UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:  03/26/2008

SUBJECT:	Registration:  08OR08; Section 18 Exemption For The Use of Bifenthrin on Orchardgrass Grown for Seed in Oregon.

Registration No.	08OR08	Decision No:	390214

DP No.:	350052	40 CFR:	§180.442

Chemical No.:	128825	Class:	Synthetic Pyrethroid

Trade Name:	Brigade 2EC	EPA Reg. No.: 	279-3313

MRID:	None

From:		William D. Wassell, Chemist

		Registration Action Branch 1 (RAB1)

		Health Effects Division (HED, 7509P)

Through:	Dana Vogel, Branch Chief

		RAB1/HED (7509P)

To:		Daniel Rosenblatt/Andrea Conrath (RM 05)

	Registration Division (7505P)

Introduction

The Department of Agriculture of Oregon has requested an emergency exemption for the use of bifenthrin [(2-methyl [1,1'-biphenyl]-3-yl) methyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylate] on orchardgrass grown for seed for control of billbug.  This is the seventh year this request has been made.  Capture 2EC, containing bifenthrin as the active ingredient (ai), is to be applied to orchardgrass at the rate of 0.10 pounds (lb) ai per acre (A) using ground equipment.  Up to 2 applications for a total rate of 0.2 lb ai/A may be made (one in the spring and one after harvest), with a pre-harvest interval (PHI) of 30 days.  The proposed use period is from March 25 to November 15, 2008.

Summary

Bifenthrin is a broad-spectrum, non-systemic insecticide/miticide in the class of synthetic pyrethroids.  It is registered to FMC Corporation for use as foliar applications on a variety of field, fruit, and vegetable crops.

Tolerances for residues of bifenthrin are currently expressed in terms of bifenthrin per se.  Permanent tolerances are established for bifenthrin residues in/on several food commodities under 40 CFR §180.442(a)(1).  The established tolerances for plant and livestock commodities, range from 0.05 ppm (various plant and poultry commodities) to 25 ppm (coriander, dried leaves).  A tolerance of 0.05 ppm is also established for residues of bifenthrin in food/feed handling establishments under §180.422(a)(2).  In addition, time-limited tolerances for residues of bifenthrin have been established under §180.422(b) in connection with Section 18 emergency exemptions; these include tolerances for orchardgrass, forage and hay each at 0.05 ppm with a 12/31/09 expiration date.

There are no direct human feed items associated with orchardgrass grown for seed.  Based upon HED’s previous evaluation of secondary residues of bifenthrin in livestock tissues (Memo, 7/25/07, W.D. Wassell, DP# 335688), residues of bifenthrin in/on forage or hay from orchardgrass grown for seed will not result in higher residues for livestock commodities.

Considering that this Section 18 is not expected it increase human dietary exposure to bifenthrin, HED concludes that no human-health risk assessment is needed for this Section 18 use on orchardgrass grown for seed.  HED's previous risk assessment (Memo, 7/25/07, W.D. Wassell, et al., DP# 371449) adequately covers the subject use.

Estimates of handler exposure and risk for the proposed application of bifenthrin to orchardgrass at 0.1 lb ai/acre are expected to be no higher than that calculated in HED’s previous risk assessment for bifenthrin (Memo, 7/25/07, W.D. Wassell, et al., DP# 371449) as rates up to 0.3 lb ai/A were evaluated.  Provided that mixer/loaders wear protective gloves, all MOEs are above 100, and, therefore, are not of concern to HED.

Estimates of post-application exposure and risk for the proposed application of bifenthrin to orchardgrass are expected to be no higher than that calculated in HED’s previous risk assessment (Memo, 7/25/07, W.D. Wassell, et al., DP# 371449).  A restricted-entry interval (REI) of 24 hours is specified on the proposed Section 18 label.  Based on the lowest acute toxicity of bifenthrin technical (category III for acute dermal), an REI of at least 12 hours is required by the Worker Protection Standard.  Currently, 12 hours is the shortest REI appearing on the Section 3 label.

As concluded in the 7/25/07 human-health risk assessment, aggregate risk estimates for acute, chronic, short- and intermediate-term exposure are not of concern to HED.  Provided the rotational crop restrictions on the Section 18 label are modified (see below), this Section 18 exemption should not pose an unacceptable aggregate risk to infants, children, or adults.  HED has no objection to the issuance of the Section 18 emergency exemption for the use of bifenthrin on orchardgrass grown for seed in OR.  To support this Section 18 use, time-limited tolerances for residues of bifenthrin per se should be established as follows:

Crop (commodity)

Tolerance Level (ppm)

Grass, forage

2.5

Grass, hay

4.5

The rotational crop restrictions on the current label may be replaced with the following restrictions:  Crops having bifenthrin tolerances may be replanted at any time, and all other crops may be replanted 30 days following the last application of bifenthrin.

Detailed Discussion

Magnitude of the Residues

The Interregional Research Project No. 4 (IR-4) has conducted field trial data for residues of bifenthrin in/on orchardgrass.  A very brief summary of these data were included in the Section 18 submission.  IR-4 expects to submit the data and a petition for tolerances before the end of 2008.  These data are summarized in Table 1.

Table 1.  Residues of Bifenthrin per se in or on Orchardgrass Forage and Hay.

Trial ID, Location, Year	NAFTA Growing Region	Variety	Commodity	Total rate

(lb ai/A)	PHI

(days)	Bifenthrin residues

(ppm)

ID07, Swan Valley ID, 2005	11	Bannock wheat grass	Forage	0.203	29	1.72

	Hay

29	2.93

OR11, Aurora, OR, 2005	12	Adams Valley tall fescue	Forage	0.201	29	0.62

	Hay

38	0.32

OR12, Aurora, OR, 2005	12	Icon rye grass	Forage	0.207	36	0.10

	Hay

43	0.13

OR13, Aurora, OR, 2005	12	Fawn tall fescue	Forage	0.199	30	0.43

	Hay

40	0.10

WA05, Prosser, WA, 2005	11	Pulte orchard

grass	Forage	0.201	29	0.14

	Hay

36	0.15

HED concludes bifenthrin residues in/on orchard grass forage and hay should not exceed 2.5 ppm and 4.5 ppm, respectively.  These tolerance levels are as per IR-4 recommendation and were determined using the EPA MRL calculator.  Therefore, time- limited tolerances for residues of bifenthrin in/on orchardgrass forage and hay should be established at 2.5 ppm and 4.5 ppm, respectively.

Processed Commodities

There are no processed commodities associated with orchardgrass grown for seed for which residue data are required.

Meat, Milk, Poultry and Eggs

Although forage and hay from orchardgrass grown for seed are considered to be livestock feed items, they contribute a minor percentage of livestock diets compared to the contribution from corn and aspirated grain fractions (Memo, 7/25/07, W.D. Wassell, DP# 371449).  HED thus concludes that residues of bifenthrin in/on forage and hay from orchardgrass grown for seed will not result in higher livestock dietary burdens and that increased tolerances are not required for residues in livestock commodities from this Section 18 use.

Rotational Crop Restrictions

The following rotational crop restrictions were included on the label:  Leafy vegetables and root crops may be rotated 30 days following the final application of bifenthrin.  Crops for which bifenthrin tolerances exist may be rotated at any time.  All other crops may be rotated seven months following the final application of bifenthrin.

Adequate confined and field rotational crop studies are available for bifenthrin.  Based on these data, HED has previously determined the following rotational crop restrictions are adequate:  Crops having bifenthrin tolerances may be replanted at any time, and all other crops may be replanted 30 days following the last application of bifenthrin.  No rotational crop tolerances are required.  These restrictions are less limiting than the rotational crop restrictions included on the proposed label. A revised label with the approved rotational crop restrictions may be submitted if the less limiting rotational crop restrictions are desired.

International Residue Limits

There are no Codex maximum residue limits (MRLs) established for bifenthrin on grass forage and hay (see Attachment 1).  Therefore, no compatibility problems exist for the proposed tolerances.

RDI: M. Clock-Rust:  03/26/2008, G.F. Kramer:  03/26/2008

Registration:  08OR08

DP Number:  350052

PC Code:  128825

WDWassell:S10316:Potomac Yard:703-305-6135:7509P:RAB1

ATTACHMENT 1:  IRLS Sheet

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:

(2-Methyl [1,1'-biphenyl]-3-yl) methyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropane carboxylate

Common Name:

BIFENTHRIN

( Proposed tolerance

( Reevaluated tolerance

( Other

Date:

3/25/08

Codex Status (Maximum Residue Limits)

U. S. Tolerances

X No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested

Petition Number:  08OR08

DP Number:  350052

Other Identifier:

Residue definition:

Reviewer/Branch:  W.D. Wassell

Residue definition:  bifenthrin per se

Crop (s)

MRL (mg/kg)

Crop(s)

Tolerance (ppm)

Grass, forage

2.5

Grass, hay

4.0

Limits for Canada

Limits for Mexico

X No Limits

( No Limits for the crops requested

X No Limits

( No Limits for the crops requested

Residue definition:

Residue definition:

Crop(s)

MRL (mg/kg)

Crop(s)

MRL (mg/kg)

Notes/Special Instructions:

Rev. 1998

 PAGE

Page   PAGE  2  of   NUMPAGES  5


[Federal Register Volume 88, Number 126 (Monday, July 3, 2023)]
[Notices]
[Pages 42704-42705]
[FR Doc No: 2023-14058]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Combined Notice of Filings

    Take notice that the Commission has received the following Natural
Gas & Oil Pipeline Rate and Refund Report filings:

Filings Instituting Proceedings

    Docket Numbers: RP23-844-000.
    Applicants: El Paso Natural Gas Company, L.L.C.
    Description: Sec.  4(d) Rate Filing: Negotiated Rate Agreement
Update (SRP August 2023) to be effective 8/1/2023.
    Filed Date: 6/26/23.
    Accession Number: 20230626-5112.
    Comment Date: 5 p.m. ET 7/10/23.

    Docket Numbers: RP23-845-000.
    Applicants: Iroquois Gas Transmission System, L.P.
    Description: Sec.  4(d) Rate Filing: 6.27.23 Negotiated Rates--
Mercuria Energy America, LLC R-7540-02 to be effective 7/1/2023.
    Filed Date: 6/27/23.
    Accession Number: 20230627-5003.
    Comment Date: 5 p.m. ET 7/10/23.

