Specifications for GMP Dietary Supplements
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Every manufacturer or distributor of dietary supplements has to be in compliance with Good Manufacturing Practices (GMP) requirements. GMP compliance for dietary supplements requires that products must meet specifications for identity, purity, strength, and composition and limits on contaminants. Also specifications are necessary to prevent adulteration as a result of what the manufacturer may do or fail to do in its manufacturing operation.
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Specifications for GMP Dietary Supplements
- 1. Specifications for GMP Dietar y Supplements A Presentation from InstantGMP InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 2. Dietary Supplements Orally ingested products that contain an ingredient that is intended to supplement the diet Not controlled by the FDA until 2007 Now every manufacturer or distributor of dietary supplements has to be in compliance with Good Manufacturing Practices (GMP) requirements InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations 2
- 3. Dietary Ingredients A ingredient intended to supplement the diet Could be one or more of: an amino acid a concentrate or extract of a plant material an herb or other botanical a mineral a vitamin “New Dietary Ingredient” Not sold in US before 1994 FDA requires pre-market review InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 4. GMP for Dietary Supplements FDA requires compliance in manufacturing, packaging, labeling, or holding operations Packaging and labeling has to be done per master manufacturing record Products must meet specifications for identity, purity, strength, and composition and limits on contaminants Demonstrate that product has been manufactured, packaged, labeled, and held under conditions to prevent adulteration All requirements for GMP compliance are in the FDA’s “Final Rule” on dietary supplements Does not apply to establishments that only manufacture dietary ingredients InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 5. Specifications: Control Points Needed for any point where control in the manufacturing process ensures quality, for example: Heating steps Cooling steps Specific sanitation procedures to protect product Points where cross-contamination might occur Where environmental hygiene is necessary InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 6. Specifications: Materials Specifications have to be established for all materials and components used in production Dietary ingredients (when received) In-process production materials Labels Packaging components Finished batch Product received from a supplier for packaging and labeling InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 7. Specifications: Production Specifications have to be established to prevent adulteration in manufacturing operations Critical equipment has to be cleaned and/or sanitized, then tested For example, eliminating possible microbial contamination that might be introduced by a raw material InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 8. Specifications: Packaging/Labeling Firms Firms who perform labeling operations must establish specifications Ensure product received is adequately identified Ensure product is consistent with purchase order InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 9. Specifications: Components Specifications needed for each component used in manufacturing Vitamins or minerals might include: ○ Identification ○ Assay ○ Appearance ○ Odor ○ Solubility ○ Melting Point ○ Loss on Drying or Residue on Ignition ○ Heavy Metals ○ Organic Volatile Impurities InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 10. Specifications: Components Specifications needed for each component used in manufacturing Botanicals might include: ○ Identification such as visual comparison to standard or picture ○ Part of the plant such as root or leaves ○ Color ○ Odor ○ Characteristics that differentiate the desired species from related species InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 11. Specifications: Not Required Specifications are not needed for: Aesthetic appearance of dietary supplement Various constituents that are normally present in a natural product areas where scientific study is still evolving ○ Dissolution ○ Disintegration ○ Bioavailability InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 12. Specifications: Exempted Specifications are exempted if you show that: The spec selected is not able to verify that the control system is producing a dietary supplement that is within that spec There is no scientifically valid method for testing or examining the exempted product spec at the finished batch stage You document why other information, such as component and in-process testing, will show the spec is met without finished batch testing for that spec InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 13. Specifications Parts: Test - Measurement of a quality attribute such as potency or water content Method - The procedure by which the quality attribute is measured Limit - The acceptable range for the attribute Other Requirements Safety and Handling Sampling Instructions InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 14. Quick Facts Developed by the manufacturing and quality experts at PharmaDirections Integrated internet based application developed through “Quality by Design” approach Standard Operating Procedures and Policies come with the application 21 CFR Part 11 Compliant System has been in use since 2004 InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 15. InstantGMP™ Summary Electronic Batch Records for GMP manufacturing Takes full advantage of cloud-based application 21 CFR Part 11 compliant database with SOP requirements hard coded into the software Streamlines entire process of producing GMP materials Simplifies the documentation and approval procedures to reduce production time lines Ideally suited for any GMP manufacturing such as APIs, drugs, OTCs, generics and dietary supplements For more information, contact: JPittman@InstantGMP.com InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
