Federal Register: February 6, 1997 (Volume 62, Number 25)
Proposed Rules
Page 5699-5709
From the Federal Register Online via GPO Access wais.access.gpo.gov
 
Page 5699
_______________________________________________________________________
 
Part IV
Department of Health and Human Services
_______________________________________________________________________
 
Food and Drug Administration
_______________________________________________________________________
 
21 CFR Ch. I
 
Current Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Supplements; Proposed Rule
 
Page 5700
 
 
DEPARTMENT OF HEALTH AND HUMAN SERVICES
 
Food and Drug Administration
 
21 CFR Ch. I
 
Docket No. 96N-0417
RIN 0910-AA59
 
 
Current Good Manufacturing Practice in Manufacturing, Packing, or
Holding Dietary Supplements
 
AGENCY: Food and Drug Administration, HHS.
 
ACTION: Advance notice of proposed rulemaking.
 
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SUMMARY: The Food and Drug Administration (FDA) is announcing that it
is considering whether to institute rulemaking to develop current good
manufacturing practice (CGMP) regulations for dietary supplements and
dietary supplement ingredients. FDA solicits comments on whether it
should do so, and if it should, what constitutes CGMP for these
products. In issuing this notice, FDA is responding to the section of
the Federal Food, Drug, and Cosmetic Act (the act) that provides that
the Secretary of Health and Human Services (the Secretary) may, by
regulation, prescribe good manufacturing practice for dietary
supplements and to a submission from representatives of the dietary
supplement industry asking FDA to consider a framework that the
industry had developed as a basis for CGMP regulations. FDA is
publishing the industry submission and is asking for public comment on
the framework that the submission presents. In addition, FDA is
requesting comment on a number of other related issues.
 
DATES: Written comments by May 7, 1997.
 
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
 
FOR FURTHER INFORMATION CONTACT: Robert J. Moore, Center for Food
Safety and Applied Nutrition (HFS-456), Food and Drug Administration,
200 C St. SW., Washington, DC 20204, 202-205-4605.
 
SUPPLEMENTARY INFORMATION:
 
I. Background
 
    On October 25, 1994, the Dietary Supplement Health and Education
Act (the DSHEA) (Pub. L. 103-417) was signed into law. The DSHEA, among
other things, amended the act by adding section 402(g) (21 U.S.C.
342(g)), which provides, in part, that:
    The Secretary may by regulation prescribe good manufacturing
practices for dietary supplements. Such regulations shall be modeled
after current good manufacturing practice regulations for food and
may not impose standards for which there is no current and generally
available analytical methodology. No standard of current good
manufacturing practice may be imposed unless such standard is
included in a regulation promulgated after notice and opportunity
for comment in accordance with chapter 5 of title 5, United States
Code.
While section 402(g) of the act does not require that the Secretary
(and by delegation, FDA) adopt regulations that prescribe CGMP, a
significant segment of the dietary supplement industry has told the
agency that such regulations would be helpful for ensuring that dietary
supplements are safe for their intended use.
    On November 20, 1995, representatives of the dietary supplement
industry submitted to FDA a suggested outline for the development of
CGMP regulations for dietary supplements. FDA evaluated the outline and
determined that it provided an extremely useful starting point should
FDA decide to proceed to rulemaking to adopt such regulations. However,
the agency recognizes that the first question that must be addressed is
whether there is a need for such regulations or whether part 110 (21
CFR part 110) continues to be adequate. The agency also recognizes that
if it decides that there is a need for CGMP regulations, certain issues
were not addressed in the submission, and that other interested
parties, such as consumers, segments of the industry not represented by
the manufacturers and trade associations who submitted the outline, and
the health care community, should have an opportunity to provide
comment before the agency developed a proposal. Therefore, the agency
is issuing this notice to solicit comments and other information on
whether it should propose new CGMP regulations for dietary supplements
and, if it should, what those regulations should include. Based on the
submission and the comments that the agency receives in response to
this notice, FDA will consider whether to develop a proposed rule that
is designed to establish CGMP that will ensure that dietary supplements
are produced under conditions that will result in a safe and properly
labeled product but that does not impose any unnecessary burden on the
industry.
 
II. The Industry Submission
 
A. Introduction
 
    On November 30, 1995, FDA met with representatives of the dietary
supplement industry at their request (Ref. 1). At that meeting, the
industry representatives submitted a document that outlined suggested
CGMP for dietary supplements (Ref. 2). The objectives of the CGMP, as
stated by the industry representatives, are to ensure that consumers
are provided with dietary supplement products that: (1) Are safe and
not adulterated or misbranded; (2) have the identity and provide the
quantity of dietary ingredients declared in labeling; and (3) meet the
quality specifications that the supplement is represented to meet. The
industry submission was patterned after the CGMP for food regulation
contained in part 110, but also contained requirements beyond those in
part 110 that the industry representatives stated that they ``consider
essential to the manufacture of safe and properly labeled dietary
supplements.'' FDA is publishing the industry suggested dietary
supplements CGMP and soliciting comments from industry, consumers, and
other interested parties on the need for dietary supplement CGMP
regulations and on the requirements that should be included in such
regulations.
 
B. The Industry Draft
 
     The text of the industry suggested dietary supplements CGMP
follows:
 
Good Manufacturing Practices (GMP's) for Dietary Supplements: Statement
of Purpose
 
    This document describes Good Manufacturing Practices to be
followed in the manufacturing and control operations for dietary
supplements and dietary ingredients. The objective of these Good
Manufacturing Practices is to assure that consumers are provided
with safe dietary supplement products which are not adulterated or
misbranded, which have the identity and provide the quantity of
dietary ingredients declared in labeling, and which meet the quality
specifications that the supplement is represented to meet.
    The Food, Drug, and Cosmetic Act defines dietary supplements in
section 201(ff). Dietary supplements include a broad spectrum of
product forms and a broad spectrum of dietary ingredients. Dietary
ingredients may include vitamins; minerals; herbs or other
botanicals; amino acids; other dietary substances used to supplement
the diet; and concentrates, metabolites, constituents, extracts, or
combinations of these. Product forms include tablets, capsules,
softgels, gelcaps, liquids, and other forms including--under some
conditions--conventional food forms. These Good Manufacturing
Practices are intended to encompass all of these types of products.
In some cases, judgment may be required in determining the
applicability of a specific provision to a particular product or
class of products.
    Dietary supplements in the physical form of conventional food
shall comply with these
 
Page 5701
 
Good Manufacturing Practices and with applicable food GMP's. For
example, if they are thermally processed low-acid products packaged
in hermetically sealed containers, they shall also comply with the
applicable GMP's covering that product category.
    These Good Manufacturing Practices are modeled after good
manufacturing practices for foods. Provisions have been adopted,
modified, or expanded as appropriate, considering the special
requirements applicable to the manufacture of dietary supplements
and dietary ingredients. There is no desire or intent to impose on
dietary supplements the type of documentation and validation
currently required in the manufacture of pharmaceutical products,
where it would be inappropriate or unnecessary to ensure safe and
unadulterated products. Dietary supplements are classified as foods,
and the Good Manufacturing Practices applicable to them are similar
to those generally applicable to other foods.
 