    Docket Numbers: RP23-846-000.
    Applicants: El Paso Natural Gas Company, L.L.C.
    Description: Sec.  4(d) Rate Filing: Negotiated Rate Agreements
Update (Pioneer 2023) to be effective 7/1/2023.
    Filed Date: 6/27/23.
    Accession Number: 20230627-5051.

    Comment Date: 5 p.m. ET 7/10/23.

    Docket Numbers: RP23-847-000.
    Applicants: Texas Eastern Transmission, LP.
    Description: Sec.  4(d) Rate Filing: Negotiated Rates--DTE eff 7-1-
23 to be effective 7/1/2023.
    Filed Date: 6/27/23.
    Accession Number: 20230627-5060.
    Comment Date: 5 p.m. ET 7/10/23.

    Any person desiring to intervene or protest in any of the above
proceedings must file in accordance with Rules 211 and 214 of the
Commission's Regulations (18 CFR 385.211 and 385.214) on or before 5:00
p.m. Eastern time on the specified comment date. Protests may be
considered, but intervention is necessary to become a party to the
proceeding.

Filings in Existing Proceedings

    Docket Numbers: RP22-501-000.
    Applicants: ANR Pipeline Company.
    Description: Refund Report: Amended Settlement Refund Report to be
effective N/A.
    Filed Date: 6/26/23.
    Accession Number: 20230626-5057.
    Comment Date: 5 p.m. ET 7/10/23.

    Any person desiring to protest in any the above proceedings must
file in accordance with Rule 211 of the Commission's Regulations (18
CFR 385.211) on or before 5:00 p.m. Eastern time on the specified
comment date.
    The filings are accessible in the Commission's eLibrary system
(https://elibrary.ferc.gov/idmws/search/fercgensearch.asp) by querying
the docket number.
    eFiling is encouraged. More detailed information relating to filing
requirements, interventions, protests, service, and qualifying
facilities filings can be found at: http://www.ferc.gov/docs-filing/efiling/filing-req.pdf. For other information, call<PHONE_NUMBER>
(toll free). For TTY, call<PHONE_NUMBER>.
    The Commission's Office of Public Participation (OPP) supports
meaningful public engagement and participation in Commission
proceedings. OPP can help members of the public, including landowners,
environmental justice communities, Tribal members and others, access
publicly available information and navigate Commission processes. For
public inquiries and assistance with making filings such as
interventions, comments, or requests for rehearing, the public is
encouraged to contact OPP at<PHONE_NUMBER> or [email protected].

    Dated: June 27, 2023.
Debbie-Anne A. Reese,
Deputy Secretary.
[FR Doc. 2023-14058 Filed 6-30-23; 8:45 am]
BILLING CODE 6717-01-P


IX.  Comments on Requirements Related to Equipment and Utensils

(Subpart D)

	A.  Organization of Final Subpart D

     Proposed subpart D contained two provisions regarding equipment,
utensils and automatic, mechanical, or electronic equipment.  Table 5
lists the sections in the final rule and identifies the corresponding
sections in the 2003 CGMP Proposal that form the basis of the final
rule.

Table 5.- Derivation of Sections in Subpart D

Final Rule	2003 CGMP Proposal

§ 111.25  What are the Requirements Under this Subpart for Written
Procedures?	§ 111.25(c)(1)

§ 111.25(e)(1)

§ 111.27  What Requirements Apply to the Equipment and Utensils that
you Use?	§ 111.25(a), (b), (d), and (e)

§ 111.30 What Requirements Apply to Automated, Mechanical, or
Electronic Equipment?	§ 111.30

§ 111.35 Under this Subpart, What Records Must you Make and Keep?	§
111.25(c)(1), (c)(2), (d) and (f), § 111.30(b)(2), (b)(5), and (c)

§ 111.50(c)(4)

B.  Highlights of Changes to the Proposed Requirements

for Equipment and Utensils

1.  Revisions

     The final rule includes:

●	Revisions that reflect the final rule applies to persons who
manufacture, package, label, or hold dietary supplements unless subject
to an exclusion in § 111.1.

2. Revisions Associated With the Reorganization.

These include:

●	Renumbering proposed § 111.25 as final § 111.27 and correcting the
numbering of the sections misnumbered in the 2003 CGMP Proposal;

●	Requiring documentation and backup files in a separate section for
recordkeeping requirements.

●	A non-substantive editorial change to refer to “automated
equipment” rather than “automatic equipment.” Although there is no
practical difference between these two terms, the term “automated”
is the customary term.

3. Changes After Considering Comments

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●	Requires you to establish and follow written procedures to fulfill
the requirements of subpart D, including written procedures for:

○ Calibrating instruments and controls;

○ Calibrating, inspecting, and checking automated, mechanical, and
electronic equipment; and

○ Maintaining, cleaning, and sanitizing, as necessary, equipment,
utensils, and other contact surfaces;

●	Requires you to keep records of the maintenance, cleaning and
sanitizing of equipment either in equipment logs or in batch records;

●	Requires that your quality control personnelunit periodically review
records of calibrations, inspections or checks of automated, mechanical,
or electronic equipment rather than approve such records when they are
made:

●	Specifies that software for a computer controlled process is
included under automated, mechanical, or electronic equipment;

●	Clarifies that the requirement to retain backup files of software
programs and of data entered into computer systems is for computer
systems that you use in the manufacture, packaging, labeling, or holding
of dietary supplements.

	C.  General Comments on Proposed Subpart D.

     (Comment 108) Some comments claim one or more proposed requirements
are unconstitutionally vague under the Fifth Amendment and arbitrary and
cap楲楣畯⁳湵敤⁲₧〷⠶⤲䈨
景琠敨䄠䅐吠敨敳瀠
潲潰敳敲畱物浥湥獴椠据畬敤›

●	§ 111.25(a)(1) which would require that equipment and utensils be
“of appropriate design, construction, and workmanship to enable them
to be suitable for their intended use and to be adequately cleaned and
properly maintained;”

●	§ 111.25(a)(2) which would require you to “use equipment and
utensils of appropriate design and construction so that use will not
result in the contamination of components, dietary ingredients, or
dietary supplements.”

     In general, these comments assert the proposed sections did not
define terms or phrases (such as “suitable” or “appropriate
design”) in a way that persons who are subject to the rule can discern
the meaning of the term.  These comments also assert the proposed
sections do not limit enforcement officers’ exercise of their
discretion as to what will satisfy the requirements and, thus, invite
exercise of unbridled discretion and disparate decision making.

      (Response)  As discussed in section V, we disagree that the terms
are unconstitutionally vague, need to be defined, may result in
discriminatory enforcement or violate the APA.  There has been
sufficient usage of these terms in the food industry to enable
manufacturers, and those who enforce the requirements, to comprehend and
apply such terms.  Agencies are permitted to use qualifying terms to
enable them to address a wide variety of conditions at companies.

D.  What Are the Requirements Under This Subpart for Written Procedures
?

(Final §  111.25)

1. Final § 111.25

	We received many comments that recommend written procedures for various
provisions.  We address the need for written procedures generally in
section IV.  We also respond to  comments on specific provisions in the
same section.  We are adding final § 111.25 that requires you to
establish and follow written procedures for certain requirements.

E.  What Requirements Apply to the

Equipment and Utensils that You Use?

(Final § 111.27)

     Final § 111.27 (proposed § 111.25) sets forth various
requirements for equipment and utensils.

1. Final § 111.27(a)

	a.  Final § 111.27(a).

 Final § 111.27(a) (proposed § 111.25(a)(1)) requires you to use
equipment and utensils that are of appropriate design, construction, and
workmanship to enable them to be suitable for their intended use and to
be adequately cleaned and properly maintained.  In order to correct the
misnumbering of this provision in the 2003 CGMP Proposal, this general
requirement has been broken out from the remaining requirements of final
§ 111.27(a)

Final § 111.27(a)(1)(i) through (a)(1)(v) provide examples of such
equipment, such as equipment used to hold or convey (§
111.27(a)(1)(i)), equipment using compressed air or gas (§
111.27(a)(1)(iii)), and equipment used in automated, mechanical, or
electronic systems (§ 111.27(a)(1)(v)).

	Final § 111.27(a)(1) is similar to proposed § 111.25(a)(1) except for
two, non-substantive editorial changes.  The first change replaces
“automatic equipment” with “automated equipment” in what is now
§ 111.27(a)(1)(v) (proposed § 111.25(a)(1)(5)).  Although there is no
practical difference between “automatic” and “automated,” the
latter is the customary term.

(Comment 109)  Some comments argue that the proposal’s use of terms
such as “appropriate design, construction, and workmanship to enable
them to be suitable for their intended use” and “adequately cleaned
and properly maintained” are unconstitutionally vague under the Fifth
Amendment and arbitrary and capricious under the APA.

(Response)  We discuss those comments generally in section V of this
document and, because we disagree that the final rule violates either
the Fifth Amendment of the Constitution or the APA, we have not revised
§ 111.27(a)(1) except for the changes mentioned immediately above.

	b. Final § 111.27(a)(2).  Final § 111.27(a)(2)(proposed §
111.25(a)(2)) requires you to use equipment and utensils of appropriate
design and construction so that use will not result in the contamination
of components or dietary supplements with: (1) Lubricants; (2) fuel; (3)
coolants; (4) metal or glass fragments; (5) filth or any other
extraneous material; (6) contaminated water, or (7) any other
contaminants.

     (Comment 110)  Several comments state we should recognize that
lubricants are an integral part of the encapsulation of gelatin-enrobed
products and other dosage forms.  These comments state lubricants are
not potential contaminants, and in fact, help move gelatin ribbons
through encapsulating machines.  The comments would revise proposed §
111.25(a)(2) to read, “lubricants not intended for product contact,”
to clarify the rule’s intent.

     (Response)  We decline to revise the final rule as suggested by the
comments.  Final § 111.27(a)(2) states that the use of equipment and
utensils must not result in the contamination of components or dietary
supplements with lubricants. If a lubricant used for encapsulation does
not result in contamination of the components or dietary supplements
then the encapsulating machine complies with final § 111.27(a)(2).

	c. Final § 111.27(a)(3).  Final § 111.27(a)(3) (proposed
§ 111.25(a)(3)) requires all equipment and utensils you use to be: (1)
Installed and maintained to facilitate cleaning the equipment, utensils,
and all adjacent spaces; (2) corrosion-resistant if the equipment or
utensils contact components or dietary supplements; (3) made of nontoxic
materials; (4) designed and constructed to withstand the environment in
which they are used, the action of components or dietary supplements,
and, if applicable, cleaning compounds and sanitizing agents; and (5)
maintained to protect components and dietary supplements from being
contaminated by any source.