- 16. InstantGMP™ www.instantgmp.com Electronic Batch Records System for GMP Manufacturing InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations
Editor's Notes
- establish specifications for components (final Sec. 111.70(b)), in-process production (final Sec. 111.70(c)), labels and packaging (final Sec. 111.70(d)), the finished batch of dietary supplement (final Sec. 111.70(e)), product that you receive from a supplier for packaging and labeling (final Sec. 111.70(f)), and the packaging and labeling for the finished packaged and labeled dietary supplement include specifications necessary to prevent adulteration under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act as a result of what the manufacturer may do or fail to do in its manufacturing operation, and not as a result of contaminants that are in or on the components received. For example, it may be critical that a certain piece of equipment be cleaned and/or sanitized after handling certain raw materials to ensure that there is no microbial contamination from microorganisms of public health significance to components processed on the equipment. If the manufacturer failed to establish a specification for cleaning and/or sanitizing after handling those raw materials before processing components, the manufacturer would have failed to establish a specification required by final Sec. specifications for identity, purity, strength, composition, and do not exceed their limits for contaminants. The identity, purity, strength, and composition, and the limits that you establish for contaminants, for a finished batch of dietary supplement are what we call ``product specifications' nonregulatory specifications include specifications that largely address the appearance of the dietary supplement in an aesthetic sense. persons who perform labeling operations are, in fact, subject to the final rule, including the requirements to establish specifications. if you receive a product from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier), you must establish specifications to ensure that the product that you receive is adequately identified and is consistent with your purchase order requires you to establish component specifications for each component you use in the manufacture of a dietary supplement. Under final Sec. 111.70(b)(1), you must establish an identity specification for each component that you use in the manufacture of a dietary supplement. A specification for identity may include more than one attribute. For example, a specification for the identity of a salt used in the manufacture of a vitamin and mineral supplement may include the physical characteristics of the solid (e.g., as a crystal or as a powder), the color, and the state of hydration (e.g., with two or three molecules of water). A specification for the identity of a botanical may include the part of the plant (e.g., roots or leaves), the color, and whether the part of the plant is in a native state or has been ground. Under final Sec. 111.70(b)(2), you must establish component specifications that are necessary to ensure that specifications for the purity, strength, and composition of dietary supplements manufactured using the components are met. Under final Sec. 111.70(b)(3) you must establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch This identity specification is necessary to ensure that the finished dietary supplement meets its specification for identity because you could not know what your final product contains if you do not know what you put into it. For example, it is likely that you will need to establish a specification for the strength of vitamin C added as a component, that you use to make a multivitamin supplement, so that you will know how much vitamin C to add to satisfy the specification for the strength of the vitamin C in the final product. Thus, if you are manufacturing a vitamin C tablet with a strength of 50 milligrams (mg) per tablet, you must determine how much vitamin C, of a given strength, you must add in order to produce tablets that will contain 50 mg, after accounting for the theoretical yield at each step in the manufacturing process. However, you may not need to establish a specification for the strength of the tablet coating agent for that multivitamin supplement, if your final specifications include the amount of the tablet coating agent as part of the specifications for the composition, but not the strength of the multivitamin supplement. In most cases, a specification for the composition of the dietary supplement would be sufficient to ensure that the tablet coating agent is used within the established level. this final rule does not require that you establish specifications for the identity, purity, strength, or composition of the various constituents that are inherently present in a natural product such as a botanical. However, the product specifications for the finished batch of a dietary supplement may include a