2750 MANUFACTURING PRACTICES FOR DIETARY SUPPLEMENTS
As is indicated in the General Notices under Significant Figures and Tolerances, tolerances are based upon the consideration that the article is produced under recognized principles of good manufacturing practice. Many of the principles in this general information chapter are basic in that they apply equally to various types of products and levels of technology, and that they are derived from the current good manufacturing practices for drugs. However, the practical application of these principles to dietary supplements may be different.
The principles set forth in this chapter contain recommended minimum current good manufacturing practices for the methods to be used in, and the facilities and controls to be used for, the manufacture of a dietary supplement to assure that such a product meets the requirements of safety, and has the identity and strength and meets the quality and purity characteristics that it is represented to possess.
Establishments engaged solely in the harvesting, storage, or distribution of one or more raw agricultural commodities as defined in section 201(r) of the Dietary Supplements Health and Education Act of 1994, which are ordinarily cleaned, prepared, treated, or otherwise processed before being marketed to the consuming public are excluded from this chapter.
A glossary of terms used in this general chapter is presented at the end.
ORGANIZATION AND PERSONNEL
Responsibilities of Quality Control Unit
A quality control unit shall be established that has the responsibility and authority to approve or reject all raw materials, product containers, closures, in-process materials, packaging material, labeling, and finished dietary supplements, and the authority to review production records to ensure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit should be responsible for approving or rejecting products manufactured, processed, packed, or held under contract by another company.
Adequate laboratory facilities for the testing and approval (or rejection) of raw materials, product containers, closures, packaging materials, in-process materials, and dietary supplements should be available to the quality control unit.
The quality control unit should have the responsibility for approving or rejecting all procedures or specifications that impact on the identity, strength, quality, and purity of the dietary supplement. All responsibilities and procedures applicable to the quality control unit shall be in writing.
Each person engaged in the manufacture of a dietary supplement should have the proper education, training, and experience (or any combination thereof) needed to perform the assigned functions. Training should be in the particular operation(s) that the employee performs as they relate to the employee's functions.
Appropriate documentation of training shall be retained by the company.
Each person responsible for supervising the manufacture of a dietary product should have the proper education, training, and experience (or any combination thereof) to perform assigned functions in such a manner as to provide assurance that the product has the safety, identity, strength, quality, and purity that it is represented to possess.
An adequate number of qualified personnel to perform and supervise the manufacture of each dietary product should be provided.
The company management shall take all reasonable measures and precautions to assure the following:
GROUNDS, BUILDINGS, AND FACILITIES
The grounds about a dietary product manufacturing plant under the control of the operator shall be kept in a condition that will protect against the adulteration of dietary products. The methods for adequate maintenance of grounds include, but are not limited to the following:
Any building or buildings used in the manufacture of a dietary product should be of suitable size and shall be constructed in such a manner that floors, walls, and ceilings may be adequately cleaned and kept clean and in good repair; that drips or condensate from fixtures, ducts, and pipes does not adulterate raw materials or in-process or finished dietary product, or contaminate product containers, utensils, or packaging materials; and that aisles or working spaces are provided between equipment and walls and are adequately unobstructed and of adequate width to permit employees to perform their duties and to protect against adulterating in-process or finished product, or contaminating processing equipment with clothing or personal contact. The building should have adequate space for the orderly placement of equipment and materials to prevent mixups between different raw materials, product containers, closures, labeling, in-process materials, or finished products, and to prevent contamination. The flow of raw materials, product containers, closures, labeling, in-process materials, and products through the building or buildings should be designed to prevent contamination.