We did not receive comments specific to proposed § 111.25(a)(3).  We
have substituted the phrase “in which they are used” for “of their
intended use” to make clear the requirement applies to equipment
actually used in the manufacture, packaging, labeling, or holding of
dietary supplements.

	d. Final § 111.27(a)(4).  Final § 111.27(a)(4) (proposed
§ 111.25(a)(4)) requires that the equipment and utensils you use have
seams that are smoothly bonded or maintained to minimize accumulation of
dirt, filth, organic material, particles of components or dietary
supplements, or any other extraneous materials or contaminants.  Final
§ 111.27(a)(4) is similar to proposed § 111.25(a)(4)and is analogous
to § 110.40(b) which requires that seams on food-contact surfaces be
smoothly bonded or maintained so as to minimize accumulation of food
particles, dirt, and organic matter and thus minimize the opportunity
for growth of microorganisms.  We have deleted the phrase “to minimize
the opportunity for growth of microorganisms” as unnecessary in this
context as the remaining wording of the provision encompasses this
concept.  In non-substantive editorial changes to final § 111.27(a)(4)
we substitute “particles of components or dietary supplements” for
“component or dietary supplement particles” to improve clarity, and
re-order the list of extraneous materials or contaminants.

     (Comment 111)  Several comments argue that proposed § 111.25(a)(4)
is overly restrictive by requiring equipment and utensils to “have
seams that are smoothly bonded or maintained” to minimize
contamination.  The comments would revise the rule as follows:
“Equipment and utensils you use must be of proper design and
maintained to minimize accumulation  . . .”

     (Response)  We disagree that proposed § 111.25(a)(4) (final §
111.27(a)(4)) is overly restrictive or that it requires a particular
design.  Final § 111.27(a)(4) requires seams that are smoothly bonded
or maintained to minimize accumulation of dirt and gives firms the
flexibility to use any design they choose, provided that the seams, by
design or maintenance, minimize accumulation of contaminants.

	e. Final § 111.27(a)(5).  Final § 111.27(a)(5)(proposed §
111.27(a)(5)) requires that each freezer, refrigerator, and other cold
storage compartment you use to hold components or dietary supplements:
(1) be fitted with an indicating thermometer, temperature-measuring
device, or temperature-recording device that indicatesshows, and
records, or allows for recording by hand, the temperature accurately
within the compartment; and (2) have an automated device for regulating
temperature or an automated alarm system to indicate a significant
temperature change in a manual operation.

     (Comment 112)  The preamble to the 2003 CGMP Proposal invited
comment as to whether we should require specific target temperatures for
dietary ingredients or dietary supplements held in freezers or cold
storage (68 FR 12157 at 12190).  Several comments assert there is no
need for us to specify storage temperatures for dietary ingredients or
dietary supplements.  The comments state most dietary supplements and
dietary ingredients are shelf stable based on their low water activity
control, which limits and slows chemical degradation and microbiological
growth.  Other comments say target temperatures are not required where
freezing is used only to enhance the milling properties (fracturing) of
dried botanicals and not to prevent microbial contamination.

     (Response)  We have not included any specific target temperature
requirements in the final rule.  Consequently, firms should determine
for themselves what temperatures are needed to ensure that the their
dietary supplements are not adulterated (see final § 111.70 regarding
the specifications you must establish).

	f.  Final § 111.27(a)(6).  Final § 111.27(a)(6)(proposed §
111.25(a)(6)) requires the instruments or controls you use in the
manufacturing, packaging, labeling, or holding of a dietary supplement,
and instruments or controls that you use to measure, regulate, or record
temperatures, pH, aw, or other conditions, to control or prevent the
growth of microorganisms or other contamination, be accurate and
precise, adequately maintained, and adequate in number for their
designated uses.

     (Comment 113)  One comment states that proposed §
111.25(a)(6)(i)’s requirements that instruments and controls be
“accurate and precise” goes beyond “typical” calibration, and
would require full validation of all instruments and controls.  The
comment argues that it is unnecessary to require both accuracy and
precision for all instruments and controls, and would require precision
only when necessary to prevent contamination.  The comment states
calibration to ensure accuracy of instruments and controls is usually
sufficient to ensure control or prevention of the growth of
microorganisms or other contaminants in most situations.  The comment
gives an example where thermometers are used to monitor temperature in a
warehouse where dietary supplements are stored.

     (Response)  We disagree that proposed § 111.27(a)(6) requires full
validation of all equipment and controls.  As discussed in the preamble
to the 2003 CGMP Proposal (68 12157 FR at 12190), accuracy means that
the recorded measurements are equal to the (true value) of the thing
being measured and precision means that individual measurements should
be close to each other when made under the same conditions.

We also disagree that instruments need not be precise.  An instrument
that gives widely varying readings from one use to the next cannot
ensure product quality over time.  The degree of accuracy and precision
is determined by the nature of the instrument or control and the process
to which it relates.  We have, however, made several non-substantive,
editorial changes to § 111.27(a)(6) as well as other edits to conform
to changes made throughout the final rule.  These are the
non-substantive editorial changes:

●	Inserting a hyphen between “hydrogen” and “ion;” and

●	Revising the end of the paragraph so that it discusses
“instruments and controls that you use * * * to control or prevent the
growth of microorganisms or other contamination * * *.”  The proposal
stated “instruments and controls that you use * * * that control or
prevent the growth of microorganisms or other contamination * * *.”.
(In other words, the final rule replaces “that” with “to.”)

	g. Final § 111.27(a)(7).  Final § 111.27(a)(7)(proposed §
111.25(a)(7)) requires that the compressed air or other gases you
introduce mechanically into or onto a component, dietary supplement, or
contact surface or you use to clean any contact surface be treated in
such a way that the component, dietary supplement, or contact surface is
not contaminated.

We received no comments specific to proposed § 111.25(a)(7).

2.  Final § 111.27(b)

Final § 111.27(b) (proposed § 111.25(b)(1)) requires you to calibrate
instruments and controls that you use in manufacturing or testing a
component or dietary supplement.  In order to correct the misnumbering
of this provision in the 2003 CGMP Proposal, this general requirement
has been broken out from the remaining requirements of final §
111.27(b) and now has paragraphs (b) and (b)(1) through (b)(3).

Final § 111.27(b)(1) – (b)(3) (proposed § 111.25(b)(1) and (b)(2))
requires you to calibrate before first use, and at the frequency
specified in writing by the manufacturer of the instrument or control,
or at routine intervals, or as otherwise necessary to ensure the
accuracy and precision of the instrument and control.

     (Comment 114)  Several comments object to the level of detail
regarding the proposed calibration.  Specifically, the comments object
to requiring that manufacturers calibrate instruments and controls “as
specified in writing by the manufacturer of the instrument and
control.”  The comments say this requirement is more prescriptive than
drug CGMP requirements.  The comments acknowledge that following
manufacturer specifications is likely to be part of the calibration
procedure, but state that firms should have the flexibility to modify
their procedures as necessary.  These comments would couple proposed §
111.25(b) with a requirement to establish and follow written procedures
for calibrating instruments and controls and redraft proposed §
111.25(b) to mirror the drug CGMP requirements, using language such as
“You must routinely calibrate instruments and controls that control or
monitor critical parameters that you use in manufacturing or testing a
component or dietary supplement.”

     (Response)  We disagree that proposed § 111.25(b) is overly
prescriptive, exceeds drug CGMP requirements, or requires what is
claimed by the comments.  We discuss, generally, the issue of whether
this final rule “exceeds drug CGMPs” in section V.   It is standard
practice to calibrate an instrument before using it for the first time.
A requirement that you calibrate as specified by the manufacturer of the
equipment, or at routine intervals, or as otherwise necessary to ensure
the accuracy and precision of the instrument and control, provides ample
flexibility.  Calibration, whether for instruments and controls used in
manufacturing or testing drugs, devices, conventional foods, or dietary
supplements, helps ensure the accuracy and precision of the instrument
and control.  We do not prescribe how frequently such calibration must
be done, but it must be done often enough to ensure that instruments and
controls are operating within the correct parameters.  We are revising
the 2003 CGMP Proposal (at § 111.27(b)(2)) to clarify that the
requirement relates to the frequency of calibration.

     (Comment 115)  Several comments claim requirements relating to
calibration of instruments and controls should be limited to those
instruments and controls that directly affect the identity, purity,
quality, strength, and composition of a dietary supplement.  According
to the comments, in most manufacturing facilities, there are many
instruments and controls that do not directly affect identity, purity,
quality, strength, and composition, and that calibrating all instruments
and controls could easily become unduly burdensome.  The comments also
would limit the requirement for periodic calibration of instruments and
controls to those instruments and controls directly involved in the
critical control parameters of the process, i.e., those parameters
needed to meet specifications or to ensure identity, purity, quality,
strength, and composition.  The comments suggest that critical control
parameters would have to be established.

     (Response)  We decline to revise the rule as suggested by the
comments.  The requirement to calibrate instruments and controls is
limited to those instruments and controls that you use in testing a
component or dietary supplement or in manufacturing a dietary
supplement.  Any such equipment has the potential to affect, directly or
indirectly, the quality of the dietary supplement.

     (Comment 116)  Some comments would revise proposed § 111.25(b)(1)
to state that “calibration should be done, where standards are
available or where it is necessary to meet product specifications.”

     (Response)  We decline to revise the rule as suggested by the
comments.  It would be customary for an equipment manufacturer to have
standards that can be used to calibrate the equipment, irrespective of
the specific composition of the dietary supplement that is manufactured
using that equipment. Equipment that is not or cannot be calibrated is
unlikely to be in compliance with the requirement of final §
111.27(a)(6)(i) which requires instruments used in the manufacturing,
packaging, labeling, and holding of dietary supplements, and instruments
and controls that you use to perform certain operations, be accurate and
precise.

     (Comment 117)  Some comments would revise proposed § 111.25 from
the active voice to the passive voice.  These comments claim that the
active voice - i.e., requiring that “you” calibrate instruments and
controls - requires that the dietary supplement manufacturer perform the
calibration, when in fact such calibrations are often performed by an
outside service.