specification, for example, of the strength of a substance that is present in the dietary supplement because it is a constituent of a natural product that you add as a component. For example, you may establish a specification for the amount of vitamin C in a dietary supplement that you manufacture by adding the component rose hips. If this is the case, then the component specifications for the natural product must include a specification for the strength of the constituent (e.g., vitamin C) in whatever amount you determine is necessary to meet the specification for the constituent (vitamin C) in the finished batch of dietary supplement. requires you, for in-process production, to provide adequate documentation of your basis for why meeting the in- process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for identity, purity, strength, and composition. requires that quality control personnel review and approve the documentation you provide. Meeting in-process specifications alone may not ensure the identity, purity, strength, or composition of the dietary supplement, but information about the component specification may be needed in order to put the results from the in-process specification in perspective. For example, if the manufacturer establishes a component specification for lead that it not be greater than ``x'' mg and establishes a specification that all piping that comes into contact with the component be lead free in the facility, and there are no other components or equipment that would be a source of lead, then there should be no added lead from processing, provided that the material only came in contact with the lead-free pipes and only the other lead-free components and equipment are used. Thus, we would not know by looking solely at the in-process specification whether the lead in the final product is not greater than ``x'' mg. You must select one or more established specifications for identity, purity, strength, composition, and limits on those types of contamination that may adulterate or that may lead to adulteration of the dietary supplement that, if tested or examined on the finished batch of the dietary supplement, would verify that the production and process control system is producing a dietary supplement that meets all product specifications (or only those product specifications not otherwise exempted from this provision by quality control personnel under final Sec. 111.75(d)); You may verify this by either testing or examining: (1) Every finished batch for each of these specifications or (2) a subset of finished batches for the dietary supplement. The subset of batches tested must be identified using a sound statistical sampling plan. If you choose to test or examine a subset of finished batches of dietary supplement, you may test or examine each subset of batches for identity, purity, strength, composition, and limits on contamination that you established. Alternatively, you may determine that you can select one, two, or three, or other number of these specifications that, if determined to be in compliance [[Page 34850]] with specifications, would be able to verify that the other untested specifications are met. tests for dissolution, disintegration, and bioavailability of dietary supplements are examples of areas where scientific study is still evolving; thus it is premature to impose requirements for such tests.
- include specifications necessary to prevent adulteration under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act as a result of what the manufacturer may do or fail to do in its manufacturing operation, and not as a result of contaminants that are in or on the components received. For example, it may be critical that a certain piece of equipment be cleaned and/or sanitized after handling certain raw materials to ensure that there is no microbial contamination from microorganisms of public health significance to components processed on the equipment. If the manufacturer failed to establish a specification for cleaning and/or sanitizing after handling those raw materials before processing components, the manufacturer would have failed to establish a specification required by final Sec. specifications for identity, purity, strength, composition, and do not exceed their limits for contaminants. The identity, purity, strength, and composition, and the limits that you establish for contaminants, for a finished batch of dietary supplement are what we call ``product specifications' nonregulatory specifications include specifications that largely address the appearance of the dietary supplement in an aesthetic sense. persons who perform labeling operations are, in fact, subject to the final rule, including the requirements to establish specifications. if you receive a product from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier), you must establish specifications to ensure that the product that you receive is adequately identified and is consistent with your purchase order requires you to establish component specifications for each component you use in the manufacture of a dietary supplement. Under final Sec. 111.70(b)(1), you must establish an identity specification for each component that you use in the manufacture of a dietary supplement. A specification for identity may include more than one attribute. For example, a specification for the identity of a salt used in the manufacture of a vitamin and mineral supplement may include the physical characteristics of the solid (e.g., as a crystal or as a powder), the color, and the state of hydration (e.g., with two or