Operations should be performed within specifically defined areas of adequate size to prevent contamination or mixups or adulterations of in-process or finished dietary product, or contamination of processing equipment, utensils, or packaging materials with microorganisms, chemicals, filth, or other extraneous material. The potential for mixups and product adulteration may be reduced by adequate product safety controls and operating practices or effective design, including the separation of operations in which contamination is likely to occur, by one or more of the following means: location, time, partition, airflow, enclosed systems, or other effective means. There should be separate or defined areas as follows:
Any building used in the manufacture of a dietary product shall permit the taking of proper precautions to protect dietary ingredients or dietary supplements in outdoor bulk fermentation vessels by any effective means, including the following:
Adequate lighting shall be provided in all areas and should not expose bulk or finished product to adulteration or contamination. Adequate lighting should be provided in hand-washing areas, dressing and locker rooms, and toilet rooms, and in all areas where product is examined, processed, or stored and where equipment or utensils are cleaned; and should provide safety-type light bulbs, fixtures, skylights, or other glass suspended over exposed product in any step of preparation or otherwise protect against product adulteration in case of glass breakage.
Ventilation, Air Filtration, Air Heating, and Cooling
Adequate ventilation shall be provided, as well as equipment for adequate control over microorganisms, dust, humidity, and temperature when used in the manufacture of a dietary product to minimize odors and vapors (including steam and noxious fumes) in areas where they may adulterate dietary products; and to locate and operate fans and other air-blowing equipment in a manner that minimizes the potential for adulterating raw materials, in-process or finished dietary products, or contaminating processing equipment, utensils, or packaging materials.
Potable water at a suitable temperature, and under pressure as needed, should be supplied in a plumbing system free of defects that could contribute contamination to any dietary product. Potable water should meet the standards prescribed in the Environmental Protection Agency's Primary Drinking Water Regulations (40 CFR Part 141) or any state or local drinking water requirements that are more stringent. Water not meeting such standards should not be permitted in the potable water system for Purified Water. If potable water is to be used as a raw material, it should be further purified to satisfy compendial requirements.
Drains should be of adequate size and, where connected directly to a sewer, should have an air break or other mechanical device to prevent back-siphonage.
Sewage and Refuse
Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner.
Washing and Toilet Facilities
Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.
General Maintenance and Sanitation
Any building used in the manufacture of a dietary product should be maintained in a clean and sanitary condition and shall be kept in repair sufficient to prevent raw materials, and in-process or finished dietary products from becoming adulterated. It shall be free of infestation by rodents, birds, insects, and other vermin. Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.
Cleaning compounds and sanitizing agents used in cleaning and sanitizing procedures shall be free from undesirable microorganisms and shall be safe and adequate under the conditions of use. Compliance with this requirement may be verified by any effective means including purchase of these substances under a supplier's guarantee or certification, or examination of these substances for contamination. Only the following toxic materials may be used or stored in a plant where product is processed or exposed:
Written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the building and facilities shall be required.
Toxic cleaning compounds, sanitizing agents, and pesticide chemicals shall be identified, used, held, and stored in a manner that protects against adulteration of raw materials, in-process or finished product, or contamination of processing equipment or packaging materials. All relevant regulations promulgated by other Federal, state, and local government agencies for the application, use or holding of these products should be followed.
No pests shall be allowed in any area of a dietary product manufacturing plant. Effective measures shall be taken to exclude pests from the processing areas and to protect against the adulteration by pests of product on the premises. The use of insecticides or rodenticides is permitted only under precautions and restrictions that will protect against the adulteration of raw materials, in-process or finished product, or contamination of processing equipment, utensils or packaging materials.
Written procedures are also required for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents. These procedures should be designed to prevent the contamination of equipment, raw materials, product containers, closures, packaging, labeling materials, or products. Rodenticides, insecticides, and fungicides should be registered and used in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act.
Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.
Equipment used in the manufacture of a dietary supplement shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
All equipment shall be constructed so that surfaces that contact raw materials, in-process materials, or finished products are not reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the product beyond the established requirements.
The design, construction and use of equipment and utensils shall preclude the adulteration of raw materials, packaging materials, in-process materials, or finished product with any substances required for operation such as lubricants, fuel, or any other contaminants such as metal fragments, contaminated water, etc.
Cleaning and Maintenance
Equipment and utensils shall be cleaned, maintained, and sanitized at adequate intervals, between the manufacture of different batches of the same product and between the manufacture of different products, to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the product beyond the established requirements.