Proposed Supplement GMP
 
 Definitions
 
    The definitions and interpretations of terms in section 201 of
the Federal Food, Drug, and Cosmetic Act (the act) are applicable to
such terms when used in this part. The following definitions shall
also apply:
    (a) ``Adequate'' means that which is needed to accomplish the
intended purpose in keeping with good public health practice.
    (b) ``Batch or Lot'' means 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.
    (c) ``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.
    (d) ``Composition'' means, as appropriate:
    (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.
    (e) ``Dietary ingredient'' means an ingredient intended for use
or used in a dietary supplement that is:
    (1) a vitamin,
    (2) a mineral,
    (3) an herb or other botanical,
    (4) an amino acid,
    (5) a dietary substance for use by man to supplement the diet by
increasing the total dietary intake, or
    (6) a concentrate, metabolite, constituent, extract, or
combination of any of the foregoing ingredients.
    (f) ``Dietary product'' means either a dietary ingredient or
dietary supplement as defined in this Part.
    (g) ``Dietary supplement'' means dietary supplement as defined
in section 201(ff) of the act.
    (h) ``In-process material'' means any material fabricated,
compounded, blended, ground, extracted, sifted, sterilized, derived
by chemical reaction or processed in any other way that is produced
for, and used in, the preparation of a dietary product.
    (i) ``Lot'' means ``batch'' as defined in this part.
    (j) ``Lot number'' means 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 a finished dietary ingredient,
dietary supplement or other material can be determined.
    (k) ``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.
    (l) ``Microorganisms'' means yeasts, 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 food 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 using an
adjectival phrase containing the word microorganism.
    (m) ``Pest'' refers to any objectionable animals or insects
including, but not limited to, bird, rodents, flies, and larvae.
    (n) ``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.
    (o) ``Quality control operation'' means a planned and systematic
procedure for taking all actions necessary to prevent a dietary
product from being adulterated within the meaning of the act.
    (p) ``Quality control unit'' means any person or organizational
element designated by the firm to be responsible for the duties
relating to quality control operations.
    (q) ``Raw material'' means 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.
    (r) ``Representable sample'' means 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.
    (s) ``Rework'' means clean, unadulterated material that has been
removed from processing for reasons other than insanitary conditions
or that has been successfully reconditioned by reprocessing and that
is suitable for use in the manufacture of a dietary product.
    (t) ``Sanitize'' means to adequately treat equipment,
containers, or utensils by a process that is effective in destroying
vegetative cells of microorganisms of public health significance,
and in substantially reducing numbers of other undesirable
microorganisms, but without adversely affecting the product or its
safety for the consumer.
    (u) ``Shall'' is used to state mandatory requirements.
    (v) ``Should'' is used to state recommended or advisory
procedures or identify recommended equipment.
    (w) ``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.
 
 Personnel
 
    The plant management shall take all reasonable measures and
precautions to assure the following:
    (a) Disease control. Any person who, by medical examination or
supervisory observation, is shown to have, or appears to have, an
illness, open lesion, including boils, sores, or infected wounds, or
any other abnormal source of microbial contamination by which there
is a reasonable possibility of an in-process or finished dietary
product becoming adulterated, or processing equipment, utensils or
packaging materials becoming contaminated, shall be excluded from
any operations which may be expected to result in such adulteration
or contamination until the condition is corrected. Personnel shall
be instructed to report such health conditions to their supervisors.
    (b) Cleanliness. All persons working in direct contact with raw
materials, in-process or finished dietary products, processing
equipment, utensils or packaging materials shall conform to hygienic
practices while on duty to the extent necessary to protect against
adulteration or contamination of such materials. The methods for
maintaining cleanliness include, but are not limited to:
    (1) Wearing outer garments suitable to the operation in a manner
that protects against the adulteration of in-process or finished
dietary products, or contamination of processing equipment, utensils
or packaging materials.
    (2) Maintaining adequate personal cleanliness.
    (3) Washing hands thoroughly (and sanitizing if necessary to
protect against contamination with undesirable microorganisms) in an
adequate hand-washing facility before starting work, after each
absence from the work station, and at any other time when the hands
may have become soiled or contaminated.
    (4) Removing all unsecured jewelry and other objects that might
fall into raw materials, in-process or finished dietary product,
equipment, or containers, and removing hand jewelry that cannot be
adequately sanitized during periods in which in-process or finished
product is manipulated by hand. If such hand jewelry cannot be
removed, it may be covered by material which can be maintained in an
intact, clean, and sanitary condition and which effectively
 
Page 5702
 
protects against the adulteration of dietary products or
contamination of processing equipment, utensils or packaging
materials.
    (5) Maintaining gloves, if they are used in-process or finished
product handling, in an intact, clean, and sanitary condition. The
gloves should be of a material that adequately protects the product
from contamination.
    (6) Wearing, where appropriate, in an effective manner, hair
nets, caps, beard covers, or other effective hair restraints.
    (7) Storing clothing or other personal belongings in areas other
than where in-process or finished product is exposed or where
processing equipment or utensils are washed.
    (8) Confining the following to areas other than where in-process
or finished product may be stored or exposed, or where processing
equipment or utensils are washed: eating food, chewing gum, drinking
beverages, or using tobacco.
    (9) Taking any other necessary precautions to protect against
adulteration of raw materials, in-process or finished product, or
contamination of processing equipment, utensils or packaging
materials with micro-organisms or foreign substances including, but
not limited to, perspiration, hair, cosmetics, tobacco, chemicals,
and medicines applied to the skin.
    (c) Education and training. Each person engaged in the
manufacture of a dietary product 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 manufacturer.
    (d) Supervision. Responsibility for assuring compliance by all
personnel with all requirements of this part shall be clearly
assigned to qualified personnel with proper education, training and
experience (or any combination thereof).
 
