data Limitations …………………………………………………………………………………………………………. 13
II. Scope (Activity/food Combinations within the Scope of the RA) ………………………………………… 14
III. Hazard Identification …………………………………………………………………………………………………….. 23
IV. Hazard Characterization ………………………………………………………………………………………………… 36
A. Biological Hazards …………………………………………………………………………………………………….. 36
B. Chemical Hazards – Non-Allergic-type Reactions ………………………………………………………….. 40
C. Chemical Hazards – Allergic-type Reactions …………………………………………………………………. 41
D. Physical Hazards ………………………………………………………………………………………………………… 42
V. Exposure Assessment …………………………………………………………………………………………………….. 43
A. Approach ………………………………………………………………………………………………………………….. 43
B. Factors That Impact the Frequency and Levels of Contamination of the Food – Biological
Hazards …………………………………………………………………………………………………………………… 44
1. Impact of water activity on growth of foodborne pathogens …………………………………………. 44
2. Impact of pH on growth of foodborne pathogens ………………………………………………………… 45
3. Impact of temperature on growth of foodborne pathogens ……………………………………………. 45
4. The impact of other factors on growth of foodborne pathogens …………………………………….. 46
5. Interaction of factors that impact the growth of foodborne pathogens ……………………………. 47
6. Inherent Controls for the Biological Hazards Relevant to This Risk Assessment …………….. 47
7. Interventions to Control the Biological Hazards Relevant to This Risk Assessment ………… 48
8. Activities That Can Introduce, or Increase the Potential for, Biological Hazards Relevant to
This Risk Assessment ………………………………………………………………………………………………….. 52
C. Factors That Impact the Frequency and Levels of Contamination of the Food – Chemical
(including Radiological) and Physical hazards …………………………………………………………….. 54
D. Frequency of Consumption and Amount of Food Consumed …………………………………………… 55
VI. Risk Characterization ……………………………………………………………………………………………………. 56
A. Approach ………………………………………………………………………………………………………………….. 56
B. Qualitative Risk Characterization of Biological Hazards …………………………………………………. 56
C. Qualitative Risk Characterization of Chemical (including Radiological) and Physical
Hazards …………………………………………………………………………………………………………………… 59
D. Characterizing Interventions with Respect to the Definition of Low-Risk Activity …………….. 60
E. Characterizing Activity/Food Combinations ………………………………………………………………….. 61
VII. Conclusions ………………………………………………………………………………………………………………… 89
A. Answers to the Questions to be Addressed in This Risk Assessment ………………………………… 89
B. Summary ……………………………………………………. signed into law. Section 103 of FSMA, Hazard Analysis and Risk-Based Preventive Controls, amends the Federal Food, Drug, and Cosmetic Act (FD&C Act) to create a new section 418 with the same name. Among other things, Section 418 requires facilities to evaluate the hazards that could affect food manufactured, processed, packed, or held by the facility, identify and implement preventive controls, monitor the performance of those controls, and maintain records of the monitoring. Section 418 is applicable to food facilities that are required to register under section 415 of the FD&C Act (Registration of Food Facilities). The registration requirement in section 415 of the FD&C Act does not apply to farms. However, it does apply to “farm mixed-type facilities,” which are establishments that are farms, but that also conduct activities outside the “farm” definition that require the establishment to be registered. Section 103(c) of FSMA directs the Secretary of HHS to conduct a science-based risk analysis to cover “(i) specific types of on-farm packing or holding of food that is not grown, raised, or consumed on such farm or another farm under the same ownership, as such packing, and holding relates to specific foods; and (ii) specific on-farm manufacturing and processing activities as such activities relate to specific foods that are not consumed on that farm or on another farm under common ownership.” We previously issued for public comment a document entitled “Draft Qualitative Risk Assessment of Risk of Activity/Food Combinations for Activities (Outside the Farm Definition) Conducted in a Facility Co-Located on a Farm” (Draft RA) (78 FR 3824, January 16, 2013; Docket No. FDA-2012-N-1258). The activities listed in the Draft RA were those on-farm activities that were outside the farm definition as it existed at the time FSMA became law. Therefore at that time all such activities triggered the registration requirements of section 415 of the FD&C Act and, thus, would make an establishment subject to the new requirements of section 418 of the FD&C Act and the mandatory inspection frequencies in section 421 of the FD&C Act. FDA has since revised the farm definition to include some of the listed activities within the farm definition, thereby narrowing the scope of the activity/food combinations that need to be considered in this risk assessment. (See Appendix 1 for the revised definition of “farm,” harvesting, holding, packing, and manufacturing/processing.) Section 103(c) of FSMA also requires that the Secretary of HHS consider the results of the sciencebased risk analysis and exempt certain facilities from the requirements in section 418 of the FD&C Act, and the mandatory inspection frequency in section 421 of the FD&C Act, or modify the requirements, as the Secretary determines appropriate, if such facilities are engaged only in specific types of on-farm manufacturing, processing, packing, or holding activities that the Secretary determines to be low risk involving specific foods the Secretary determines to be low risk. The exemptions or modifications would apply only to small businesses and very small businesses (as would be defined in the regulation implementing section 418). The purpose of this document is to satisfy these requirements of FSMA 103(c) for a science-based risk analysis covering certain manufacturing, processing, packing, and holding activities conducted on farms. Risk managers at FDA will consider the results of the risk analysis presented in this RA 10 in determining, in part, whether to establish any exemptions from, or modifications to, requirements that would otherwise apply to small or very small farm mixed-type facilities. Since issuing the Draft RA, we have considered the following information with respect to its impact on the Draft RA: • Revisions that FDA proposed to definitions that affect the regulatory status of activities that take place on farm in rulemaking entitled “Current Good Manufacturing Practice and Hazard Analysis and Risk-Based Preventive Controls for Human Food,” (proposed human preventive controls rule; Docket