Written procedures for cleaning and maintaining equipment, including utensils, used in the manufacture of a product should be established and followed. These procedures should include, but are not necessarily limited to, the following:
A written record of calibration, inspection, maintenance of equipment, and major equipment cleaning and use shall be maintained in individual equipment logs that show the date, product and lot number of each batch processed. The persons performing the cleaning shall record in the log that the work was performed. Entries in the log should be in chronological order.
RAW MATERIALS, PRODUCT CONTAINERS, AND CLOSURES
Written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of raw materials, product containers, and closures should be provided.
Raw materials, product containers, and closures at all times should be handled and stored in a manner to prevent contamination.
Raw agricultural materials that contain soil or other contaminants shall be washed or cleaned as necessary. Water used for washing, rinsing, or conveying raw agricultural materials shall be safe and of adequate sanitary quality. Notwithstanding the general requirement for potable water, water may be reused for washing, rinsing, or conveying raw agricultural materials if it does not increase the level of contamination of such materials.
Bagged or boxed raw materials of product containers or closures should be stored off the floor and suitably spaced to permit cleaning and inspection.
Each lot should be appropriately identified as to its status (i.e., quarantined, approved, or rejected).
Receipt and Storage of Untested Raw Materials, Product Containers, and Closures
Written procedures shall be established and followed describing the receipt, identification, examination, handling, and sampling of raw materials. Upon receipt and before acceptance, each container or grouping of containers of raw materials, product containers, and closures should be examined visually for appropriate labeling as to contents, container damage, or broken seals, and for contamination. They are then stored under quarantine until they have been tested or examined, as appropriate, and released.
Raw materials shall be held in bulk, or in containers designed and constructed so as to protect against adulteration and shall be held at such temperature and relative humidity and in such a manner as to prevent a dietary ingredient or dietary supplement from becoming adulterated. Frozen raw materials and other ingredients shall be kept frozen. If thawing is required prior to use, it shall be done in a manner that prevents the raw materials and other ingredients from becoming adulterated within the meaning of the Act.
Testing and Approval or Rejection
Each lot of raw materials, product containers, and closures should be sampled, tested, or examined, as appropriate, and released for use by the quality control unit. Based upon adequate process verification, in-process controls and statistical confidence, a skip-lot sampling plan is an alternative to testing every batch. An appropriate amount of each lot of raw materials should be reserved for 3 years beyond the shelf life appearing on the label of finished dietary supplements in which the raw materials were used. If adverse event reports are received, the reserved raw materials should be kept for 6 years from the date the first report is received.
Representative samples should be collected for testing or examination. Sampling of botanicals should be in compliance with the provisions set in Articles of Botanical Origin 561. The number of containers sampled, and the amount of material taken from each container, should be based upon appropriate criteria such as statistical criteria for raw material variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required. The following procedures should be used to collect the samples:
Use the following procedure to examine and test the samples:
Use of Approved Raw Materials, Product Containers, and Closures
Raw materials, product containers, and closures approved for use should be rotated so that the oldest approved stock is used first. Deviation from the requirement is permitted if such deviation is temporary and adequate.
Retesting of Approved Raw Materials, Product Containers, and Closures
Raw materials, product containers, and closures should be retested or re-examined, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit after a specified time in storage or as necessary, e.g., after exposure to air, heat, or other conditions that might adversely affect the raw material, product container, or closure or after storage of active and inactive ingredients and in-process materials for long periods of time.
Rejected Raw Materials, Product Containers, and Closures
Rejected raw materials, product containers, and closures should be identified and controlled under a quarantine system that prevents their use in manufacturing or processing operations for which they are unsuitable.
PRODUCTION AND PROCESS CONTROLS
Written procedures should be provided for production and process control designed to ensure that the dietary supplements have the identity, strength, quality, and purity they are represented to possess. These procedures should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit. These production and process control procedures should be followed in the execution of the various production and process control functions and should be documented at the time of performance. Any deviation from the written procedures should be recorded and justified.