 Exclusions
 
    The following operations are not subject to this part:
Establishments engaged solely in the harvesting, storage, or
distribution of one or more ``raw agricultural commodities,'' as
defined in section 201(r) of the act, which are ordinarily cleaned,
prepared, treated, or otherwise processed before being marketed to
the consuming public.
 
 Plant and Grounds
 
    (a) Grounds. 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:
    (1) Properly storing equipment, removing litter and waste, and
cutting weeds or grass within the immediate vicinity of the plant
buildings or structures that may constitute an attractant, breeding
place, or harborage for pests.
    (2) Maintaining roads, yards, and parking lots so that they do
not constitute a source of adulteration in areas where product is
exposed.
    (3) Adequately draining areas that may contribute to product
adulteration by seepage, foot-borne filth, or providing a breeding
place for pests.
    (4) Operating systems for waste treatment and disposal in an
adequate manner so that they do not constitute a source of
adulteration in areas where product is exposed. If the plant grounds
are bordered by grounds not under the operator's control and not
maintained in the manner described in paragraph (a)(1) through (3)
of this section, care shall be exercised in the plant by inspection,
extermination, or other means to exclude pests, dirt, and filth that
may be a source of product adulteration.
    (b) Plant construction and design. Plant buildings and
structures shall be suitable in size, construction. and design to
facilitate maintenance, cleaning and sanitary operations for dietary
product manufacturing purposes and to prevent mixups between
different raw materials and products. The plant and facilities
shall:
    (1) Provide sufficient space for such placement of equipment and
storage of materials as is necessary for the prevention of mixups,
maintenance of sanitary operations and the production of safe
dietary products.
    (2) Permit the taking of proper precautions to reduce the
potential for mixups or adulteration 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, air flow,
enclosed systems, or other effective means.
    (3) Permit the taking of proper precautions to protect dietary
ingredients or dietary supplements in outdoor bulk fermentation
vessels by any effective means, including:
    (i) Using protective coverings.
    (ii) Controlling areas over and around the vessels to eliminate
harborages for pests.
    (iii) Checking on a regular basis for pests and pest
infestation.
    (iv) Skimming the fermentation vessels, as necessary.
    (4) Be constructed in such a manner that floors, walls, and
ceilings may be adequately cleaned and kept clean and kept in good
repair; that drip or condensate from fixtures, ducts and pipes does
not adulterate raw materials, in-process or finished dietary
products, 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.
    (5) Provide adequate lighting 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 provide safety-type light bulbs, fixtures, sky-lights,
or other glass suspended over exposed product in any step of
preparation or otherwise protect against product adulteration in
case of glass breakage.
    (6) Provide adequate ventilation or control equipment to
maintain adequate control over microorganisms, dust, humidity, and
temperature, when appropriate, for the manufacture of dietary
products; to minimize odors and vapors (including steam and noxious
fumes) in areas where they may adulterate dietary products; and
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.
    (7) Provide, where necessary, adequate screening or other
protection against pests.
 
 Sanitation of Buildings and Facilities
 
    (a) General maintenance. Buildings, fixtures, and other physical
facilities of the plant shall be maintained in a sanitary condition
and shall be kept in repair sufficient to prevent raw materials, in-
process or finished dietary products from becoming adulterated
within the meaning of the act.
    (b) Cleaning and sanitizing materials.
    (1) 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:
    (i) Those required to maintain clean and sanitary conditions;
    (ii) Those necessary for use in laboratory testing procedures;
    (iii) Those necessary for plant and equipment maintenance and
operation; and
    (iv) Those necessary for use in the plant's operations.
    (2) 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
 
Page 5703
 
relevant regulations promulgated by other Federal, State, and local
government agencies for the application, use or holding of these
products should be followed. Rodenticides, insecticides, and
fungicides should be registered and used in accordance with the
Federal Insecticide, Fungicide, and Rodenticide Act.
    (c) Pest control. 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 of product on the premises by pests. 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.
    (d) Water supply. Potable water at a suitable temperature, and
under pressure as needed, shall be provided in all areas where
required for the processing of dietary products, for the cleaning of
processing equipment, utensils, and packaging materials, or for
employee sanitary facilities. Any water that contacts in-process or
finished dietary products, utensils or processing equipment shall
meet the standards prescribed in the Environmental Protection
Agency's Primary Drinking Water Regulations (40 CFR part 141).
    (e) Plumbing. Plumbing shall be of adequate size and design and
adequately installed and maintained to:
    (1) Carry sufficient quantities of water to required locations
throughout the plant.
    (2) Properly convey sewage and liquid disposable waste from the
plant.
    (3) Avoid constituting a source of adulteration to product, or
contamination of water supplies, processing equipment, or utensils
or creating an unsanitary condition.
    (4) Provide adequate floor drainage or other appropriate means
of water removal in all areas where floors are subject to flooding-
type cleaning or where normal operations release or discharge water
or other liquid waste on the floor.
    (5) Provide that there is not backflow from, or crossconnection
between, piping systems that discharge waste water or sewage and
piping systems that carry water used for the manufacture of dietary
products.
    (f) Sewage disposal. Sewage disposal shall be made into an
adequate sewerage system or disposed of through other adequate
means.
    (g) Toilet facilities. Each plant shall provide its employees
with adequate, readily accessible toilet facilities. Compliance with
this requirement may be accomplished by:
    (1) Maintaining the facilities in a sanitary condition.
    (2) Keeping the facilities in good repair at all times.
    (3) Providing self-closing doors.
    (4) Providing doors that do not open into areas where dietary
product is exposed to airborne contamination, except where alternate
means have been taken to protect against such contamination (such as
double doors or positive air-flow systems).
    (h) Hand-washing facilities. Hand-washing facilities shall be
adequate and convenient and be furnished with running water at a
suitable temperature. Compliance with this requirement may be
accomplished by providing:
    (1) Hand-washing and, where appropriate, hand-sanitizing
facilities at each location in the plant where good sanitary
practices require employees to wash and/or sanitize their hands.
    (2) Effective hand-cleaning and sanitizing preparations.
    (3) Air driers, sanitary towel service or suitable drying
devices.
    (4) Devices or fixtures, such as water control valves, so
designed and constructed to protect against recontamination of
clean, sanitized hands.
    (5) Readily understandable signs directing employees handling
unprotected product, packaging materials, utensils or processing
equipment to wash and, where appropriate, sanitize their hands
before they start work, after each absence from post of duty, and
when their hands may have become soiled or contaminated. These signs
may be posted in the processing room(s) and in all other areas where
employees may handle such products, materials, utensils or
equipment.
    (6) Refuse receptacles that are constructed and maintained in a
manner that protects against adulteration of dietary products.
    (i) Rubbish disposal. Rubbish shall be so conveyed, stored, and
disposed of as to minimize the development of odor, minimize the
potential for the waste becoming an attractant and harborage or
breeding place for pests, and protect against adulteration of raw
materials, in-process or finished dietary products, or contamination
of utensils, processing equipment, water supplies, and ground
surfaces.
    (j) Supervision. Overall sanitation of the plant shall be under
the supervision of one or more individuals qualified by education,
experience and training (or any combination thereof) assigned
responsibility for assuring that sanitation procedures are
accomplished.
 