three molecules of water). A specification for the identity of a botanical may include the part of the plant (e.g., roots or leaves), the color, and whether the part of the plant is in a native state or has been ground. Under final Sec. 111.70(b)(2), you must establish component specifications that are necessary to ensure that specifications for the purity, strength, and composition of dietary supplements manufactured using the components are met. Under final Sec. 111.70(b)(3) you must establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch This identity specification is necessary to ensure that the finished dietary supplement meets its specification for identity because you could not know what your final product contains if you do not know what you put into it. For example, it is likely that you will need to establish a specification for the strength of vitamin C added as a component, that you use to make a multivitamin supplement, so that you will know how much vitamin C to add to satisfy the specification for the strength of the vitamin C in the final product. Thus, if you are manufacturing a vitamin C tablet with a strength of 50 milligrams (mg) per tablet, you must determine how much vitamin C, of a given strength, you must add in order to produce tablets that will contain 50 mg, after accounting for the theoretical yield at each step in the manufacturing process. However, you may not need to establish a specification for the strength of the tablet coating agent for that multivitamin supplement, if your final specifications include the amount of the tablet coating agent as part of the specifications for the composition, but not the strength of the multivitamin supplement. In most cases, a specification for the composition of the dietary supplement would be sufficient to ensure that the tablet coating agent is used within the established level. this final rule does not require that you establish specifications for the identity, purity, strength, or composition of the various constituents that are inherently present in a natural product such as a botanical. However, the product specifications for the finished batch of a dietary supplement may include a specification, for example, of the strength of a substance that is present in the dietary supplement because it is a constituent of a natural product that you add as a component. For example, you may establish a specification for the amount of vitamin C in a dietary supplement that you manufacture by adding the component rose hips. If this is the case, then the component specifications for the natural product must include a specification for the strength of the constituent (e.g., vitamin C) in whatever amount you determine is necessary to meet the specification for the constituent (vitamin C) in the finished batch of dietary supplement. requires you, for in-process production, to provide adequate documentation of your basis for why meeting the in- process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for identity, purity, strength, and composition. requires that quality control personnel review and approve the documentation you provide. Meeting in-process specifications alone may not ensure the identity, purity, strength, or composition of the dietary supplement, but information about the component specification may be needed in order to put the results from the in-process specification in perspective. For example, if the manufacturer establishes a component specification for lead that it not be greater than ``x'' mg and establishes a specification that all piping that comes into contact with the component be lead free in the facility, and there are no other components or equipment that would be a source of lead, then there should be no added lead from processing, provided that the material only came in contact with the lead-free pipes and only the other lead-free components and equipment are used. Thus, we would not know by looking solely at the in-process specification whether the lead in the final product is not greater than ``x'' mg. You must select one or more established specifications for identity, purity, strength, composition, and limits on those types of contamination that may adulterate or that may lead to adulteration of the dietary supplement that, if tested or examined on the finished batch of the dietary supplement, would verify that the production and process control system is producing a dietary supplement that meets all product specifications (or only those product specifications not otherwise exempted from this provision by quality control personnel under final Sec. 111.75(d)); You may verify this by either testing or examining: (1) Every finished batch for each of these specifications or (2) a subset of finished batches for the dietary supplement. The subset of batches tested must be identified using a sound statistical sampling plan. If you choose to test or examine a subset of finished batches of dietary supplement, you may test or examine each subset of batches for identity, purity, strength, composition, and limits on contamination that you established. Alternatively, you may determine that you can select one, two, or three, or other number of these specifications that, if determined to be in compliance [[Page 34850]] with specifications, would be able to verify that the other untested specifications are met. tests for dissolution, disintegration, and bioavailability of dietary supplements are examples of areas where scientific study is still evolving; thus it is premature to impose requirements for such tests.