Charge-In of Raw Materials
Written production and control procedures should include the following, which are designed to ensure that the dietary supplements have the identity, strength, quality, and purity they are represented to possess:
Material scheduled for rework shall be identified as such.
All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a product should be properly identified to indicate their contents and, when necessary, the phase of processing of the batch.
Sampling and Testing of In-Process Materials and Dietary Products
To ensure batch uniformity and integrity of dietary supplements, written procedures should be established and followed that describe the in-process controls and tests or examinations to be conducted on appropriate samples of in-process materials. Based upon process verification, in-process controls and statistical confidence, a skip-lot sampling plan is an alternative to testing every batch. Control procedures should be established to monitor the output of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the finished product. Such control procedures may include, but are not limited to, the following, where appropriate:
In-process specifications for such characteristics should be consistent with finished product specifications. Examination and testing of samples should ensure that the in-process material and dietary supplement conform to the established specifications.
In-process materials should be tested for identity, strength, quality, and purity as adequate, and approved or rejected by the quality control unit during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.
Rejected or adulterated in-process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable and prevent the adulteration of other products.
LABELING AND PACKAGING
Materials Examination and Usage Criteria
Written procedures should be provided describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, or testing of labeling and packaging materials. Labeling and packaging materials should be representatively sampled and examined or tested upon receipt and before use in packaging or labeling of a product.
Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use. Those that do not meet such specifications should be rejected to prevent their use in operations for which they are unsuitable.
A record should be kept of each shipment received of each different labeling and packaging material, indicating receipt, date of examination or testing, and whether accepted or rejected.
Labels and other labeling materials for each different product, strength, product type, or quantity of contents should be stored separately with suitable identification. Only authorized personnel should have access to the storage area.
Gang printing of labeling to be used for different products or different strengths of the same product (or labeling of the same size and identical or similar format or color schemes) should be minimized. If gang printing is employed, packaging and labeling operations should provide for special control procedures, taking into consideration sheet layout, stacking, cutting, and handling during and after printing.
Printing devices on, or associated with, manufacturing lines used to imprint labeling upon the product unit label or case should be monitored to ensure that all imprinting conforms to the print specified in the batch production record.
Obsolete and outdated labels, labeling, and other packaging materials should be destroyed and documented.
Strict control should be exercised over labeling issued for use in product labeling operations. The control procedures employed should be in writing with sufficient detail.
Labeling materials issued for a batch should be carefully examined for identity and conformity to the labeling specified in the master or batch production records.
Procedures should be utilized to reconcile the quantities of labeling issued, used, and returned, and should require evaluation of discrepancies found. If discrepancies are found between the quantity of product finished and the quantity of labeling issued and are outside preset limits based on historical operating data, such discrepancies should be investigated.
Returned labeling should be maintained and sorted in a manner to prevent mixups and provide proper identification.
All excess labeling bearing lot or control numbers should be destroyed and documented.
Written procedures designed to ensure that correct labels, labeling, and packaging materials are used for dietary supplements should incorporate the following features:
Each manufacturer and packer who packages a dietary supplement for retail sale shall package the product in a tamper-resistant package, if this product is accessible to the public while held for sale. A tamper-resistant package is one having an indicator or barrier to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of substitution of a tamper-resistant feature after tampering, the indicator or barrier to entry is required to be distinctive by design or by the use of an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture). For purposes of this section, the term distinctive by design means that the packaging cannot be duplicated with commonly available materials or through commonly available processes. A tamper-resistant package may involve an immediate-container and closure system, or secondary-container or carton system, or any combination of systems intended to provide a visual indication of package integrity. The tamper-resistant feature should be designed to remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.
Each retail package of a dietary supplement covered by this section shall bear a statement that is prominently placed so that consumers are alerted to the specific tamper-resistant feature of the package. The labeling statement should be so placed that it will be unaffected if the tamper-resistant feature of the packaging is breached or missing. If the tamper-resistant feature chosen to meet the requirement above is one that uses an identifying characteristic, that characteristic should be referred to in the labeling statement. For example, the labeling statement on a bottle with a shrink band could say For your protection, this bottle has an imprinted seal around the neck.