 Equipment and Utensils
 
    (a) Design and construction.
    (1) All plant equipment and utensils shall be so designed and of
such material and workmanship as to be adequately cleanable, and
shall be properly maintained.
    (2) 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 lubricants,
fuel, metal fragments, contaminated water, or any other
contaminants.
    (3) All equipment should be so installed and maintained as to
facilitate the cleaning of the equipment and of all adjacent spaces.
Processing equipment and utensils shall be corrosion-resistant when
in contact with raw materials, in-process or finished dietary
product. They shall be made of nontoxic materials and designed to
withstand the environment of their intended use and the action of
dietary products, and, if applicable, cleaning compounds and
sanitizing agents. Processing equipment and utensils shall be
maintained to protect dietary products from being adulterated by any
source.
    (4) Seams on utensils and processing equipment shall be smoothly
bonded or maintained so as to minimize accumulation of product,
dirt, and organic matter and thus minimize the opportunity for
growth of microorganisms.
    (5) Equipment that is in the manufacturing or product handling
area and that does not come into contact with a dietary product
shall be so constructed that it can be kept in a clean condition.
    (6) Holding, conveying, and manufacturing systems, including
gravimetric, pneumatic, closed, and automated systems, shall be of a
design and construction that enables them to be maintained in an
appropriate clean condition.
    (7) Each freezer and cold storage compartment used to store and
hold a dietary product capable of supporting growth of
microorganisms shall be fitted with an indicating thermometer,
temperature-measuring device, or temperature-recording device so
installed as to show the temperature accurately within the
compartment, and should be fitted with an automatic control for
regulating temperature or with an automatic alarm system to indicate
a significant temperature change in a manual operation.
    (8) Instruments and controls used in the manufacture,
processing, packing or holding dietary products, including
instruments and controls used for measuring, regulating, or
recording temperatures, pH, acidity, water activity, or other
conditions that control or prevent the growth of undesirable
microorganisms in such products shall be accurate and adequately
maintained, and adequate in number for their designated uses.
    (9) Compressed air or other gases mechanically introduced into a
dietary product or used to clean equipment or utensils shall be
treated in such a way that dietary ingredients or dietary
supplements are not adulterated.
    (b) Sanitation of equipment and utensils.
    (1) Cleaning and sanitizing of utensils and equipment shall be
conducted in a manner that protects against adulteration of raw
materials, in-process or finished dietary product, processing
equipment, utensils or packaging materials.
    (2) All utensils and processing equipment shall be cleaned as
frequently as necessary to protect against product adulteration.
    (3) Utensils and processing equipment used for manufacturing or
holding of dry dietary products shall be in a dry, sanitary
condition at the time of use. When the surfaces are wet-cleaned,
they shall, when necessary, be sanitized and thoroughly dried before
subsequent use.
 
Page 5704
 
    (4) In wet processing, when cleaning is necessary to protect
against the introduction of microorganisms into a dietary product,
all utensils and processing equipment shall be cleaned and sanitized
as appropriate before use and after any interruption during which
the utensils or processing equipment may have become contaminated.
Where equipment and utensils are used in a continuous production
operation or in back-to-back operations involving different batches
of the same products, the utensils and product-contact surfaces of
the equipment shall be cleaned and sanitized as appropriate.
    (5) Nonproduct-contact surfaces of equipment should be cleaned
as frequently as necessary to protect against product adulteration.
    (6) Single-service articles (such as utensils intended for one-
time use, paper cups, and paper towels) should be stored in
appropriate containers and shall be handled, dispensed, used, and
disposed of in a manner that protects against adulteration of
dietary products, and contamination of utensils and processing
equipment.
    (7) Sanitizing agents shall be adequate and safe under
conditions of use. Any facility, procedure, or machine is acceptable
for cleaning and sanitizing equipment and utensils if it is
established that the facility, procedure, or machine will routinely
render equipment and utensils clean and provide adequate cleaning
and sanitizing treatment.
    (8) Cleaned and sanitized portable equipment with product-
contact surfaces and utensils should be stored in a location and
manner that protects product-contact surfaces from contamination.
    (9) Equipment and utensils and finished product containers shall
be maintained in an acceptable condition through appropriate
cleaning and sanitizing, as necessary. Insofar as necessary,
equipment shall be taken apart for thorough cleaning.
    (10) Written procedures shall be established and followed for
cleaning and maintaining equipment and utensils used in the
manufacture of dietary products.
    (11) A written record of 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.
    (12) Equipment, containers, and utensils used to convey, hold,
or store raw materials, in-process material, rework, or finished
product shall be constructed, handled, and maintained during
manufacturing or storage in a manner that protects against
contamination.
 
 Quality Control and Laboratory Operations
 
    Appropriate quality control operations shall be employed to
assure that dietary products conform to appropriate standards of
purity, quality and composition, and that packaging materials are
safe and suitable for their intended purpose.
    (a) Quality control unit.
    (1) There shall be a quality control unit that has the
responsibility and authority to:
    (i) Approve or reject all procedures, specifications, controls,
tests and examinations, or deviations from them, that impact the
purity, quality and composition of a dietary ingredient or dietary
supplement;
    (ii) Approve or reject all raw materials, packaging materials
labeling, and finished dietary products, including products
manufactured. processed, packed, or held under contract by another
company, based on adequate determination of conformance to
established specifications; and
    (iii) Assure that completed production records are reviewed as
appropriate. Quality control shall be responsible for evaluation of
errors committed in the manufacture of a product and shall have the
final authority to determine if the error may be corrected in such
manner that the product can be approved for distribution or must be
destroyed. Such evaluations and their resolution must be documented
and maintained with and/or cross referenced in the batch production
record.
    (2) Adequate laboratory facilities should be available, as
needed, to the quality control unit.
    (3) The responsibilities and procedures applicable to the
quality control unit shall be established in writing and followed.
    (b) Laboratory records. Laboratory records shall be maintained
and shall include complete data derived from all specified tests.
    (c) Expiration dating.
    (1) Whenever a dietary ingredient or dietary supplement bears an
expiration date, such date shall be supported by data and rationale
to reasonably assure that the product meets established
specifications at the expiration date.
    (2) Appropriate accelerated stability studies or data from
similar product formulations may be used for an initial
determination of shelf life. Product shelf life shall be confirmed
and may be extended on the basis of real time studies on product
stored under labeled storage conditions.
 