     (Response)  You may use an outside service.  We would not consider
that calibration done for you by an outside service is any different
than calibration done by your employees, and it is you (rather than an
outside service) whom we will hold responsible to ensure that the
calibration is performed.  Accordingly, we decline to revise the
provisions as suggested.

     (Comment 118)  Several comments say calibration before first use
should not be required for certified, precalibrated instrumentation.
The comments state precalibrated instrumentation is much more expensive
than non-calibrated instrumentation, with the additional expense
attributed to the precalibration.  Several comments would revise
proposed § 111.25(b)(2) to read, “you must calibrate, or be able to
verify that the calibration has been completed, before first use”,
instead of, “you must calibrate before first use”.  The comments
state that performance test results could be made available for this
verification.

     (Response)  As written, the requirement that equipment be
calibrated before first use includes calibration performed by a third
party as a pre-calibration because we would consider that calibration
performed by a third party as no different from calibration performed by
one of your own employees.  Under final § 111.35(b)(3) you must have
documentation of the calibration.

     If you purchase a precalibrated instrument, we strongly recommend
that the vendor conduct the certification onsite after installation.  If
not, we strongly recommend that you verify that the instrument remains
calibrated after it has been installed.

     (Comment 119)  Several comments ask whether the proposed
requirement to calibrate “before first use” refers to the first use
after installation or the first use after each start-up.

     (Response)  Final § 111.27(b)(1) refers to the first use after
installation and does not require calibration after each start-up.

     (Comment 120) Some comments would require that instruments and
controls be calibrated, but argue that the final rule should not include
detailed procedures specifying calibration methods. The comments said
the rule should stay focused on end results and not process.

     (Response)  We disagree that the regulations should not focus on
process.  The essence of the CGMP requirements established by these
regulations is a production and process control system, i.e., a process,
that is designed to ensure the quality of the dietary supplement.  The
final rule gives firms the flexibility to use different calibration
methods as long as the method used is established in a written
procedure.

3.  Final § 111.27(c)

     Final § 111.27(c) (proposed § 111.25(d)) requires that you repair
or replace instruments or controls that cannot be adjusted to agree with
the reference standard.

We received no comments specific to proposed § 111.25(d).

4.  Final § 111.27(d)

     Final § 111.27(d) (proposed § 111.25(e)) requires you to
maintain, clean, and sanitize, as necessary, all equipment, utensils,
and any other contact surfaces used to manufacture, package, label, or
hold components or dietary supplements.  In order to correct the
misnumbering of this provision in the 2003 CGMP Proposal, this general
requirement has been broken out from the remaining requirements of final
§ 111.27(d) and now has paragraphs (d) and (d)(1) through (d)(7).

	a.  Final § 111.27(d)(1).  Final § 111.27(d)(1) requires that the
equipment and utensils be taken apart as necessary for thorough
maintenance, cleaning, and sanitizing.

	(Comment 121)  Some comments argue that individual manufacturing
operations will determine when sanitizing agents are needed after
cleaning because of the wide variety of processes in the industry.  The
comments also say widespread use of sanitizing agents is creating
resistant microbial strains, and incorporating unnecessary sanitization
processes would contribute to this health concern.

	Some comments recommend manufacturers calibrate sanitizing procedures
to the particular process in a declared fashion depending upon the risk
factors of their process and materials.  The comments set out several
standards for sanitation procedures.

     (Response)  Final § 111.27(d) requires you to maintain,  clean,
and sanitize, as necessary, equipment, utensils, and any other contact
surfaces, used to manufacture, package, label, or hold dietary
supplements.  The final rule thus gives you discretion to decide when
sanitizers or sanitizing treatments, such as heat, are necessary and
does not mandate the incorporation of unnecessary sanitization
processes.

	Additionally, under final § 111.27(d) you have flexibility to
determine when sanitizing is appropriate and to sanitize only as
necessary.  We note that this flexibility was also present in proposed
§ 111.25(e)(1).  Some comments suggested calibrating sanitation
operations based on risk.  The final rule largely leaves it up to firms
to decide whether to sanitize or to just clean without sanitizing, based
on the risks associated with the materials and process used.  However,
under final § 111.27(d)(3), if you use wet processing, if you determine
that it is necessary to clean a contact surface, you must also sanitize
that surface.

     (Comment 122)  Several comments state the final rule should include
a requirement for validating cleaning procedures.  The comments argue
that testing requirements for finished dietary supplements might not
test for certain contaminants that could arise as a result of cleaning.
One comment asserts these potential contaminants would be discovered in
a properly designed and executed cleaning validation protocol, and that
including these written cleaning procedures in the final rule would help
prevent adulteration and help ensure the identity, purity, quality,
strength, and composition of dietary supplements.

     (Response)  We decline to require specific cleaning validation
procedures in the final rule.  Final § 111.27(d) and the requirements
for written procedures under final § 111.25(c) are sufficient to ensure
the use of cleaning procedures to ensure the quality of the dietary
supplement.

	b. Final § 111.27(d)(2).  Final § 111.27(d)(2) (proposed §
111.25(e)(2)) requires you to ensure that all contact surfaces, used for
manufacturing or holding low-moisture components or dietary supplements,
are in a dry and sanitary condition when in use.  When the surfaces are
wet-cleaned, you must sanitize them, when necessary, and allow them to
dry thoroughly before you use them again.

We received no comments specific to proposed § 111.25(e)(2).  We have
substituted the phrase “when in use” for “at the time of use” of
clarity.

	c. Final § 111.27(d)(3).  Final § 111.27(d)(3) (proposed §
111.25(e)(3))requires you, if you use wet processing during
manufacturing, to clean and sanitize all contact surfaces, as necessary,
to protect against the introduction of microorganisms into components or
dietary supplements.  Final § 111.27(d)(3) also requires that:

●	When cleaning and sanitizing is necessary, you clean and sanitize
all contact surfaces before use and after any interruption during which
the contact surface may become contaminated; and

●	If you use contact surfaces in a continuous production operation or
in consecutive operations involving different batches of the same
dietary supplement, you must adequately clean and sanitize the contact
surfaces, as necessary.  In this provision, we substituted
“consecutive” for “back-to-back,” a non-substantive change.  We
also inserted “adequately” to make clear that cleaning and
sanitizing must be adequate.

     (Comment 123)  Several comments argue against using the term
“sanitize” in proposed § 111.25(e)(3).  The comments state that,
based on the proposed definition of “sanitize,”  § 111.25(e)(3)
would require evaluation of any sanitation steps to ensure that the
level of log reduction is reached, for example, by taking “before and
after” swab samples.  The comments would revise proposed §
111.25(e)(3) to state that equipment, utensils, etc. shall be cleaned
and sanitized in a manner that keeps microorganisms and other
adulterants from contaminating all components, ingredients, in-process
materials, and finished goods.

(Response)  The final rule now defines “sanitize” as “to
adequately treat cleaned equipment, containers, utensils, or any other
cleaned product contact surface by a process that is effective in
destroying vegetative cells of microorganisms of public health
significance, and in substantially reducing numbers of other
microorganisms, but without adversely affecting the product or its
safety for the consumer.”  The definition no longer specifies a level
of log reduction, so the revised definition should eliminate the
comments’ concern as to any possible need for “before and after”
samples.

	d.  Final § 111.27(d)(4).  Final § 111.27(d)(4) (proposed §
111.25(e)(4)) requires you to clean surfaces that do not come into
direct contact with components or dietary supplements as frequently as
necessary to protect against contamination.  Final § 111.27(d)(4)
relates to final § 111.27(d)(2) and (3).  For example, you would not
have to clean your ceilings as often as you clean your contact surfaces
because your ceilings normally do not touch components or dietary
supplements.  However, you would have to clean your ceilings as
frequently as necessary to prevent dust or other contaminants from
falling onto your components, dietary supplements, and contact surfaces.

     We received no comments specific to proposed § 111.25(e)(4).  We
substituted “do not come into direct contact with” for “do not
touch” as a non-substantive editorial revision.

	e.  Final § 111.27(d)(5).  Final § 111.27(d)(5) (proposed §
111.25(e)(5)) requires that single-service articles (such as utensils
intended for one-time use, paper cups, and paper towels) be: (1) stored
in appropriate containers and (2) handled, dispensed, used, and disposed
of in a manner that protects against contamination of components,
dietary supplements, or any contact surface.

	We received no comments specific to proposed § 111.25(e)(5).

	f. Final § 111.27(d)(6).  Final § 111.27(d)(6) (proposed §
111.25(e)(6))requires your cleaning compounds and sanitizing agents to
be adequate for their intended use and safe under their conditions of
use.

     (Comment 124)  One comment would delete proposed § 111.25(e)(6),
stating it is redundant to proposed § 111.15(b), which would require
you to use cleaning compounds and sanitizing agents that are free from
microorganisms of public health significance and safe and adequate under
the conditions of use.

     (Response)  We disagree with this comment.  Proposed §§
111.15(b)(1) and 111.25(e)(6) (now final §§ 111.15(b)(1) and
111.27(d)(6) respectively) differed in their requirements and their
applicability.  Proposed § 111.15(b)(1) would apply to cleaning
compounds and sanitizing agents used in the physical plant and would
require them to be “safe and adequate under the conditions of use.”
In contrast, proposed § 111.25(e)(6) would apply to cleaning compounds
and sanitizing agents used on equipment, utensils, and contact surfaces
used to manufacture, package, or hold components, dietary ingredients,
or dietary supplements, and it would require such cleaning compounds or
sanitizing agents to be “adequate for intended use and safe under
condition [sic] of use.”  By using the phrase “adequate for intended
use,” proposed § 111.25(e)(6) would have you consider whether a
particular cleaning compound or sanitizing agent was appropriate for the
particular use to which it was being applied.

	Furthermore, depending on the situation, a cleaning compound or
sanitizing agent that is appropriate for use on a physical plant may be
inappropriate for use on equipment, utensils, and contact surfaces.  For
example, a powdered cleaning compound might be suitable for cleaning
your physical plant’s floors, but inappropriate for cleaning equipment
that mixes components.  In other words, the “conditions of use” can
also vary between final §§ 111.15(e)(1) and 111.27(d)(6) and lead to
different conclusions regarding use of the same cleaning compound.

	Additionally, on our own initiative, we have made two editorial,
non-substantive changes to final § 111.27(d)(6).  The final rule now
states that the cleaning compounds and sanitizing agents must be
adequate for “their” intended use and safe under “their
conditions” of use.

	g.  Final § 111.27(d)(7).  Final § 111.27(d)(7) (proposed §
111.25(e)(7)) requires you to store cleaned and sanitized portable
equipment and utensils that have contact surfaces in a location and in a
manner that protects them from contamination.  We received no comments
specific to proposed § 111.25(e)(7).