- nonregulatory specifications include specifications that largely address the appearance of the dietary supplement in an aesthetic sense. persons who perform labeling operations are, in fact, subject to the final rule, including the requirements to establish specifications. if you receive a product from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier), you must establish specifications to ensure that the product that you receive is adequately identified and is consistent with your purchase order requires you to establish component specifications for each component you use in the manufacture of a dietary supplement. Under final Sec. 111.70(b)(1), you must establish an identity specification for each component that you use in the manufacture of a dietary supplement. A specification for identity may include more than one attribute. For example, a specification for the identity of a salt used in the manufacture of a vitamin and mineral supplement may include the physical characteristics of the solid (e.g., as a crystal or as a powder), the color, and the state of hydration (e.g., with two or three molecules of water). A specification for the identity of a botanical may include the part of the plant (e.g., roots or leaves), the color, and whether the part of the plant is in a native state or has been ground. Under final Sec. 111.70(b)(2), you must establish component specifications that are necessary to ensure that specifications for the purity, strength, and composition of dietary supplements manufactured using the components are met. Under final Sec. 111.70(b)(3) you must establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch This identity specification is necessary to ensure that the finished dietary supplement meets its specification for identity because you could not know what your final product contains if you do not know what you put into it. For example, it is likely that you will need to establish a specification for the strength of vitamin C added as a component, that you use to make a multivitamin supplement, so that you will know how much vitamin C to add to satisfy the specification for the strength of the vitamin C in the final product. Thus, if you are manufacturing a vitamin C tablet with a strength of 50 milligrams (mg) per tablet, you must determine how much vitamin C, of a given strength, you must add in order to produce tablets that will contain 50 mg, after accounting for the theoretical yield at each step in the manufacturing process. However, you may not need to establish a specification for the strength of the tablet coating agent for that multivitamin supplement, if your final specifications include the amount of the tablet coating agent as part of the specifications for the composition, but not the strength of the multivitamin supplement. In most cases, a specification for the composition of the dietary supplement would be sufficient to ensure that the tablet coating agent is used within the established level. this final rule does not require that you establish specifications for the identity, purity, strength, or composition of the various constituents that are inherently present in a natural product such as a botanical. However, the product specifications for the finished batch of a dietary supplement may include a specification, for example, of the strength of a substance that is present in the dietary supplement because it is a constituent of a natural product that you add as a component. For example, you may establish a specification for the amount of vitamin C in a dietary supplement that you manufacture by adding the component rose hips. If this is the case, then the component specifications for the natural product must include a specification for the strength of the constituent (e.g., vitamin C) in whatever amount you determine is necessary to meet the specification for the constituent (vitamin C) in the finished batch of dietary supplement. requires you, for in-process production, to provide adequate documentation of your basis for why meeting the in- process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for identity, purity, strength, and composition. requires that quality control personnel review and approve the documentation you provide. Meeting in-process specifications alone may not ensure the identity, purity, strength, or composition of the dietary supplement, but information about the component specification may be needed in order to put the results from the in-process specification in perspective. For example, if the manufacturer establishes a component specification for lead that it not be greater than ``x'' mg and establishes a specification that all piping that comes into contact with the component be lead free in the facility, and there are no other components or equipment that would be a source of lead, then there should be no added lead from processing, provided that the material only came in contact with the lead-free pipes and only the other lead-free components and equipment are used. Thus, we would not know by looking solely at the in-process specification whether the lead in the final product is not greater than ``x'' mg. You must select one or more established specifications for identity, purity, strength, composition, and limits on those types of contamination that may adulterate or that may lead to adulteration of the dietary supplement that, if tested or examined on the finished batch of the dietary supplement, would verify that the production and process control system is producing a dietary supplement that meets all product specifications (or only those product specifications not otherwise exempted from this provision by quality control personnel under final Sec. 111.75(d)); You may verify this by either testing or examining: (1) Every finished batch for each of these specifications or (2) a subset of finished batches for the dietary supplement. The subset of batches tested must be identified using a sound statistical sampling plan. If you choose to test or examine a subset of finished batches of dietary supplement, you may test or examine each subset of batches for identity, purity, strength, composition, and limits on contamination that you established. Alternatively, you may determine that you can select one, two, or three, or other number of these specifications that, if determined to be in compliance [[Page 34850]] with specifications, would be able to verify that the other untested specifications are met. tests for dissolution, disintegration, and bioavailability of dietary supplements are examples of areas where scientific study is still evolving; thus it is premature to impose requirements for such tests.