 Production and Process Controls
 
    (a) Master production and control records.
    (1) To assure uniformity from batch to batch, a master
production and control record shall be prepared for the manufacture
of each dietary ingredient and dietary supplement, and shall be
reviewed and approved by the quality control unit.
    (2) Master production and control records shall include, as
appropriate.
    (i) A complete list of raw materials used in the manufacture of
a dietary product, designated by names or codes sufficiently
specific to indicate any special quality characteristic(s).
    (ii) An accurate statement of the weight or measure of each raw
material used in the manufacture of a dietary product. Each batch
shall be formulated with the intent to provide not less than 100
percent of each claimed dietary ingredient.
    (iii) For dietary supplements, the name and weight or measure of
each dietary ingredient per unit or portion or per unit of weight or
measure of the supplement.
    (iv) A statement concerning any calculated excess of dietary
ingredient contained in a dietary supplement.
    (v) A statement of the total weight or measure of any dietary
supplement unit.
    (vi) A statement of theoretical weight or measure of a dietary
ingredient or dietary supplement expected at the conclusion of
manufacture, including the maximum and minimum percentages of
theoretical yield beyond which investigation is required.
    (vii) A description of the product container(s), closure(s), and
other packaging materials, including positive identification of all
labeling used.
    (viii) Manufacturing and control instructions, designed to
assure that the dietary product has the purity, composition, and
quality it is represented to possess.
    (b) Batch production and control records.
    (1) Individual batch production and control records shall be
prepared and followed for each batch of dietary product produced and
shall include complete information relating to the production and
control of each batch.
    (2) These records shall be an accurate reproduction of the
appropriate master production and control record and shall include
documentation that each significant step in the manufacture,
processing, packing, or holding of the batch was accomplished,
including:
    (i) Dates;
    (ii) Identity of individual major equipment and lines used;
    (iii) Specific identification, including lot number, of each raw
material or in-process material used;
    (iv) Weight or measure of each raw material used in the course
of processing;
    (v) Quality control results;
    (vi) Inspection of the packaging and labeling area;
    (vii) A statement of the actual yield at the conclusion of
manufacture and a statement of the percentage of theoretical yield,
as appropriate;
    (viii) Label control records, including specimens, copies, or
records of all labels used;
    (ix) Description of product containers and closures used; and
    (x) Any special notes of investigations or deviations from the
described process.
    (3) Any deviation from written, approved specifications,
standards, test procedures, or other laboratory control mechanisms
shall be recorded and justified.
    (c) Handling and storage of raw materials, in-process materials
and rework.
 
Page 5705
 
    (1) Raw materials, in-process materials and rework shall be
inspected and segregated or otherwise handled as necessary to
ascertain that they are clean and suitable for processing into
dietary products and shall be stored under conditions that will
protect against adulteration and minimize deterioration.
    Containers of raw materials should be inspected on receipt to
assure that their condition has not contributed to the adulteration
or deterioration of the contents.
    Liquid or dry raw materials and other ingredients received and
stored in bulk form shall be held in a manner that protects against
contamination.
    (2) 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 the such materials.
    (3) Raw materials, in-process materials, and rework 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 within
the meaning of the act. Material scheduled for rework shall be
identified as such.
    (4) 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.
    (5) Written procedures shall be established and followed
describing the receipt, identification, examination, handling,
sampling, testing and approval or rejection of raw materials.
    (6) Each lot of raw material shall be identified with a
distinctive lot number and shall be appropriately controlled
according to its status (e.g., quarantined, approved, rejected).
    (7) Raw material samples shall be examined and tested as
follows:
    (i) Each lot of raw material, in-process material, and rework
that is liable to adulteration with filth, insect infestation, or
other visually evident extraneous material shall be examined against
established specifications for such adulteration, and shall comply
with any applicable Food and Drug Administration regulations and
guidelines. In lieu of such examination by the manufacturer, a
guarantee or certification of examination may be accepted from the
supplier of a component provided that the manufacturer establishes
the reliability of the supplier's examination.
    (ii) Each lot of a raw material that is liable to
microbiological contamination that is objectionable in view of its
intended use shall be subjected to microbiological tests before use.
Raw materials shall either not contain levels of microorganisms that
may produce food poisoning or other disease in humans, or they shall
be otherwise treated during manufacturing operations so that they no
longer contain levels that would cause the product to be adulterated
within the meaning of the act. In lieu of such testing by the
manufacturer, a guarantee or certification of analysis may be
accepted from the supplier of a component provided that the
manufacturer establishes the reliability of the supplier's analyses.
    (iii) Raw materials and other ingredients susceptible to
adulteration with aflatoxin or other natural toxins shall comply
with current Food and Drug Administration regulations, guidelines,
and action levels for poisonous or deleterious substances before
these materials or ingredients are incorporated into a finished
dietary ingredient or dietary supplement. Compliance with this
requirement may be accomplished by analyzing these materials and
ingredients for aflatoxins and other natural toxins or, in lieu of
such testing by the manufacturer, a guarantee or certification of
analysis may be accepted from the supplier of a component provided
that the manufacturer establishes the reliability of the supplier's
analyses.
    (iv) Each lot of raw material shall undergo at least one test by
the manufacturer to verify its identity. Such tests may include any
appropriate test with sufficient specificity to determine identity,
including chemical and laboratory tests, gross organoleptic
analysis, microscopic identification, or analysis of constituent
markers.
    (v) Each lot of raw material shall be tested for conformity with
all other established specifications. In lieu of such testing by the
manufacturer, a guarantee or certification of analysis may be
accepted from the supplier of a component provided that the
manufacturer establishes the reliability of the supplier's analyses.
    (8) Approved raw materials shall be rotated so that the oldest
approved stock is used first. Deviation from this requirement is
permitted if such deviation is temporary and appropriate.
    (9) Raw materials shall be retested or reexamined and approved
or rejected by the quality control after a specified time in storage
or after exposure to air, heat, or other conditions that are likely
to adversely affect the purity, quality, or composition of the raw
material.
    (10) Rejected raw materials, shall be identified and controlled
under a system that prevents their use in manufacturing or
processing operations for which they are unsuitable.
    (d) Manufacturing operations.
    (1) All operations in the receiving, inspecting, transporting,
segregating, preparing, manufacturing, packaging, and storing of
dietary products shall be conducted in accordance with adequate
sanitation principles.
    (2) All reasonable precautions shall be taken to assure that
production procedures do not contribute adulteration from any
source. Chemical, microbial, or extraneous-material testing
procedures shall be used where necessary to identify sanitation
failures or possible product adulteration.
    (3) All product that has become contaminated to the extent that
it is adulterated within the meaning of the act shall be rejected,
or if permissible, treated or processed to eliminate the
contamination.
    (4) All product manufacturing, including packaging and storage,
shall be conducted under such conditions and controls as are
necessary to minimize the potential for the growth of
microorganisms, or for the adulteration of raw materials, in-process
materials and finished product.
    (5) Measures such as sterilizing, irradiating, pasteurizing,
freezing, refrigerating, controlling pH or controlling water
activity (aw) that are taken to destroy or prevent the growth
of undesirable microorganisms, particularly those of public health
significance, shall be adequate under the conditions of manufacture,
handling, and distribution to prevent dietary products from being
adulterated within the meaning of the act.
    (6) Work-in-process shall be handled in a manner that protects
against adulteration.
    (7) Effective measures shall be taken to protect finished
dietary ingredients and dietary supplements from adulteration by raw
materials, in-process materials or refuse. When raw materials, in-
process materials or refuse are unprotected, they shall not be
handled simultaneously in a receiving, loading, or shipping area if
that handling could result in adulterated dietary products. Dietary
ingredients and dietary supplements transported by conveyor shall be
protected against adulteration as necessary.
    (8) All raw material containers, compounding and storage
containers, processing lines and major equipment used during the
production of a batch shall be properly identified at all times to
indicate their contents and when necessary, the phase of processing
of the batch.
    (9) Effective measures shall be taken as necessary to protect
against the inclusion of metal or other extraneous material in
product. Compliance with this requirement may be accomplished by
using sieves, traps, magnets, electronic metal detectors, or other
suitable effective means.
    (10) Dietary products, raw materials, and in-process materials
that are rejected or adulterated within the meaning of the act shall
be identified, stored and disposed of in a manner that protects
against the adulteration of other products.
    (11) Written procedures shall be established and followed that
describe
 