F. Reorganization of Certain Paragraphs in Proposed § 111.25.

Proposed § 111.25 would impose certain requirements relating to written
procedures for calibrating instruments and controls (proposed §
111.25(c) and (d)) and keeping calibration records (proposed §
111.25(f)).  The final rule now contains a new recordkeeping section (§
111.35) that combines elements of proposed § 111.25(c), (d), and (f),
as well as other sections.  We discuss comments on proposed §
111.25(c), (d), and (f) and describe final § 111.35 in this section.

G.  What Requirements Apply to Automated, Mechanical, or Electronic
Equipment?

(Final § 111.30)

     Final § 111.30 sets forth requirements for automated, mechanical,
or electronic equipment that you use to manufacture, package, label, or
hold a dietary supplement.

1.  Comments on the Organization and Framework of Proposed § 111.30

     (Comment 125)  Some comments would revise proposed § 111.30(a) to
replace “equipment to manufacture, package, label, and hold” with
“equipment to manufacture, package, label, or hold.” The comments
said that the same piece of equipment will not serve to manufacture,
package, label, and hold components or dietary supplements.

     (Response)  We agree, and have revised § 111.30 accordingly. Final
§ 111.30 also contains the following changes:

●	“Automatic” (as in “automatic equipment”) is replaced with
“automated” as an editorial, non-substantive change;

●	The phrase “determine the suitability of your equipment” has
been revised to, “determine the suitability of the equipment * * *”
in § 111.30(b) and has no substantive impact.

●	We have substituted the word “met” for “achieved” to comply
with “plain language” initiatives and to be consistent with other
provisions.

	We describe other changes to proposed § 111.30 immediately below.

(Comment 126)  Several comments support proposed § 111.30 particularly
with respect to computers.  The comments state computers are susceptible
to erroneous data input, are subject to malfunctions and software
problems, and thus should be regulated under the final rule.

     One comment questions why we organized proposed § 111.30 into two
paragraphs (a) and (b).  The comment claims there was no meaningful
difference between the two paragraphs.

     Other comments say some proposed requirements for automatic,
mechanical, and electronic equipment, such as the proposed requirement
for maintaining backup files of data entered into computer systems,
would apply to automatic, mechanical, and electronic equipment that are
not related to CGMPs.  The comments argue that proposed § 111.30(b)
would apply to computers on which payroll records are maintained, and
that such a requirement does not belong in these CGMPs.

     (Response)  We agree, in part, and disagree, in part, with the
comments.  We agree that computers used in the manufacture, packaging,
labeling, or holding of dietary supplements should be, and are, subject
to final § 111.30.

	We disagree, however, with those comments that interpreted proposed §
111.30(a) and (b) as being the same or interpreted proposed § 111.30 as
applying to equipment that has no direct bearing on dietary supplements.
 Proposed § 111.30(a) differed from proposed § 111.30(b) in that
paragraph (a) would pertain to the operation and suitability of your
equipment within your manufacturing process.  In contrast, proposed §
111.30(b) would apply to calibration of your equipment and controls you
establish for your equipment.

	We disagree with those comments that would interpret proposed §
111.30(b) as applying to payroll computers or other equipment that has
no CGMP function.  To prevent misinterpretations of final § 111.30, we
have revised it to apply to equipment “that you use to manufacture,
package, label, or hold a dietary supplement” and renumbered proposed
§ 111.30(a)(1), (a)(2), (b)(1), (b)(3), and (b)(4) as § 111.30(a)
through (e) respectively.  Proposed § 111.30(b)(2) which would require
you to make and keep written records of equipment calibrations,
inspections, and checks, and proposed § 111.30(b)(5) which would
require you to make and keep backup files of software programs and data,
are now incorporated into final § 111.35, and we discuss these
provisions later in this section.

     (Comment 127)  Several comments would limit proposed § 111.30(a)
and (b) to automatic, mechanical, or electronic equipment that actually
affects product specifications.  The comments argue that, in a modern
manufacturing facility, most, if not all, equipment used to manufacture,
package, label, or hold any food product is automatic, mechanical, or
electronic.  The comments say that equipment, such as forklifts, should
not be required to be designed or selected in a manner that ensures that
product specifications are met, as would be required in proposed §
111.30(a)(1), or to be calibrated, as would be required in §
111.30(b)(1).

     (Response)  As we stated immediately above, we have revised §
111.30 so that it applies to equipment “that you use to manufacture,
package, label, or hold a dietary supplement.”  This revision should
prevent the rule from being interpreted as applying to forklifts or
other equipment that have no bearing on the manufacture, packaging,
labeling, or holding of dietary supplements.

     (Comment 128)  Several comments argue that proposed § 111.30 is
redundant with proposed § 111.25 and could be removed without
meaningful effect.  One comment argues that proposed § 111.30(a) and
(b) (i.e., that all automatic, mechanical, and electronic equipment be
designed or selected to ensure that product specifications are
consistently achieved and operate satisfactorily within operating limits
required by the process) are redundant to proposed § 111.25(a)(1)
(which would require that all equipment be of appropriate design,
construction, and workmanship to enable them to be suitable for their
intended use) and proposed § 111.25(a)(1)(v) (which would state that
“equipment” includes automatic, mechanical electronic systems).  The
comment states that, for equipment to be suitable for its intended use,
the equipment must operate satisfactorily within operating limits and,
by extension, ensure that product specifications are consistently
achieved.  The comment states the separate regulations for automatic
equipment in the drug CGMPs is less detailed despite our efforts to
present the 2003 CGMP Proposal in “simplified language.”

     (Response)  We disagree that proposed § 111.30 is redundant with
proposed § 111.25 (final § 111.27).  Although both proposed §§
111.25 and 111.30 pertained to equipment, they differed in their focus.
Proposed § 111.25 would focus on equipment design, construction,
maintenance, cleaning, sanitizing, and calibration.  In contrast,
proposed § 111.30 would focus on the equipment’s operation or
suitability within your manufacturing process.  For example, proposed §
111.30(a)(2) would require you to determine the suitability of your
equipment by ensuring that your equipment is capable of operating
satisfactorily “within the operating limits required by the
process.”  In contrast, proposed § 111.25 had no comparable
suitability requirement insofar as your manufacturing processes were
concerned.  Thus, the proposed sections are not redundant, and the final
rule retains both § 111.27 (proposed § 111.25) and § 111.30.

2.	Comments Specific to Proposed § 111.30

a.  Final § 111.30(a) and (b).  Final § 111.30(a) (proposed §
111.30(a)(1)) requires you, for any automated, mechanical, or electronic
equipment you use to manufacture, package, label, or hold a dietary
supplement, to design or select the equipment to ensure that dietary
supplement specifications are consistently met.

     Final § 111.30(b) (proposed § 111.30 (a)(2)) requires you, for
any automated, mechanical, or electronic equipment that you use to
manufacture, package, label, or hold a dietary supplement, to determine
the suitability of the equipment by ensuring that the equipment is
capable of operating satisfactorily within the operating limits required
by the process.

     (Comment 129)  Some comments argue that the requirements of
proposed § 111.30(a) might be impossible to meet because, in many
instances, dietary supplement manufacturers cannot predict, at the time
of purchase, the entire range of ingredients and products for which a
particular piece of equipment might be used.  The comments argue that a
particular piece of equipment’s suitability for a particular
ingredient or product must be evaluated at the time the need arises.
The comments would revise proposed § 111.30(a)(1).  The words “Design
and select equipment to ensure” would be replaced with the words
“Use equipment that ensures;” and proposed § 111.30(a)(2) would be
revised to replace the words “is capable of operating” with the
word, “operates.”

     (Response)  We disagree with the comments.  Although a company may
not know the entire range of products that a machine may be used for,
proposed § 111.30(a)(1) and (2) would neither require you to determine
all uses of equipment at the time of purchase nor prevent you from
evaluating an old machine for a new use (these provisions are renumbered
as final § 111.30(a) and (b) respectively).  Thus, even if you chose to
use old equipment for a new use, you still must select that equipment to
ensure that dietary supplement specifications are consistently met with
the new equipment use and determine the suitability of the new equipment
use by ensuring that the equipment is capable of operating
satisfactorily within the operating limits required by the new process.

	(Comment 130)  Several comments express concern that facilities and
much equipment in the industry are old and lack historical
documentation.  These comments ask us to clarify whether manufacturers
would have to establish baseline information for old facilities and
equipment.

     (Response)  All equipment that you use, regardless of whether it is
old or new, must be capable of doing what you intend it to do.  Just as
you could evaluate old equipment for a new use, you can demonstrate that
old equipment does, in fact, do what you intend it to do for uses that
you developed before these CGMP requirements were established, and
thereby comply with final § 111.30(a) and (b).

     (Comment 131)  Several comments argue that our statement in the
preamble to the 2003 CGMP Proposal that “systems need to be installed
in a manner that takes into account the inherent limitations of the
system, tested under conditions that reflect actual conditions of use”
(68 FR 12157 at 12193) is vague and subject to multiple interpretations.

     (Response)  We disagree with the comment.  The statement in
question should be read in context because the preamble to the 2003 CGMP
Proposal described several conditions for consideration. The preamble to
the 2003 CGMP Proposal stated, in relevant part:

Some systems may work properly only within a narrow range of
environmental conditions, such as temperature and humidity, and some
might be particularly sensitive to electromagnetic interference.  The
actual conditions of use of a system should be considered as early as
possible in its design and development.  Systems need to be installed in
a manner that takes into account the inherent limitations of each
system, tested under conditions of use, and properly maintained to
ensure that they continue to function as expected during their lifetime.

(68 FR 12157 at 12193.)  Thus, suitability under final § 111.30(b)
involves considerations of how the equipment would be affected by
environmental conditions, whether the equipment is appropriate for its
intended use, and whether the equipment can be maintained properly to
ensure satisfactory operation.

     (Comment 132)  Several comments argue that the requirement of
proposed § 111.30(a)(2) to “determine the suitability of your
equipment by ensuring that your equipment is capable of operating
satisfactorily within the operating limits required by the process” is
vague and subject to many interpretations.  These comments assert that
this may cause an uneven playing field among companies as they apply
differing standards to this requirement.  The comments also argue that
the vagueness of this requirement could potentially cause uneven
enforcement, depending on the experience and understanding of individual
inspectors.