- nonregulatory specifications include specifications that largely address the appearance of the dietary supplement in an aesthetic sense. requires you to establish component specifications for each component you use in the manufacture of a dietary supplement. Under final Sec. 111.70(b)(1), you must establish an identity specification for each component that you use in the manufacture of a dietary supplement. A specification for identity may include more than one attribute. For example, a specification for the identity of a salt used in the manufacture of a vitamin and mineral supplement may include the physical characteristics of the solid (e.g., as a crystal or as a powder), the color, and the state of hydration (e.g., with two or three molecules of water). A specification for the identity of a botanical may include the part of the plant (e.g., roots or leaves), the color, and whether the part of the plant is in a native state or has been ground. Under final Sec. 111.70(b)(2), you must establish component specifications that are necessary to ensure that specifications for the purity, strength, and composition of dietary supplements manufactured using the components are met. Under final Sec. 111.70(b)(3) you must establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch This identity specification is necessary to ensure that the finished dietary supplement meets its specification for identity because you could not know what your final product contains if you do not know what you put into it. For example, it is likely that you will need to establish a specification for the strength of vitamin C added as a component, that you use to make a multivitamin supplement, so that you will know how much vitamin C to add to satisfy the specification for the strength of the vitamin C in the final product. Thus, if you are manufacturing a vitamin C tablet with a strength of 50 milligrams (mg) per tablet, you must determine how much vitamin C, of a given strength, you must add in order to produce tablets that will contain 50 mg, after accounting for the theoretical yield at each step in the manufacturing process. However, you may not need to establish a specification for the strength of the tablet coating agent for that multivitamin supplement, if your final specifications include the amount of the tablet coating agent as part of the specifications for the composition, but not the strength of the multivitamin supplement. In most cases, a specification for the composition of the dietary supplement would be sufficient to ensure that the tablet coating agent is used within the established level. this final rule does not require that you establish specifications for the identity, purity, strength, or composition of the various constituents that are inherently present in a natural product such as a botanical. However, the product specifications for the finished batch of a dietary supplement may include a specification, for example, of the strength of a substance that is present in the dietary supplement because it is a constituent of a natural product that you add as a component. For example, you may establish a specification for the amount of vitamin C in a dietary supplement that you manufacture by adding the component rose hips. If this is the case, then the component specifications for the natural product must include a specification for the strength of the constituent (e.g., vitamin C) in whatever amount you determine is necessary to meet the specification for the constituent (vitamin C) in the finished batch of dietary supplement. requires you, for in-process production, to provide adequate documentation of your basis for why meeting the in- process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for identity, purity, strength, and composition. requires that quality control personnel review and approve the documentation you provide. Meeting in-process specifications alone may not ensure the identity, purity, strength, or composition of the dietary supplement, but information about the component specification may be needed in order to put the results from the in-process specification in perspective. For example, if the manufacturer establishes a component specification for lead that it not be greater than ``x'' mg and establishes a specification that all piping that comes into contact with the component be lead free in the facility, and there are no other components or equipment that would be a source of lead, then there should be no added lead from processing, provided that the material only came in contact with the lead-free pipes and only the other lead-free components and equipment are used. Thus, we would not know by looking solely at the in-process specification whether the lead in the final product is not greater than ``x'' mg. You must select one or more established specifications for identity, purity, strength, composition, and limits on those types of contamination that may adulterate or that may lead to adulteration of the dietary supplement that, if tested or examined on the finished batch of the dietary supplement, would verify that the production and process control system is producing a dietary supplement that meets all product specifications (or only those product specifications not otherwise exempted from this provision by quality control personnel under final Sec. 111.75(d)); You may verify this by either testing or examining: (1) Every finished batch for each of these specifications or (2) a subset of finished batches for the dietary supplement. The subset of batches tested must be identified using a sound statistical sampling plan. If you choose to test or examine a subset of finished batches of dietary supplement, you may test or examine each subset of batches for identity, purity, strength, composition, and limits on contamination that you established. Alternatively, you may determine that you can select one, two, or three, or other number of these specifications that, if determined to be in compliance [[Page 34850]] with specifications, would be able to verify that the other untested specifications are met. tests for dissolution, disintegration, and bioavailability of dietary supplements are examples of areas where scientific study is still evolving; thus it is premature to impose requirements for such tests.