Page 5706
 
appropriate tests, and/or examinations to be conducted that may be
necessary to assure the purity, composition, and quality of the
finished product.
    (12) Written procedures shall be established and followed
prescribing the method for reprocessing batches or operational
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.
    (13) Mechanical manufacturing steps such as cutting, sorting,
inspecting, shredding, drying, grinding, blending, and sifting shall
be performed so as to protect dietary ingredients and dietary
supplements against adulteration. Compliance with this requirement
may be accomplished by providing adequate physical protection of
dietary products from contact with adulterants. Protection may be
provided by adequate cleaning and sanitizing of all processing
equipment between each manufacturing step.
    (14) Heat blanching, when required in the preparation of a
dietary product, should be effected by heating the product to the
required temperature, holding it at this temperature for the
required time, and then either rapidly cooling the material or
passing it to subsequent manufacturing without delay. Thermophilic
growth and contamination in blanchers should be minimized by the use
of adequate operating temperatures and by periodic cleaning. Where
the blanched product is washed prior to filling, potable water shall
be used.
    (15) Intermediate or dehydrated dietary products that rely on
the control of water activity (aw) for preventing the growth of
undesirable microorganisms shall be processed to and maintained at a
safe moisture level. Compliance with this requirement may be
accomplished by any effective means, including employment of one or
more of the following practices:
    (i) Monitoring the water activity (aw) of the material.
    (ii) Controlling the soluble solids-water ratio in finished
product.
    (iii) Protecting finished product from moisture pickup, by use
of a moisture barrier or by other means, so that the water activity
(aw) of the product does not increase to an unsafe level.
    (16) Dietary ingredients and dietary supplements that rely
principally on the control of pH for preventing the growth of
undesirable microorganisms shall be monitored and maintained at an
appropriate pH. Compliance with this requirement may be accomplished
by any effective means, including employment of one or more of the
following practices:
    (i) Monitoring the pH of raw materials, in process material, and
finished product.
    (ii) Controlling the amount of acid added to the product.
    (17) When ice is used in contact with dietary products, it shall
be made from potable water, and shall be used only if it has been
manufactured in accordance with current good manufacturing practice
as outlined in 21 CFR part 110.
    (e) Packaging and labeling operations.
    (1) Filling, assembling, packaging, and other operations shall
be performed in such a way that dietary products are protected
against adulteration. Compliance with this requirement may be
accomplished by any effective means, including:
    (i) Adequate cleaning and sanitizing of all filling and
packaging equipment, utensils, and product containers, as
appropriate.
    (ii) Using materials for product containers and packaging
materials that are safe and suitable.
    (iii) Providing physical protection from adulteration,
particularly airborne contamination.
    (iv) Using sanitary handling procedures.
    (2) Written procedures shall be established and followed
describing in sufficient detail the control procedures employed for
the receipt, storage, handling, sampling, examination, and/or
testing that may be necessary to assure the identity of labeling and
the appropriate identity, cleanliness and quality characteristics of
packaging materials for dietary products.
    (3) For dietary supplements, labels and other labeling materials
for each different product type, strength, or quantity of contents
shall be stored separately with suitable identification.
    (4) Obsolete labels, labeling, and other packaging materials for
dietary products shall be destroyed.
    (5) Written procedures shall be established and followed to
assure that correct labels, labeling, and packaging materials are
issued and used for dietary products.
    (6) Dietary ingredient and dietary supplement packages shall be
identified with a lot number that permits determination of the
history of the manufacture and control of the batch.
    (7) Packaged and labeled dietary supplements shall be examined
to provide assurance that containers and packages in the lot have
the correct label and lot number. Products not meeting
specifications shall be rejected by the quality control unit.
 