Dietary Supplement Inspection
Packaged and labeled products should be examined during finishing operations to ensure that containers and packages in the lot have the correct label. A representative sample of units should be collected at the completion of finishing operations and visually examined for correct labeling. Results of these examinations should be recorded in the batch production or control records.
The manufacturer, packer, or distributor of dietary supplements is required to comply with the current labeling requirements in the law that also include a domestic address or phone number through which an adverse event report for a dietary supplement may be received.
Dietary supplements should bear a date indicative of its shelf life, determined by appropriate testing, to ensure that they meet applicable standards of identity, strength, quality, and purity at or before the labeled shelf-life date.
Shelf life should be related to any storage conditions stated on the labeling.
HOLDING AND DISTRIBUTION
Storage and transportation of finished product shall be under conditions that will protect product against physical, chemical, and microbial adulteration as well as against deterioration of the product and the container.
Written procedures describing the warehousing of dietary supplements should be established and followed and should include the following:
Written procedures describing the distribution of dietary supplements shall be established and followed and should include the following:
QUALITY CONTROL OPERATIONS
The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this general chapter, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this section should be followed and documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.
Quality control operation includes the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that raw materials, product containers, closures, in-process materials, labeling, and finished products conform to adequate standards of identity, strength, quality and purity. These controls include the following:
Testing and Release for Distribution
There should be appropriate laboratory determination of satisfactory conformance to specifications for the finished product, including the identity and strength prior to release. Based upon adequate process verification, in-process controls, or statistical confidence, a skip-lot or composite sampling plan is an alternative to testing every batch.
There should be appropriate laboratory testing, as necessary, of each batch of dietary supplement required to be free of objectionable microorganisms. The accuracy, linearity, sensitivity, specificity, and precision of test methods employed by the firm, when they differ from compendial methods, should be established and documented.
Written procedures should describe any sampling and testing plans, which should include the method of sampling and the number of units per batch to be tested.
Products failing to meet established standards or specifications and any other relevant quality control criteria should be rejected. Rejected or adulterated dietary products shall be identified, stored, and disposed of in a manner that protects against the adulteration of the other products. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet established standards, specifications, and any other relevant criteria. Written procedures shall be established and followed prescribing the method for reprocessing batches or operations start-up materials that do not conform to finished goods standards or specifications. Finished goods manufactured using such materials shall meet all established purity, composition, and quality standards.
There should be a written protocol designed to assess the stability characteristics of dietary supplements. The results of such testing should be used in determining appropriate storage conditions and shelf life. This protocol should include the following:
An adequate number of batches of each dietary supplement should be tested to determine an adequate shelf-life, and a record of these data should be maintained. Accelerated studies combined with basic stability information on the raw materials, dietary supplements, and container-closure systems may be used to support tentative shelf life provided full shelf-life studies are not available. Simplified stability testing procedures may be used where data from similar product formulations are available to support a shelf-life estimation of a new product. Where data from accelerated studies are used to project a tentative shelf life date that is beyond a date supported by actual shelf-life studies, stability studies should be conducted, including dietary supplement testing at appropriate intervals, until the tentative shelf life is verified or the adequate shelf life is determined.
An appropriately identified reserve sample that is representative of each lot or batch of dietary supplement should be retained and stored under conditions consistent with product labeling until at least 3 years after the shelf life of the product. The reserve sample should be stored in the same immediate containerclosure system in which the finished product is marketed or in one that has essentially the same characteristics. The reserve sample consists of at least twice the quantity necessary to perform all the required tests. If an adverse event report is received, the reserve samples of dietary supplements and dietary ingredients from the same lot or batch must be analyzed by the appropriate procedure to confirm their identity and determine any adulteration or contamination. The recovered samples associated with adverse event reports from consumers, distributors, or both should also be analyzed, following the same method used for the reserved samples, if available. The results should be reported with other required information to the federal authority, using the required form. The reserve samples from a particular lot or batch associated with the adverse event reports should be held for 6 years from the date when the first adverse event report is received by the manufacturer, packer, or distributor.