- nonregulatory specifications include specifications that largely address the appearance of the dietary supplement in an aesthetic sense. Under final Sec. 111.70(b)(2), you must establish component specifications that are necessary to ensure that specifications for the purity, strength, and composition of dietary supplements manufactured using the components are met. Under final Sec. 111.70(b)(3) you must establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch This identity specification is necessary to ensure that the finished dietary supplement meets its specification for identity because you could not know what your final product contains if you do not know what you put into it. For example, it is likely that you will need to establish a specification for the strength of vitamin C added as a component, that you use to make a multivitamin supplement, so that you will know how much vitamin C to add to satisfy the specification for the strength of the vitamin C in the final product. Thus, if you are manufacturing a vitamin C tablet with a strength of 50 milligrams (mg) per tablet, you must determine how much vitamin C, of a given strength, you must add in order to produce tablets that will contain 50 mg, after accounting for the theoretical yield at each step in the manufacturing process. However, you may not need to establish a specification for the strength of the tablet coating agent for that multivitamin supplement, if your final specifications include the amount of the tablet coating agent as part of the specifications for the composition, but not the strength of the multivitamin supplement. In most cases, a specification for the composition of the dietary supplement would be sufficient to ensure that the tablet coating agent is used within the established level. this final rule does not require that you establish specifications for the identity, purity, strength, or composition of the various constituents that are inherently present in a natural product such as a botanical. However, the product specifications for the finished batch of a dietary supplement may include a specification, for example, of the strength of a substance that is present in the dietary supplement because it is a constituent of a natural product that you add as a component. For example, you may establish a specification for the amount of vitamin C in a dietary supplement that you manufacture by adding the component rose hips. If this is the case, then the component specifications for the natural product must include a specification for the strength of the constituent (e.g., vitamin C) in whatever amount you determine is necessary to meet the specification for the constituent (vitamin C) in the finished batch of dietary supplement. requires you, for in-process production, to provide adequate documentation of your basis for why meeting the in- process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for identity, purity, strength, and composition. requires that quality control personnel review and approve the documentation you provide. Meeting in-process specifications alone may not ensure the identity, purity, strength, or composition of the dietary supplement, but information about the component specification may be needed in order to put the results from the in-process specification in perspective. For example, if the manufacturer establishes a component specification for lead that it not be greater than ``x'' mg and establishes a specification that all piping that comes into contact with the component be lead free in the facility, and there are no other components or equipment that would be a source of lead, then there should be no added lead from processing, provided that the material only came in contact with the lead-free pipes and only the other lead-free components and equipment are used. Thus, we would not know by looking solely at the in-process specification whether the lead in the final product is not greater than ``x'' mg. You must select one or more established specifications for identity, purity, strength, composition, and limits on those types of contamination that may adulterate or that may lead to adulteration of the dietary supplement that, if tested or examined on the finished batch of the dietary supplement, would verify that the production and process control system is producing a dietary supplement that meets all product specifications (or only those product specifications not otherwise exempted from this provision by quality control personnel under final Sec. 111.75(d)); You may verify this by either testing or examining: (1) Every finished batch for each of these specifications or (2) a subset of finished batches for the dietary supplement. The subset of batches tested must be identified using a sound statistical sampling plan. If you choose to test or examine a subset of finished batches of dietary supplement, you may test or examine each subset of batches for identity, purity, strength, composition, and limits on contamination that you established. Alternatively, you may determine that you can select one, two, or three, or other number of these specifications that, if determined to be in compliance [[Page 34850]] with specifications, would be able to verify that the other untested specifications are met. tests for dissolution, disintegration, and bioavailability of dietary supplements are examples of areas where scientific study is still evolving; thus it is premature to impose requirements for such tests.