     (Response)  We disagree that proposed § 111.30(a)(2)(final §
111.30(b)) is vague or may result in uneven enforcement.  There has been
sufficient common usage of terms such as “suitable,” “capable,”
and “satisfactorily” in the industry to enable firms, and those who
enforce the requirements, to comprehend and apply such terms to
particular operations.  Agencies may use qualifying terms to enable them
to address a wide variety of conditions, and such terms provide the
flexibility needed for various operations.

     (Comment 133)  Several comments assert that proposed §
111.30(a)(2) is without justification and overly prescriptive when
compared to conventional food CGMPs.

     (Response)  As discussed in section V, the mere fact that a dietary
supplement CGMP requirement has no counterpart in the food CGMP
regulations, or has more detail than a counterpart in such regulations,
does not mean that it is overly prescriptive.  Rather, what is important
is whether proposed § 111.30(a)(2) (final § 111.30(b)) is necessary to
ensure the quality of the dietary supplements.  For example, the
preamble to the 2003 CGMP Proposal (68 FR 12157 at 12193) discussed how
the incorporation of software into the operation of automatic equipment
has both increased the complexity of such equipment and resulted in a
process that may operate differently for each execution, because a
software-based control system can be configured at will by the operator
or by the system itself.  Therefore, it is essential that you ensure
that automated equipment is capable of operating satisfactorily within
the operating limits required by the process.

     (Comment 134)  Several comments urge us to develop a separate
guidance document with respect to determining the suitability and
capability of equipment used in the manufacture of dietary supplements.

     (Response)  We believe that firms have sufficient experience to
determine whether equipment is suitable and capable of performing its
intended function.  However, if we find that guidance will be helpful,
we will consider whether to issue guidance at a later date.

b.  Final § 111.30(c).  Final § 111.30(c) (proposed § 111.30 (b)(1))
requires, for any automated, mechanical, or electronic equipment you use
to manufacture, package, label, or hold a dietary supplement, you to
routinely calibrate, inspect, or check the equipment to ensure proper
performance.  Final § 111.30(c) also requires your quality control
personnelunit to periodically review these calibrations, inspections, or
checks.

     (Comment 135)  Several comments claim the requirement for the
quality control unit to approve calibrations, inspections, or checks of
equipment is too prescriptive and that qualified persons outside of the
quality control unit should be able to approve these calibrations,
inspections, or checks.  The comments also state the quality control
unit should perform audits of the records generated to ensure the
appropriate calibrations, inspections, or checks are being adequately
performed at the required intervals.

     Other comments refer to related requirements in proposed §
111.37(b)(8) that the quality control unit review all records for
equipment calibrations, inspections, or checks.  The comments state the
requirements for oversight by the quality control unit in proposed §
111.37(b)(8) are excessive and go beyond requirements for both the drug
CGMPs and food CGMPs.  One comment would revise proposed § 111.37(b)(8)
to require a review of all records when there is a negative impact on
the dietary supplement due to a calibration failure.

     (Response)  Final § 111.12(b) requires that you identify who is
responsible for your quality control operations, and each person who is
designated to perform quality control operations must be qualified to do
so and have distinct and separate responsibilities related to performing
such operations from those responsibilities that the person otherwise
has when not performing such operations.  Thus, you may identify any
person whom you believe is qualified to approve calibrations,
equipments, or checks to perform quality control operationsthese
functions of the quality control unit.

     We disagree that the review by the quality control personnelunit
should be limited to circumstances when there has been a calibration
failure.  One function of the quality control personnelunit is to
provide oversight to prevent problems with the product that you
distribute by finding any problems with the equipment that you use to
produce the product rather than to investigate the cause of a problem
with a product that you already distributed.  However, we agree that it
is sufficient to periodically review the records of calibrations,
inspections, or checks of automated, mechanical, or electronic
equipment, for example, on an annual basis, rather than to approve each
record when it is made.  A periodic review can uncover trends in the
performance of the equipment that have the potential to adversely affect
the quality of the dietary supplement and that may not be obvious by
merely approving each record when it is made.  Seeing such trends would
enable the quality control personnelunit to recommend corrective
actions.  This periodic review is consistent with proposed §
111.37(b)(8) which would require the quality control unit to
“review” all records for equipment calibration, inspections, or
checks rather than “approve” these records.  Therefore, we have
revised the requirement that the quality control unit approve
calibrations, inspections, or checks of automatic, mechanical or
electronic equipment so that final § 111.30(c) requires that the
quality control personnelunit periodically review such operations rather
than approve them when they are made.

	Additionally, we have made a minor change to § 111.30(c).  The change
inserts the words “the equipment” after “Routinely calibrate,
inspect, or check * * *.”  This insertion simply reiterates that
“the equipment” must be routinely calibrated, inspected, or checked.

c.  Final § 111.30(d).  Final § 111.30(d) (proposed § 111.30(b)(3))
requires you, for any automated, mechanical, or electronic equipment you
use to manufacture, package, label, or hold a dietary supplement, to
establish and use appropriate controls for the equipment (including
software for a computer-controlled process) to ensure that any changes
to the manufacturing, packaging, labeling, holding, or other operations
are approved by the quality control personnelunit and instituted only by
authorized personnel.

(Comment 136)  The preamble to the 2003 CGMP Proposal invited comment on
whether we should regulate computerized systems separately from other
automatic equipment, given the broad range in sophistication,
complexity, and computerization in manufacturing equipment (68 FR 12157
at 12194).

     Several comments state that computers are susceptible to erroneous
data input and subject to malfunctions and software problems and, thus,
should be regulated under the final rule.

     (Response)  We agree that computers used in the manufacturing
processes should be regulated under the final rule.  As the preamble to
the 2003 CGMP Proposal stated (68 FR 12157 at 12193), the incorporation
of software into the operation of automatic equipment has increased the
complexity of such equipment and resulted in a process that may operate
differently for each execution, because a software-based control system
can be configured at will by the operator or by the system itself.
Additionally, final § 111.35(b)(5) requires you to make and keep backup
files of software programs and data to keep them secure from
alterations, inadvertent erasures, or loss.  The issue in the preamble
to the 2003 CGMP Proposal, however, was whether computerized systems
should be regulated separately from other equipment; in the absence of
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●	We are inserting the words “for automated, mechanical, and
electronic equipment (including software for a computer controlled
process)” after “Establish and use appropriate controls.”  This
change simply reiterates the types of equipment for which appropriate
controls must be established and used, and makes it clear that software
is included under the rule; and

●	We are rephrasing the purpose of § 111.30(d).  The proposal stated
that you must establish and use appropriate controls “to ensure that
your quality control unit approves changes in the master manufacturing
record batch control records, packaging operations, and label
operations, or changes to other operations related to the equipment that
you use and that only authorized personnel institute the changes.”
The final rule states that you must establish and use appropriate
controls for your equipment “to ensure that any changes to the
manufacturing, packaging, labeling, holding, or other operations are
approved by the quality control personnelunit and instituted only by
authorized personnel.”

As revised, final § 111.30(d) shifts its emphasis from the person(s)
who must approve or institute the changes to the types of changes that
must be approved and instituted.  This shift in emphasis is appropriate
given that the final rule addresses responsibilities of the  the quality
control personnel unit’s responsibilities elsewhere.

d.  Final § 111.30(e).  Final § 111.30(e) (proposed § 111.30(b)(4))
requires you, for any automated, mechanical, or electronic equipment you
use to manufacture, package, label, or hold a dietary supplement, to
establish and use appropriate controls to ensure that the equipment
functions in accordance with its intended use.  The qQuality control
personnnelunit must approve these controls.

     We did not receive comments specific to proposed § 111.30(b)(4).

	3. Reorganization of Certain Paragraphs in Proposed § 111.30

	As we explained earlier in this section, proposed § 111.30 would
impose certain requirements relating to written records of equipment
calibrations, inspections, or checks (proposed § 111.30(b)(2)) and
making and keeping backup files of software programs and data (proposed
§ 111.30(b)(5)).  The final rule now contains a new recordkeeping
section, final § 111.35, that combines elements of proposed §
111.30(b)(2) and (b)(5), as well as other sections.

Additionally, proposed § 111.30(c) would require you to keep records in
accordance with the written procedure and recordkeeping requirements at
proposed § 111.125.  Section 111.35 of the final rule now incorporates
proposed § 111.30(c) as well.  We discuss final § 111.35 immediately
below.

H.  Under This Subpart, What Records

Must You Make and Keep?

(Final § 111.35)

     Final § 111.35 describes the recordkeeping requirements.  It
represents a combination of proposed § 111.25(c)(1) through (c)(2),
(d)(1) through (d)(7), and (f), and § 111.30(b)(2) and (5) and (c) and
§ 111.50(c)(4).

 Final § 111.35(a)

Final § 111.35(a) states that you must make and keep records required
under subpart D in accordance with subpart P.  Subpart P is the subpart
dealing with records and recordkeeping.

	Final Section § 111.35(a) is broader than proposed § 111.25(f), which
stated that you “must keep calibration records as required by this
section in accordance with” the 2003 CGMP Proposal’s recordkeeping
section, and compared to proposed § 111.30(c), which stated that you
must keep “automatic, mechanical, or electronic equipment records
required by this section in accordance with” the 2003 CGMP
Proposal’s recordkeeping section.  However, final § 111.35(a) has the
same effect as proposed §§ 111.25(f) and 111.30(c).

	We did not receive any substantive comments on proposed § 111.25(f) or
111.30(c).

Final 111.35(b)(1) and (b)(2)

Final § 111.35(b) combines the various recordkeeping requirements that
were in proposed §§ 111.25(c) (written procedures for calibrating
instruments and controls and documentation that those procedures were
followed and that the calibration was performed), 111.25(d) (written
procedures or documentation for calibration, such as the instrument or
control calibrated and the calibration date), 111.30(b)(2) and (b)(5)
(written records of equipment calibrations, inspections, or checks, and
backup files of software and data respectively), and  111.50(b)(4)
(inclusion of date and time of maintenance, cleaning, and sanitizing of
equipment and processing lines in the batch record).