Warehousing, Distribution and Post-Distribution Procedures
 
    (a) Storage and distribution.
    (1) 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.
    (2) Adequate distribution records shall be maintained and
retained by the manufacturer at least 1 year beyond expected product
shelf life, whereby an effective product recall can be achieved
should one become necessary.
    (b) Reserve samples. An appropriately identified reserve sample
that is representative of each batch of a dietary product should be
retained and stored under conditions consistent with the product
labeling until at least 1 year after the expiration date, or if no
expiration date is identified on the product, for at least 3 years
after the date of manufacture. The reserve sample should be stored
in the same immediate container-closure system in which the finished
product is marketed or in one that provides similar protection. The
reserve sample shall consist of at least twice the quantity
necessary to perform all the required tests.
    (c) Records retention.
    (1) Any laboratory, production, control or distribution record
specifically associated with a batch of product shall be retained
for at least 1 year after the expiration date of the batch, or if no
expiration date is identified on the product, for at least 3 years
after the date of manufacture.
    (2) Raw material records shall be maintained for at least 1 year
after the expiration date of the last batch of product incorporating
the raw material, or if no expiration date is identified on the
product, for at least 3 years after the date of manufacture of the
finished product.
    (d) Complaint files.
    (1) Written procedures describing the handling of all written
and oral complaints regarding a dietary product shall be established
and followed. Such procedures shall 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, for such
products, a determination as to the need for an investigation.
    (2) A written record of each complaint shall be maintained,
until at least 1 year after the expiration date of the product, or 1
year after the date that the complaint was received, whichever is
longer.
    (3) The written record shall include, where known: The name and
description of the product, lot number, name of complainant, nature
of complaint, and reply to complainant, if any.
    (4) Where an investigation is conducted, the written record
shall include the findings of the investigation and followup action
taken.
    (e) Returned products. Returned dietary products shall 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 purity, composition or quality of the product, the returned
product shall be destroyed unless examination, testing, or other
investigations prove the product meets appropriate standards of
purity, composition, and quality. A product may be reprocessed
provided the subsequent product meets appropriate specifications.
Records pertaining to returned products that are subsequently
reprocessed and/or redistributed shall be maintained and shall
include the name and description of the
 
Page 5707
 
product, lot number, reason for the return, quantity returned, date
of disposition, and ultimate disposition of the returned product.
    (f) Product salvaging. Dietary products that have been subjected
to improper storage conditions including extremes in temperature,
humidity smoke, fumes, pressure, age, or radiation due to natural
disasters, fires, accidents, or equipment failures shall 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: (1) Evidence
from laboratory tests that the products meet all applicable
standards of purity, quality, and composition; and (2) evidence from
inspection of the premises that the products and their associated
packaging were not subjected to improper storage conditions as a
result of the disaster or accident. Records including name, lot
number, and disposition shall be maintained for products subject to
this section.
    (g) Defect action levels.
    (1) 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.
    (2) 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.
    (3) 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.
    (4) 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.
    (5) 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
Programs Branch (HFF-326), Center for Food Safety and Applied
Nutrition, Food and Drug Administration, 200 C St. SW., Washington,
DC 20204.
 
III. Economic Issues
 
    FDA requests comment on and descriptions of CGMP in the dietary
supplement industry. The agency seeks information on how closely the
current practices of firms manufacturing dietary supplements conform to
the industry submission, and on how costly it would be to bring those
practices into conformity. The agency asks for comments on whether
there should be new CGMP regulations, whether the regulations should be
mandatory or voluntary, and, if mandatory, how long it would take
establishments to come into compliance. Because FDA would like to
determine how current manufacturing practices differ with plant size,
the agency particularly requests comments from both small businesses
and large businesses.
    The establishment of CGMP could have effects on small businesses in
the dietary supplement industry. There are several possible definitions
of ``small'' that can be applied to dietary supplements. Although the
Small Business Administration (SBA) does not define small for the
dietary supplement industry, the industry's products are generally
closest to foods and botanicals. The SBA size standards for small
businesses are 500 or fewer employees for food preparations, 750 or
fewer employees for botanical products, and annual sales revenue less
than $5 million for businesses that cannot be classified into a
specific industry. The Nutrition Business Journal (August 1996) divides
firms into large (annual sales over $100 million), medium (annual sales
between $20 and $100 million), and small (annual sales under $20
million). Under any of the possible definitions, instituting CGMP's for
the industry has the potential to affect a significant number of small
businesses. FDA asks for comments on this matter.
 
IV. Summary and Request for Comments
 
    FDA asks for comments on the regulatory framework presented in the
industry submission in section II. of this document and the economic
issues discussed above. In addition, the agency requests comments on
the following issues:
    1. Is there a need to develop specific defect action levels (DAL's)
for dietary ingredients? While FDA has established DAL's for many food
ingredients, including botanical food ingredients, these DAL's reflect
their use for specific purposes, for example, the use of many
botanicals as spices, flavorings, or other trace ingredients in foods.
The DAL's are designed to provide reasonable assurance of the safety
and wholesomeness of the ingredient when it is present in the food
supply in small quantities. However, the use of a botanical in a
dietary supplement may result in a much greater exposure to the
botanical ingredient for consumers because the dietary supplement will
be consumed in greater amounts than if the ingredient was in a food as
a spice or flavoring agent. Therefore, FDA tentatively concludes that
it would not be appropriate to apply the current DAL's to dietary
supplements, and the agency requests comments that would assist in
developing DAL's for dietary supplements.
    2. FDA requests comments on appropriate testing requirements to
provide positive identification of dietary ingredients, particularly
plant materials, used in dietary supplements. The misidentification of
dietary ingredients, particularly plant materials, used in dietary
supplements may present a significant public health and economic
concern. However, the analytical methodology available for identifying
many dietary ingredients is limited. Furthermore, section 402(g)(2) of
the act states that CGMP regulations may not impose standards for which
there is no current and generally available analytical methodology. FDA
is asking for comments on the technical and scientific feasibility for
the identification of different types of dietary ingredients. The
agency also solicits information on what constitutes ``adequate
testing'' for identity of different types of ingredients, and, in the
absence of testing, what types of practices would be effective
alternatives to testing to ensure the identity of different types of
dietary ingredients.
    3. FDA requests comments on standards that should be met in
certifying that a dietary ingredient or dietary supplement is not
contaminated with filth; that it is free of harmful contaminants,
pesticide residues, or other impurities; that it is microbiologically
safe; and that it meets specified quality and identity standards. For
food (Sec. 110.80), it is CGMP for a manufacturer to accept
certification from a supplier that products do not contain
microorganisms or filth or other foreign material that would adulterate
the product in lieu of direct testing or evaluation of the raw
materials or final product. However, many ingredients used in dietary
supplements do not have a history of food use in the United
 