- nonregulatory specifications include specifications that largely address the appearance of the dietary supplement in an aesthetic sense. this final rule does not require that you establish specifications for the identity, purity, strength, or composition of the various constituents that are inherently present in a natural product such as a botanical. However, the product specifications for the finished batch of a dietary supplement may include a specification, for example, of the strength of a substance that is present in the dietary supplement because it is a constituent of a natural product that you add as a component. For example, you may establish a specification for the amount of vitamin C in a dietary supplement that you manufacture by adding the component rose hips. If this is the case, then the component specifications for the natural product must include a specification for the strength of the constituent (e.g., vitamin C) in whatever amount you determine is necessary to meet the specification for the constituent (vitamin C) in the finished batch of dietary supplement. requires you, for in-process production, to provide adequate documentation of your basis for why meeting the in- process specifications, in combination with meeting component specifications, will help ensure that the specifications are met for identity, purity, strength, and composition. requires that quality control personnel review and approve the documentation you provide. Meeting in-process specifications alone may not ensure the identity, purity, strength, or composition of the dietary supplement, but information about the component specification may be needed in order to put the results from the in-process specification in perspective. For example, if the manufacturer establishes a component specification for lead that it not be greater than ``x'' mg and establishes a specification that all piping that comes into contact with the component be lead free in the facility, and there are no other components or equipment that would be a source of lead, then there should be no added lead from processing, provided that the material only came in contact with the lead-free pipes and only the other lead-free components and equipment are used. Thus, we would not know by looking solely at the in-process specification whether the lead in the final product is not greater than ``x'' mg. You must select one or more established specifications for identity, purity, strength, composition, and limits on those types of contamination that may adulterate or that may lead to adulteration of the dietary supplement that, if tested or examined on the finished batch of the dietary supplement, would verify that the production and process control system is producing a dietary supplement that meets all product specifications (or only those product specifications not otherwise exempted from this provision by quality control personnel under final Sec. 111.75(d)); You may verify this by either testing or examining: (1) Every finished batch for each of these specifications or (2) a subset of finished batches for the dietary supplement. The subset of batches tested must be identified using a sound statistical sampling plan. If you choose to test or examine a subset of finished batches of dietary supplement, you may test or examine each subset of batches for identity, purity, strength, composition, and limits on contamination that you established. Alternatively, you may determine that you can select one, two, or three, or other number of these specifications that, if determined to be in compliance [[Page 34850]] with specifications, would be able to verify that the other untested specifications are met. tests for dissolution, disintegration, and bioavailability of dietary supplements are examples of areas where scientific study is still evolving; thus it is premature to impose requirements for such tests.
- you may exempt a product specification from the verification requirements of final Sec. 111.75(c)(1) if you show that: (1) The specifications selected to verify that the product meets all product specifications are not able to verify that the control system is producing a dietary supplement that meets the exempted product specification and (2) there is no scientifically valid method for testing or examining the exempted product specification at the finished batch stage. Final Sec. 111.75(c)(1) also requires you to document why other information, such as component and in-process testing, will determine whether the exempted product specification is met without finished batch testing. Although we agree that there may be some circumstances where there is not a scientifically valid method available for finished product testing, we believe that there would be some scientifically valid method available for component or in-process testing.