RECORDS AND REPORTS
Any production, control, or distribution record that is required to be maintained and is specifically associated with a batch of a product should be retained for at least 3 years after the shelf life of the batch.
Records should be maintained for all raw materials, product containers, closures, and labeling for at least 3 years after the shelf life of the last lot of product incorporating the raw material or using the container, closure, or labeling.
Master Production and Control Records
To ensure uniformity from batch to batch, master production and control records for each product should be prepared, dated, and signed by one person and independently checked, dated, and signed by a second person from the quality control unit.
Master production and control records should include the following:
Batch Production and Control Records
Batch production and control records should be prepared for each batch of product produced and should include complete information relating to the production and control of each batch. These records should be reviewed and signed by a second person from the quality control unit. These records should include accurate reproduction of the appropriate master production or control record and documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including the following:
Laboratory records should include complete data derived from all tests necessary to ensure compliance with established specifications and standards, including examinations and assays, as follows:
Complete records should be maintained of any modification of an established method employed in testing. Such records should include the reason for the modification and data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method.
Complete records should be maintained of any testing and standardization of laboratory reference standards, reagents, and standard solutions, the periodic calibration of laboratory instruments, and all stability testing performed. Any deviation should be reviewed and signed by the management of the quality control unit.
Distribution records should contain the name and strength of the product, name and address of the consignee, date and quantity shipped, and lot or control number of the finished product.
The manufacturer, packer, or distributor of dietary supplements must keep all required records, as shown in this chapter, for 3 years beyond the shelf life of dietary supplements associated with those records. If adverse event reports are received, those records must be kept for 6 years from the date when the first report is received. All records must be accessible by the regulatory authority when requested.
Written procedures describing the handling of all written and oral complaints regarding a dietary supplement shall be established and followed. These procedures should include provisions for review by the quality control unit of any complaint involving the possible failure of a product to meet any of its specifications and a determination as to the need for an investigation.
Each complaint should be recorded in a file designed especially for dietary supplement complaints. Written records should be maintained until at least 3 years after the shelf life of the product, or 3 years after the date when the complaint was received, whichever is longer.
The written record should include the following information, where known: the name and strength of the product, lot number, name of complainant, nature of complaint, and reply to complainant.
If an investigation is necessary, the written record should include the findings of the investigation and follow-up.
Adverse Event Reports
The manufacturer, packer, or distributor of a dietary supplement (responsible person) whose name appears on the label shall be responsible for reporting any serious adverse event reported and associated with a dietary supplement that is marketed and used in the same country, to the regulatory authority as soon as appropriate, but no later than 15 business days after receipt of the report, using the appropriate form as defined by the regulation. A serious adverse event is an event that results in
A retailer whose name appears on the label as a distributor may, by agreement, authorize the manufacturer or packer to submit the required reports to the regulatory authority, as long as the retailer directs all received adverse event reports to the manufacturer or packer. Each serious adverse event report should include a copy of the product's label, the information described in the preceding section Complaint Files, and if possible, the contact information of the complainant; daily intake; alcohol consumption and amount; use of prescription medicine and OTC medicine, including a daily dose; and other medical information. The information associated with personal identification and medical records should be obtained only for the reports and kept safe from disclosure. Any new medical information that is related to an already submitted serious adverse event report that is received within 1 year of the initial report shall be submitted to the regulatory authority as soon as appropriate, but no later than 15 business days after receipt of the information. The records related to each report of an adverse event received by the manufacturer, packer, or retailer should be maintained for 6 years. The authorized person who is designated by the regulatory authority should be permitted to access to those records.