Page 5708
 
States, and thus the potential for contamination with microorganisms or
filth is unknown. The agency does not have information that provides a
basis for it to determine whether certification by a supplier provides
adequate assurance that a dietary ingredient is what it purports to be
and is not adulterated. Therefore, the agency asks for comments on
whether a certification will provide assurance that dietary ingredients
are not contaminated, or whether specific testing requirements are
necessary and would effectively ensure the safety and wholesomeness of
these products.
    4. CGMP is intended to ensure that a firm follows quality control
and other procedures necessary to ensure that a food is safe for its
intended use. It is possible that a firm will develop adequate standard
operating procedures and other mechanisms to achieve this end, but that
such procedures will not be followed. The agency asks for comments on
whether there is a need for CGMP to include requirements for
manufacturers to establish procedures to document that the procedures
prescribed for the manufacture of a dietary supplement are followed on
a continuing or day-to-day basis.
    FDA is aware that no provision of part 110 deals with the
establishment of documentation that a manufacturer is following
established procedures prescribed for the manufacture of a dietary
supplement, and that section 402(g) of the act states that any CGMP
regulations for dietary supplements are to be modeled after the CGMP
regulations for food. However, FDA's tentative judgment is that section
402(g) of the act does not preclude FDA from adopting CGMP regulations
for dietary supplements that have no counterpart in part 110 if there
is an appropriate basis for so doing. FDA requests comments on this
issue.
    5. The agency asks for comments on whether dietary supplement CGMP
should require that reports of injuries or illnesses to a firm be
evaluated by competent medical authorities to determine whether
followup action is necessary to protect the public health. Many dietary
supplements contain pharmacologically active substances, and some may
contain potential allergens that result in adverse events in certain
consumers. The presence of pharmacologically active substances in these
products distinguishes them from most other foods. Because of the
potential for serious injury or illness in some persons from the
consumption of such substances, it may be necessary that trained
medical professionals, rather than quality control or nonmedical
scientific/regulatory personnel, evaluate all reported adverse events
associated with the use of a specific substance and advise responsible
management of their findings. FDA also asks for comments on whether
CGMP for dietary supplements should contain a requirement that a firm
establish procedures for determining whether a reported injury
constitutes a serious problem, and what actions are to be taken when
serious problems are identified.
    FDA is aware that no provision of part 110 deals with followup to
reports of illness or injury, and that section 402(g) of the act states
that any CGMP regulations for dietary supplements are to be modeled
after the CGMP regulations for food. However, as stated above, FDA's
tentative judgment is that section 402(g) of the act does not preclude
FDA from adopting CGMP regulations for dietary supplements that have no
counterpart in part 110 if there is an appropriate basis for so doing.
    6. FDA asks for comments on whether CGMP for dietary supplements
should require that manufacturers establish procedures to identify,
evaluate, and respond to potential safety concerns with dietary
ingredients. As discussed above, many dietary ingredients have little
history of use in food in the United States or of use in the amounts
that would be used in a dietary supplement. Moreover, dietary
ingredients are excepted from the definition of ``food additive'' in
section 201(s)(6) of the act (21 U.S.C. 321(s)(6)). In these
circumstances, it may be appropriate to provide that CGMP requires that
a manufacturer critically evaluate the available scientific information
on the safety of the dietary ingredients that it intends to use in its
products to assure itself that those products will be safe. FDA asks
for comments on whether such an evaluation is necessary, and, if so,
what elements need to be included in such an evaluation and their
relative importance (e.g., the presence and potency of
pharmacologically active substances, the presence of different
microorganisms, the presence of different contaminants and impurities).
In addition, the agency asks for comments on whether it should require
that such an evaluation be documented in a firm's records, and, if so,
what type of records would be adequate to document that such an
evaluation had occurred.
    7. The agency asks for comments on whether specific controls are
necessary for computer controlled or assisted operations. Many modern
manufacturing operations rely on computers to ensure that proper
procedures are followed in the handling and processing of ingredients
and the manufacture of food products. If such equipment is used in the
production of dietary supplements, FDA requests comment on how best to
ensure that the software programs and equipment used to direct and
monitor the manufacturing process are properly designed, tested,
validated, and monitored.
    8. The agency asks for comments on whether certain, or all, of the
requirements for manufacturing and handling dietary ingredients and
dietary supplements may be more effectively addressed by a regulation
based on the principles of Hazard Analysis and Critical Control Points
(HACCP), rather than the system outlined in the industry submission.
FDA has issued regulations based on HACCP to ensure the safety of other
foods (i.e., seafood) (Ref. 3) and has issued an advance notice of
proposed rulemaking on the appropriateness of extending the HACCP
concept to other segments of the food industry (Ref. 4). HACCP-based
requirements enable manufacturers to develop and implement processes
and controls that are tailored to their specific products and
manufacturing operations. Because of the wide variety of dietary
ingredients and dietary supplements and because of the heterogenous
composition of the dietary supplement industry, CGMP based on the
principles of HACCP may provide a more flexible and less burdensome
regulatory framework for manufacturers and distributors than the
approach set out in the industry submission.
    9. The dietary supplement industry includes a broad spectrum of
firms that conduct one or more distinct operations, such as the
manufacture or distribution of raw dietary ingredients, the manufacture
of finished products, or solely the distribution and sale of finished
products (manufactured by a separate firm) at the wholesale or retail
level. Consequently, the dietary supplement CGMP regulations may need
to address the distinctive requirements of each of these segments of
the industry in order to effectively ensure that dietary supplements
are what they are represented to be and are safe for their intended
use. The agency asks for comments on whether broad CGMP regulations
will be adequate, or whether it will be necessary to address the
operations of particular segments of the dietary supplement industry.
 
VII. Comments
 
    Interested persons may, on or before May 7, 1997, submit to the
Dockets Management Branch (address above)
 
Page 5709
 
written comments regarding this proposal. Two copies of any comments
are to be submitted, except that individuals may submit one copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. Received comments may be seen in the
office above between 9 a.m. and 4 p.m., Monday through Friday.
 
VIII. References
 
    The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Memorandum of Meeting, Center for Food Safety and Applied
Nutrition, Food and Drug Administration, Washington, DC, November
30, 1995.
    2. Discussion Draft of GMP's for Dietary Supplements, submitted
to the Food and Drug Administration, November 21, 1995.
    3. Food and Drug Administration, ``Procedures for the Safe and
Sanitary Processing and Importing of Fish and Fishery Products,''
final rule, 60 FR 65096, December 18, 1995.
    4. Food and Drug Administration, Food and Safety Assurance
Program; ``Development of Hazard Analysis Critical Control Points
for the Food Industry,'' proposed rule, 59 FR 39888, August 4, 1994.
 
    Dated: December 11, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
FR Doc. 97-3014 Filed 2-5-97; 8:45 am
BILLING CODE 4160-01-F