	Specifically, final § 111.35(b)(1) states that you must make and keep
records of “written procedures for fulfilling the requirements of this
subpart,” including written procedures for:

●	Calibrating instruments and controls that you use in manufacturing
or testing a component or dietary supplement.  This paragraph is similar
to proposed § 111.25(c).  Although we did not receive any substantive
comment on proposed § 111.25(c), we are rephrasing the paragraph due to
its reorganization as part of final § 111.35.  Additionally, although
proposed § 111.25(c) would require you to document that the written
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●	Calibrating, inspecting, and checking automated, mechanical, and
electronic equipment.  This paragraph is similar to proposed §
111.30(b)(2), although we are rephrasing the paragraph due to its
reorganization as part of final § 111.35.

●	Maintaining, cleaning, and sanitizing, as necessary, all equipment,
utensils, and any other contact surfaces that are used to manufacture,
package, label, or hold components or dietary supplements.  This
paragraph relates to final § 111.25(c) which requires you to establish
and follow written procedures for such activities.

	We did not receive any comments specific to proposed §§ 111.25(c) or
111.30(b)(2).

     Final § 111.35(b)(2) (proposed § 111.50(c)(4)) requires you to
make and keep documentation, in individual equipment logs, of the date
of the use, maintenance, cleaning, and sanitizing of equipment, unless
such documentation is kept with the batch record.

(Comment 137)  Proposed § 111.50(c)(4) would require that the batch
record include the date and time of the maintenance, cleaning, and
sanitizing of the equipment and processing lines used in producing the
batch.  The preamble to the 2003 CGMP Proposal also invited comment on
whether the person performing the maintenance, cleaning, and sanitizing
of portable equipment and utensils should document at the time of
performance the maintenance, cleaning, and sanitizing (68 FR 12157 at
12192).  Several comments argue that the final rule should require
documentation at the time of performance of equipment, utensil, and
contact surface maintenance, cleaning, and sanitation and should also
require this documentation to be kept as records.  The comments explain
that such recordkeeping is common practice in the industry, is an
important part of batch history, and omitting such a requirement would
diminish the industry standard.  In addition, the comments state that
written records are an effective way to ensure that there is consistency
in how employees are trained and to assess compliance.

     Several comments agree that equipment maintenance, cleaning, and
sanitizing records should be kept and state that this information should
be kept with individual pieces of equipment, rather than in the batch
record as proposed § 111.50(c)(4) would require.  The comments say it
is easier and more efficient for some companies to maintain equipment
logs that can be referenced when necessary.

     Other comments say manufacturers should have flexibility to design
a recordkeeping program is suited to their operations, and should have
the option of using an equipment log as it provides an efficient way to
document, trace and review equipment use, maintenance, cleaning, and
sanitization of equipment.  According to these comments, because the
2003 CGMP Proposal would require batch production records to identify
all equipment used during production, this will allow for
cross-referencing with the equipment log should the need occur.  The
comments argue that the proposed approach will be awkward for some
companies to comply with and would not result in collection of
information in a logical order or location where it can be easily
referenced and reviewed, such as on the production floor, or to provide
data for trend analysis.  The comments also contend requiring all
information to be maintained in the batch record will be difficult in
practice and place an enormous burden on companies.

     (Response)  We agree that documenting the cleaning, sanitizing, and
maintenance of equipment is important.  However, we have revised the
provision so that these records need not be part of the batch record.
Instead, final § 111.35(b)(2) requires you to make and keep
documentation of the date of use, maintenance, cleaning, and sanitizing
of equipment in individual equipment logs, unless such documentation is
kept with the batch record.  By “equipment log,” we mean a written
record that includes information about the history of a piece of
equipment.  This history includes items such as date of installation,
routine maintenance, repairs, and cleaning.

Additionally, final § 111.260 requires you to identify the equipment
and processing lines used in producing the batch and either provide a
cross-reference that will make it possible to find the applicable
equipment log as needed or include documentation that equipment was
cleaned, sanitized, or maintained (we discuss final § 111.260 later in
section XIV). For example, you may keep records documenting that you
cleaned containers you will use for holding a finished batch either in
records associated with the equipment you use for cleaning, or with the
applicable batch record, depending on what is most convenient and
practical for your operations.

     (Comment 138)  Several comments state documenting the cleaning of
contact surfaces would be unnecessarily labor-intensive because the term
is so broadly defined.  Other comments argue that documenting the
cleaning of utensils is unnecessary and inappropriate.  These comments
support requiring documentation for the cleaning of large equipment, but
claim that requiring manufacturers to uniquely identify each spoon,
spatula, container, and hose (or other general cleaning) in order to
document each cleaning would be inappropriate and create an enormous
burden on the manufacturer.  According to these comments, such a
requirement would slow and complicate the cleaning process, making
proper cleaning more cumbersome.  The comments assert that contamination
from these sources has not caused any recalls and is not justified.

     (Response)  We disagree with these comments.  The final rule
requires you to document the work that was done, but gives you the
flexibility to decide how to document that work was done.  For contact
surfaces such as containers you use to hold a finished batch, you could,
for example, record the cleaning either on a single line that you
provide in your batch record, or as a line entry in the log of the
equipment that you use to clean the containers, or in some other way
that suits your needs.  These are not labor-intensive requirements.

     It is important that you have procedures in place to know that
small items, such as spatulas, are clean when you use them.  For
example, if you have a log where you designate equipment that has been
cleaned, your batch record could simply have a place to check that you
used equipment designated as clean.

3.  Final § 111.35(b)(3)

     Final § 111.35(b)(3) (proposed § 111.25(d)(1)through (d)(7))
requires you to make and keep documentation of any calibration, each
time the calibration is performed, for instruments and controls that you
use in manufacturing or testing a component or dietary supplement.  In
the documentation you must: (1) Identify the instrument or control
calibrated; (2) provide the calibration date; (3) identify the reference
standard used, including the certification of accuracy of the known
reference standard and a history of recertification of accuracy; (4)
identify the calibration method used, including appropriate limits for
accuracy and precision of instruments and controls when calibrating; (5)
provide the calibration reading or readings found; (6) identify the
recalibration method used, and reading or readings found, if accuracy or
precision or both accuracy and precision limits for instruments and
controls were not met; and (7) include the initials of the person who
performed the calibration and any recalibration.

     (Comment 139)  Some comments support proposed § 111.25(d).
However, other comments argue that the documentation requirements are
unduly prescriptive.  Some comments would revise proposed § 111.25(d)
to more closely mirror the requirements in drug CGMPs.  Some comments
suggest the requirement to maintain written records of calibrations
should simply state “You must maintain written records of calibrations
according to Sec. 111.125.”  Other comments suggest detailed
calibration requirements would not be needed if the final rule included
requirements to establish and follow written procedures.

     (Response)  The information required under final § 111.35(b)(3)
(proposed § 111.25(d)) is the minimum amount necessary to provide
sufficient information concerning equipment calibration.  For example,
some firms may have more than one machine to perform a given function;
in those situations, documentation that identified the exact machine
that was calibrated would distinguish it from other, seemingly
identical, but non-calibrated machines.  Likewise, if the maintenance
instructions for a machine called for calibration checks every month,
documenting the date of calibration would show you whether calibrations
were done on schedule.  As another example, if a machine required
calibration according to a particular standard, identifying the
reference standard would help verify that the calibration was done
correctly.

	Thus, we disagree with those comments claiming that proposed §
111.25(d) was too prescriptive.  If, for example, the final rule simply
directed you to document calibration, without specifying what
information should be contained in that documentation, then the
resulting documentation could have little or no value.  For example,
assume that you have two identical pieces of equipment, but only one had
been calibrated.  If the documentation simply said, “machine was
calibrated,” you would not know which machine had been calibrated.  As
another example, if you had a machine that had to be recalibrated every
year, and the documentation merely said, “recalibration completed,”
you would not know whether the machine had been recalibrated yesterday,
last month, last year, or four years ago.

	With respect to the argument that proposed § 111.25(d) should be
revised to resemble the drug CGMPs, we disagree.  We recognize that the
drug CGMPs are less detailed with respect to documentation; for example,
§ 211.68(a), “Automatic, mechanical, and electronic equipment,”
simply states, in relevant part, “If such equipment is so used, it
shall be routinely calibrated, inspected, or checked according to a
written program designed to assure proper performance” and “Written
records of those calibration checks and inspections shall be
maintained.”  However, the comments overlook the fact that, from 1993
to 2003, the Center for Drug Evaluation and Research (CDER) issued
periodic guidance, in the form of “Human Drug CGMP Notes,” and those
guidances offered advice on various drug CGMP issues.  With respect to
calibration, for example, the December 1997 edition dealt with the
question of whether the drug CGMP regulations require equipment to be
labeled with calibration dates.  The guidance identified various
regulations that would be applicable and also said that:

During an inspection a firm should be able to document when a specific
piece of equipment was last calibrated/ maintained, the results or
action, and when its next calibration/maintenance is scheduled.  The
absence of such documentation is a CGMP deviation.

(See CDER, “Human Drug CGMP Notes,” December 1997, at page 3. Ref.
296)

	This advice is comparable, in several respects, to the information
required by final § 111.35(b)(3).  For example, it refers to a
“specific piece of equipment,” which is similar to final §
111.35(b)(3)(i)’s requirement to identify the instrument or control
calibrated.  It refers to the time when calibration occurred; this is
similar to final § 111.35(b)(3)(ii)’s requirement to provide the
calibration date.  Although public distribution of “Human Drug CGMP
Notes” ended in 2003, and the document was circulated only within FDA
from 2001 to 2003 (but was available through FOIA) the Freedom of
Information Act), the guidances offered the drug industry advice on
complying with the drug CGMPs, and we have retained the guidances on our
internet site.  In other words, the drug CGMP regulations did not have
to be as “prescriptive” because the drug industry learned about our
interpretations or expectations of the drug CGMPs through guidance.

	Here, in contrast, there is no comparable history of issuing periodic
guidances to inform the dietary supplement industry about specific CGMP
issues.

	Yet, even if final § 111.35 is more “prescriptive” than the drug
CGMPs, that difference does not mean that we must revise the rule to
“mirror” the drug CGMPs.  The dietary supplement industry is more
diverse compared to the drug industry, and so, at least with respect to
documenting calibration, more – rather than less – detail is
appropriate.