RETURNED AND SALVAGED PRODUCTS
Returned Dietary Supplements
Returned products should be identified as such and held. If the conditions under which returned dietary products have been held, stored, or shipped before or during their return, or if the condition of the product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality, or purity of the product, the returned product should be destroyed unless examination, testing or other investigations prove the product meets appropriate standards of safety, identity, strength, quality, or purity. The returned products associated with adverse events must be destroyed after a sufficient sample of products is stored for the purpose of further investigation only. The products related to the adverse event that have been returned should be kept for 6 years from the date when the first report is received. A product may be reprocessed provided the subsequent product meets adequate standards, specifications, and characteristics. Records of returned products should be maintained and should include the name and label potency of the product, lot number (or control number or batch number), reason for the return, quantity returned, date of disposition, and ultimate disposition of the returned product. If the reason for a product being returned implicates associated batches, an appropriate investigation is necessary.
Dietary Supplement Salvaging
Products that have been involved in adverse events or subjected to improper storage conditions, including extremes in temperature or humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures should not be salvaged and returned to the marketplace. Whenever there is a question whether products have been subjected to such conditions, salvaging operations may be conducted only if there is (a) evidence from laboratory tests and assays that the products meet all applicable standards of identity, strength, quality, and purity, and (b) evidence that the products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident. Organoleptic examinations should be accepted only as supplemental evidence that the dietary supplement meets appropriate standards of identity, strength, quality, and purity. Records including name, lot number, and disposition should be maintained for salvaged products. If the products are involved in adverse events, the instructions described in the preceding section Records and Reports should be followed.
Defect Action Levels
Some dietary ingredients and dietary supplements, even when produced under current good manufacturing practice, contain natural or unavoidable defects that at low levels are not hazardous to health. The Food and Drug Administration establishes maximum levels for these defects in dietary products produced under current good manufacturing practice and uses these levels in deciding whether to recommend regulatory action.
Defect action levels are established for dietary products whenever it is necessary and feasible to do so. These levels are subject to change upon the development of new technology or the availability of new information.
Compliance with defect action levels does not excuse violation of the requirement in section 402(a)(4) of the Act that dietary products not be prepared, packed, or held under unsanitary conditions or the requirements in this part that dietary product manufacturers, distributors, and holders shall observe current good manufacturing practice. Evidence indicating that such a violation exists causes a dietary product to be adulterated within the meaning of the Act, even though the amounts of natural or unavoidable defects are lower than the currently established defect action levels. The manufacturer, distributor, and holder of a dietary product shall at all times utilize quality control operations that reduce natural or unavoidable defects to the lowest level currently feasible.
The mixing of a dietary ingredient or dietary supplement containing defects above the current defect action level with another lot of dietary ingredient or dietary supplement is not permitted and renders the final product adulterated within the meaning of the Act, regardless of the defect level of the final product.
A compilation of the current defect action levels for natural or unavoidable defects in dietary products that present no health hazard may be obtained upon request from the Industry Activities Staff (HFS-565), Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, 5100 Paint Branch Parkway, College Park, MD 20740-3835.
Act means Federal Food, Drug and Cosmetic Act (United States Code [USC] Title 21, Chapter 9).
Acceptance criteria is the product specifications and acceptance or rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units).
Adequate means that which is needed to accomplish the intended purpose in keeping with good public health practice.
Adverse event means any health-related event that is adverse and that is associated with the use of a dietary supplement.
Adverse event report means a report of an adverse event (see definition above). (See also Serious adverse event report.)
Batch is a specific quantity of a finished product or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.
Blanching means a prepackaging heat treatment of a dietary product for a sufficient time and at a sufficient temperature to partially or completely inactivate the naturally occurring enzymes and to effect other physical or biochemical changes in the product.
Composition is (1) the identity of a dietary ingredient or dietary supplement, and (2) the concentration of a dietary ingredient (e.g., weight or other unit of use/weight or volume), or the potency or activity of one or more dietary ingredients, as indicated by appropriate procedures.
Dietary ingredient is an ingredient intended for use or used in a dietary supplement that is
Dietary product means either a dietary ingredient or dietary supplement as defined in this chapter.