No. FDA-2011-N-0920): o Proposed rule, 78 FR 3646, January 16, 2013; o Supplemental notice of proposed rulemaking (79 FR 58524, September 29, 2014). • Comments submitted to Docket FDA-2012-N-1258 on the Draft RA; • Comments submitted to Docket FDA-2011-N-0920 on the proposed rule relevant to activities conducted on foods on farms; and • A Food Processing Sector Study on domestic establishments co-located on farms, (Capogrossi et al., 2015), updated from the Food Processing Sector Study available in 2011 (Muth et al., 2011). We revised the Draft RA as appropriate after considering all of this information. A summary of key changes in this final risk assessment compared to the draft risk assessment is available (FDA, 2015). B. Approach to the Qualitative Risk Assessment We focused on activity/food combinations that we identified as being conducted on farms (and, thus, might be conducted by farm mixed-type facilities), but we did not consider activity/food combinations that would be solely within the farm definition (such as growing, harvesting and packing fruits and vegetables on farm) and, thus, are not relevant to the requirements of section 103 of FSMA. We focused on considering the risk of activity/food combinations rather than separately considering the risk of specific food categories because doing so would better enable us to focus on whether a specific manufacturing, processing, packing, or holding activity conducted on food by a farm mixed-type facility warranted an exemption from, or modified requirements for, the provisions of section 418 of the FD&C Act. The decision before FDA was in part to determine the need for preventive controls required by section 418 of the FD&C Act for small and very small farm mixed-type facilities. Therefore, in this RA we assessed whether the types of controls that would be required by section 418 of the FD&C Act are needed to ensure the safety of the food manufactured, processed, packed, or held by small or very small farm mixed-type facilities in light of the regulatory framework that would apply to such facilities that would become exempt from, or subject to modified requirements for, the requirements for hazard analysis and risk-based preventive controls that would be established under section 418 of the FD&C Act. Examples of the types of controls that facilities may implement under section 418 include process controls (where a process is used to significantly minimize or prevent a hazard), sanitation controls, and food allergen controls. The regulatory framework that would apply to small or very small farm mixed-type facilities includes FDA’s long-standing current good manufacturing practice (CGMP) requirements for manufacturing, packing, or holding human food and the adulteration provisions of section 402 of the FD&C Act. Any classification of an activity/food 11 combination as “low risk” should not be interpreted to suggest that facilities engaged in these activities do not have an obligation to ensure the safety of the food they manufacture, process, pack, or hold; such facilities must comply with applicable requirements of the FD&C Act and its implementing regulations, including CGMP requirements. C. Food Types That Are Out of Scope of the Qualitative Risk Assessment The following foods are not within the scope of this RA: • Baked goods that require time/temperature control for safety (e.g., cream-filled pastries) • Eggs; • Game meat and game meat products that require time/temperature control for safety; • Honey infused with fresh herbs1 ; • Low-acid2 cut fruits and vegetables; • Milk and milk products (e.g., butter, cheese, cream, and ice cream mixes); and • Oils infused with fruits and vegetables with pH>4.6 or with fresh herbs (e.g., fresh garlic in oil)3 . All of these food types require one or more preventive controls (e.g., heat treatment, time/temperature control for safety) to significantly minimize or prevent a hazard that is reasonably likely to cause serious adverse health consequences or death. (For additional discussion regarding foods that require time/temperature control for safety, see FDA’s Model Food Code (FDA, 2013a).) Additionally, we considered that when a food requires refrigeration to control pathogens (Institute of Food Technologists, 2001b; FDA, 2013d; FDA, 2013b; FDA, 2013e; FDA, 2013c), temperature control is necessary at all steps, and therefore no activity involving such food would be low risk. Thus, activities involving baked goods that require time/temperature control for safety, eggs, game meat and game meat products that require time/temperature control for safety, honey infused with fresh herbs, low-acid cut produce, milk and a number of milk products, and oils infused with fruits and vegetables with pH>4.6 or with fresh herbs could not be considered low-risk activity/food combinations, and we eliminated these foods and on-farm activities that applied solely to them (e.g., churning, curing, eviscerating) from further consideration. In addition, based on the statutory framework of FSMA, activities solely related to the production of seafood, juice, dietary supplements, and alcoholic beverages are outside the scope of this RA and activities related to low-acid canned foods are within the scope of the RA only with respect to chemical (including radiological) and physical hazards. 1 Fresh herbs have a moisture content that could allow sporeforming pathogens such as C. botulinum to grow in an anaerobic environment; honey could create such an environment. 2 Low-acid foods have a pH greater than 4.6; acid foods are those that have a natural pH of 4.6 or below. This pH has long been used to separate foods that may support growth of C. botulinum from those that do not. However, other pathogens are capable of growing at pH values of 4.6 or below, e.g., E. coli O157:H7 (Conner and Kotrola, 1995) and Salmonella (Chung and Goepfert, 1970; Jung and Beuchat, 2000) have been shown to grow at pH 4.0 in laboratory media under certain conditions. The minimum pH at which growth of pathogens occurs is higher in foods than the 4.0 minimum in laboratory media; the Food Code considers foods with a pH<4.2 to not require time/temperature control for safety (non-TCS food) (Food Code 2013d). 3 Fruits and vegetables with pH>4.6, including fresh herbs, in oil provide conditions (e.g., aw and anaerobic conditions) that present a risk of toxin production by C. botulinum (Nummer et al., 2011; Solomon et al. 1991). 12 D. Specific Questions to be Addressed in the .

source:https://www.fda.gov/downloads/Food/GuidanceRegulation/FSMA/UCM461399.

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