Law Library


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

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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.

 

-----------------------------------------------------------------------

 

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 (a<INF>w)'' 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 (a<INF>w) 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 (a<INF>w) 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 (a<INF>w) 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

(a<INF>w) 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