Dietary supplement is a product (other than tobacco) that is intended to supplement the diet and that bears or contains one or more of the following dietary ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract or combination of these ingredients, that is intended for ingestion in a pill, capsule, tablet or liquid form, that is not represented for use as a conventional food or as the sole item of a meal or diet, and that is labeled as a dietary supplement, and includes products such as new drug, certified antibiotic, or licensed biologic that was marketed as a dietary supplement or food before approval, certification, or license unless a sanitary authority waives this provision).
Inactive ingredient is any raw material other than a dietary ingredient.
In-process material is any material fabricated, compounded, blended, ground, extracted, sifted, sterilized, or processed in any other way that is produced for, and used in, the preparation of the dietary supplement.
Lot is a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits.
Lot number, control number, or batch number is any distinctive combination of letters, numbers, or symbols, or any combination of them from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of finished dietary ingredient, dietary supplement, or other material can be determined.
Manufacture or manufacturing includes all operations associated with the production of dietary products, including packaging and labeling operations, testing, and quality control of a dietary ingredient or dietary supplement.
Microorganisms means yeast, molds, bacteria, and viruses and includes, but is not limited to, species having public health significance. The term undesirable microorganisms includes those microorganisms that are of public health significance, that subject a dietary product to decomposition, that indicate that a dietary ingredient or dietary supplement is contaminated with filth, or that otherwise may cause a dietary product to be adulterated within the meaning of the act. Occasionally in these regulations, the adjective microbial is used instead of an adjectival phrase containing the word microorganism.
Pest refers to any objectionable animals or insects including, but not limited to, bird, rodents, flies, and larvae.
Plant means the building or facility or parts thereof, used for or in connection with the manufacturing, packaging, labeling, or holding of a dietary product.
Process evaluation is a set of tests performed on a process intended to evaluate its capacity to consistently produce the results that it is intended for.
Quality control operation is a planned and systematic procedure for taking all actions necessary to prevent a dietary product from being adulterated.
Quality control unit is any person or organizational element designated by the firm to be responsible for the duties relating to quality control operations.
Raw material is any ingredient intended for use in the manufacture of a dietary ingredient or dietary supplement, including those that may not appear in such finished product. (A dietary ingredient is a raw material when considering the manufacture of a dietary supplement.)
Representative sample is a sample that consists of a number of units that are drawn based on rational criteria such as random sampling and is intended to assure that the sample accurately portrays the material being sampled.
Rework is a clean, unadulterated material that has been removed from processing for reasons other than unsanitary conditions or that has been successfully reconditioned by reprocessing and that is suitable for use in the manufacture of a dietary product.
Sanitize is the adequate treatment of equipment, containers, or utensils by a process that is effective in destroying vegetative cells of microorganisms of public health significance and in substantially reducing other undesirable microorganisms but without affecting the product or its safety for the consumer.
Serious adverse event report means a report of an adverse event that is termed serious because it meets certain criteria (see the subsection Adverse Event Report). The new law requires manufacturers and distributors of dietary supplements and OTC drugs to report all serious adverse events to the Secretary of the Food and Drug Administration (FDA). This is an entirely new requirement for dietary supplements.
Shall is used to state requirements that must be met under the provisions of this guideline.
Shelf life is the period of time after manufacturing in which the dietary supplement is assured to meet applicable standards of identity, strength, quality, and purity.
Shelf-life (Use by) date is the date beyond which the dietary supplement is no longer assured to meet applicable standards of identity, strength, quality, and purity.
Should is used to state recommended or advisory procedures or identify recommended equipment.
Skip-lot sampling is a reduced level of sampling or testing for a particular specified parameter(s) based upon one or more of the following:
Strength means the concentration of the active substance (weight/weight, weight/volume, or unit of use/volume or weight basis); and/or the potency, that is, the activity of the product as indicated by appropriate laboratory tests.
Water activity (aW) is a measure of the free moisture in a dietary ingredient or dietary supplement and is the quotient of the water vapor pressure of the substance divided by the vapor pressure of pure water at the same temperature.
Auxiliary Information Please check for your question in the FAQs before contacting USP.
USP32NF27 Page 786Pharmacopeial Forum: Volume No. 33(5) Page 1035