	We do note, however, that final § 111.35(b)(3) differs from proposed
§ 111.25(d) in the following respects:

●	§ 111.25(d) would require you to identify specific
calibration-related information “in any written procedure or at the
time of performance,” final § 111.35(b)(3) requires documentation
“each time the calibration is performed.”  Final section
111.35(b)(1) requires you to have records of the written procedures for
calibrating instruments and controls, but does not specify the
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●	§ 111.25(d) would refer to “instruments and controls.”  Final
§ 111.35(b)(3) now refers to “instruments and controls that you use
in manufacturing or testing a component or dietary supplement.”  This
change clarifies the instruments and controls that are subject to final
§ 111.35(b)(3) and is consistent with final § 111.27(b), which
requires you to calibrate instruments and controls;

●	The type of information that must be documented under §
111.35(b)(3)(i) through (b)(3)(vii) is essentially identical to that in
proposed § 111.25(d)(1) through (d)(7), but we revised the sentence
structure due to the manner in which we reorganized final § 111.35;

●	§ 111.25(d)(6) would have you identify the recalibration method
used.  Final § 111.35(b)(3)(vi) requires you to identify the
recalibration method used “and reading or readings found.”  The
addition of “reading or readings found” is consistent with the
remainder of proposed § 111.25(d)(6) (final § 111.35(b)(3)(vi)) which
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●	§ 111.25(d)(7) would require the initials of the person who
performed the calibration. Final § 111.35(b)(3)(vii) requires the
initials of the person who performed the calibration and any
recalibration.  Arguably, recalibration is a type of calibration, but we
have added “any recalibration” to final § 111.35(b)(3)(vii) to
ensure that recalibrations are included in the rule.

    (Comment 140)  Several comments would revise proposed § 111.25(d)
to read, “The following must be identified...”, rather than “you
must identify.”  The comments explain that calibrations and
re-calibrations are often performed by the equipment manufacturer,
vendor, or other outside service, rather than by the dietary supplement
manufacturer.  The comments argue that the proposal requires that the
calibration or re-calibration must be performed on-site (i.e., at the
plant manufacturing the dietary ingredient or supplement) when in fact
many calibrations can, or even must, be performed off-site.

     (Response)  We decline to revise the paragraph as requested.  As we
discuss in section VI, the term “you” can refer to someone with whom
you contract, but you are responsible for ensuring that the calibration
requirements are met, and to have documentation of the calibration, even
though the steps may be performed offsite.

4.  Final § 111.35(b)(4)

    Final § 111.35(b)(4) (proposed § 111.30(b)(2)) requires you to
make and keep written records of calibrations, inspections, and checks
of automated, mechanical, and electronic equipment that is used to
manufacture, package, label, or hold a dietary supplement.

     We did not receive comments specific to proposed § 111.30(b)(2).
We have made non-substantive editorial changes to the rule.  For
example, proposed § 111.30(b)(2) would require you to “make and
keep” written record; final § 111.35(b)(4) omits the words “ make
and keep” because that requirement appears earlier in § 111.35.

5.  Final §  111.35(b)(5)

     Final § 111.35(b)(5) (proposed § 111.30(b)(5)) requires you to
make and keep backup file(s) of current software programs (and of
outdated software that is necessary to retrieve records that you are
required to keep in accordance with subpart P, when current software is
not able to retrieve such records) and of data entered into computer
systems that you use to manufacture, package, label, or hold dietary
supplements.  Under final § 111.35(b)(5)(i), your backup file (e.g., a
hard copy of data you have entered, diskettes, tapes, microfilm, or
compact disks) must be an exact and complete record of the data you
entered.  Under final § 111.35(b)(5)(ii), you must keep your backup
software programs and data secure from alterations, inadvertent
erasures, or loss.

     (Comment 141)  Several comments would limit the requirement for
maintaining backup files of data entered into computer systems to those
data entered into computer systems that are relied upon for compliance
with CGMPs.  These comments argue that the paragraph, as written, calls
for a firm to  make and keep backup files of data entered into computers
on which personnel payroll records are maintained, and state that no
such requirement should be imposed.  Therefore, these comments would
replace the words “your computer system” with the words “any of
your computer systems that are relied upon for compliance with this
part.”

     (Response)  We have modified the provision to clarify that the
requirement is for computer systems that you use to manufacture,
package, label, or hold dietary supplements.

     (Comment 142)  Several comments argue that many software programs
are in a near constant state of revision and that it is not a common
business practice for a firm in any industry to maintain records of
outdated software programs, at least if the firm is still able to use a
revised program to access data it entered using an outdated program.
The comments assert that, although the drug CGMPs require the
maintenance of certain backup files of data entered into computer
systems, they do not require the maintenance of backup files of software
programs.       	(Response) Keeping backup copies of software helps
ensure that data can be retrieved if the primary software develops a
problem.  When we use the term “backup,” we mean a second copy of
the software in question rather than a copy of previous versions of the
software that are outdated, provided that data can be retrieved.
However, if the data collected using outdated software cannot be
retrieved by the newer software, there would still be a need to maintain
a primary copy and a backup copy of the outdated software used to
collect or manage the data.

     We have narrowed the requirement to retain backup files of software
to current software and of outdated software that is necessary to
retrieve records that you are required to keep in accordance with
subpart P, when current software is not able to retrieve such records.

     (Comment 143) Some comments claim that, although the drug CGMPs
require the maintenance of certain backup files of data entered into
computer systems, they do not require the maintenance of backup files of
software programs.  Several comments also assert that it is not always
possible to keep backup files of the software programs used in certain
pieces of equipment, because the equipment manufacturer may be the only
one having access to the programming of its equipment.  The comments
would delete the words “software programs and” be stricken from
proposed § 111.30(b)(5).

	(Response)  In most cases, we anticipate that firms will have access to
backup copies of their software programs.  We acknowledge that in rare
instances, backup copies may not be available and in these situations,
we will take that into account in reviewing compliance with this
provision.  We decline to revise the provision as suggested.

6. Final § 111.35(b)(6)

	Final § 111.35(b)(6) states that you must make and keep
“documentation of the controls that you use to ensure that equipment
functions in accordance with its intended use.”

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omatic, mechanical, and electronic equipment consistently produce an
outcome that meets a predetermined specification and any predetermined
quality characteristics.  Verification would show whether your
automatic, mechanical, or electronic processes will consistently operate
as they should.

     (Comment 144)  Several comments argue against including equipment
verification requirements.  The comments argue that the verification
discussion in the preamble to the 2003 CGMP Proposal is difficult to
distinguish from drug validation.  The comments argue that validation
should be allowed to evolve in the dietary supplement industry as it
evolved in drug CGMPs.  According to these comments, the dietary
supplement industry, being largely self regulated in CGMPs to date and
not generally practicing verification, would be more readily adaptable
to, and better controlled by, strict operating controls and quality
control checks including sufficient input and output checks on computer
operated systems, than having to digest the concept of verification and
implement verification processes.  The comments state that, in the
future, verification may be a means of offsetting some of the extensive
testing of finished products.

     Other comments state we should not require verification of
processes that use automatic, mechanical, or electronic equipment given
the different processes that dietary supplement manufacturers use.  The
comments argue that although dietary supplement manufacturers, depending
on the unique circumstances of a particular manufacturing process, may
choose to verify processes using a sound verification system, we should
not require verification.

     Several comments ask us to clarify whether we intended to require
full validation of equipment used to process dietary supplements because
terms such as “suitability” and “capable,” which we used in
proposed § 111.30(a)(1) and (2), might be interpreted to require
validation.  These comments state validation is unnecessary and overly
burdensome for equipment used in manufacturing dietary supplements.

     Several comments argue that proposed § 111.30(a)(1) and (2) have
the effect of establishing unnecessarily formal, stringent, and
expensive validation requirements on equipment design, selection, and
capability.  The comment states that this language represents a de facto
“IQ/OQ/PQ” (installation qualification/operational
qualification/performance qualification) requirement.  According to
these comments, emphasis should instead be directed to actual use and
operation.

     In contrast, several comments argue we should require manufacturers
to develop and maintain data that demonstrate that equipment is suitable
and that the production process consistently delivers expected results.
The comments argue that one key CGMP element is the requirement for
systems to operate consistently and to produce an outcome that meets a
predetermined specification.  According to these comments, demonstration
of system capability is best achieved through systems verification.  The
comments explain that, in an industry where the complexity of finished
products often precludes finished product testing, the capability of the
systems employed is of paramount importance.  The comments state if the
processes used fail to produce a product meeting predetermined
specifications and quality characteristics, then the product should not
be sold.  The comments add that, although verification imposes
additional costs on manufacturers, frequently rejected product, adequate
rework procedures, and extensive in-process and finished product testing
also would be costly.

     Several comments also claim the use of an appropriate verification
system may, under certain circumstances, allow for lot testing as
opposed to batch testing.  These comments state that, with process
verification and an appropriate testing scheme, a manufacturer could
demonstrate that lot testing provides sufficient assurance of quality
and lack of adulteration.  The comments ask us to address these
alternatives in the final rule.  Many comments said written records of
verification should be maintained.  The comments offer several
suggestions on how this could be accomplished, including using
statistical process control techniques or other appropriate statistical
tools.

     (Response)  We used the term “verification” rather than
“validation” to signal that we did not expect that a final rule
would include requirements for formal process validation requirements,
such as an IQ/OQ/PQ requirement, for equipment.  Regardless, several
comments interpreted our request for comments as a suggestion that we
were considering such formal validation requirements.  At this time, we
are not requiring formal process validation for equipment.  However, we
will monitor the development of systems that evolve within this diverse
industry.

     We disagree that proposed § 111.30(a)(1) and (2) would have the
effect of establishing unnecessarily formal, stringent, and expensive
validation requirements on equipment design, selection, and capability,
and that the language would represent a de facto “IQ/OQ/PQ”
requirement for equipment.  Final § 111.30(e) requires you to ensure
equipment operates in accordance with its intended use.  We agree with
the comments that argued that data demonstrating that equipment is
suitable, and that the production process consistently delivers expected
results, are a key element of CGMP.  Therefore, final § 111.35(b)(6)
requires you to make and keep documentation of the controls that you use
to ensure that the equipment functions in accordance with its intended
use. Examples of such controls include temperature settings, fill rates,
and blending times that must be set, checked, and adjusted as necessary.

 Although the preamble to the 2003 CGMP Proposal discussed this issue in
relation to proposed § 111.25 (“What Requirements Apply to the
Equipment and Utensils You Use?”) the same principle applies to
proposed § 111.50(c)(4).

FDA-Internal-Deliberative-Confidential

Final Subpart D 9-28-05, 6-26-06, 3-30-07, 5-04-07

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