[Federal Register Volume 83, Number 67 (Friday, April 6, 2018)]
[Notices]
[Pages 14861-14865]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-07031]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0362]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Current Good Manufacturing Practice 
Regulations for Finished Pharmaceuticals

AGENCY: Food and Drug Administration, HHS.

[[Page 14862]]


ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by May 7, 
2018.

ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
Fax: 202-395-7285, or emailed to [email protected]. All 
comments should be identified with the OMB control number 0910-0139. 
Also include the FDA docket number found in brackets in the heading of 
this document.

FOR FURTHER INFORMATION CONTACT: Domini Bean, Office of Operations, 
Food and Drug Administration, Three White Flint North, 10A-12M, 11601 
Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
[email protected].

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Current Good Manufacturing Practice Regulations for Finished 
Pharmaceuticals (21 CFR parts 210 and 211)

OMB Control Number 0910-0139--Extension

    This information collection supports FDA regulations. Specifically, 
under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 351(a)(2)(B)), a drug is adulterated if the methods used in 
or the facilities or controls used for its manufacture, processing, 
packing, or holding do not conform to or are not operated or 
administered in conformity with Current Good Manufacturing Practice 
(CGMP). The CGMP regulations help ensure drug products meet the 
statutory requirements for safety and have their purported or 
represented identity, strength, quality, and purity characteristics. 
The information collection requirements in the CGMP regulations provide 
FDA with the necessary information to perform its duty to protect 
public health and safety. CGMP requirements establish accountability 
for manufacturing and processing drug products, provide for meaningful 
FDA inspections, and enable manufacturers to improve the quality of 
drug products over time. The CGMP recordkeeping requirements also serve 
preventive and remedial purposes and provide crucial information if it 
is necessary to recall a drug product.
    The general requirements for recordkeeping under part 211 (21 CFR 
part 211) are set forth in Sec.  211.180. Any production, control, or 
distribution record associated with a batch and required to be 
maintained in compliance with part 211 must be retained for at least 1 
year after the expiration date of the batch and, for certain over-the-
counter (OTC) drugs, 3 years after distribution of the batch (Sec.  
211.180(a)). Records for all components, drug product containers, 
closures, and labeling are required to be maintained for at least 1 
year after the expiration date and 3 years for certain OTC products 
(Sec.  211.180(b)).
    All part 211 records must be readily available for authorized 
inspections during the retention period (Sec.  211.180(c)), and such 
records may be retained either as original records or as true copies 
(Sec.  211.180(d)). Additionally, Sec.  11.2(a) (21 CFR 11.2(a)) 
provides that ``for records required to be maintained but not submitted 
to the Agency, persons may use electronic records in lieu of paper 
records or electronic signatures in lieu of traditional signatures, in 
whole or in part, provided that the requirements of this part are 
met.'' To the extent this electronic option is used, the burden of 
maintaining paper records should be substantially reduced, as should 
any review of such records.
    To facilitate improvements and corrective actions, records must be 
maintained so data can be used to evaluate the quality standards of 
each drug product on at least an annual basis and determine whether to 
change any drug product specifications or manufacturing or control 
procedures (Sec.  211.180(e)). Written procedures for these evaluations 
are to be established and include provisions for a review of a 
representative number of batches and, where applicable, records 
associated with the batch; provisions for a review of complaints, 
recalls, returned or salvaged drug products; and investigations 
conducted under Sec.  211.192 for each drug product.
    The specific information collection provisions are as follows:
     Section 211.34--Consultants advising on the manufacture, 
processing, packing, or holding of drug products must have sufficient 
education, training, and experience to advise on the subject for which 
they are retained. Records must be maintained stating the name, 
address, and qualifications of any consultants and the type of service 
they provide.
     Section 211.67(c)--Records must be kept of maintenance, 
cleaning, sanitizing, and inspection as specified in Sec. Sec.  211.180 
and 211.182.
     Section 211.68--Appropriate controls must be exercised 
over computer or related systems to assure that changes in master 
production and control records or other records are instituted only by 
authorized personnel.
     Section 211.68(a)--Records must be maintained of 
calibration checks, inspections, and computer or related system 
programs for automatic, mechanical, and electronic equipment.
     Section 211.68(b)--All appropriate controls must be 
exercised over all computers or related systems and control data 
systems to assure that changes in master production and control records 
or other records are instituted only by authorized persons.
     Section 211.72--Filters for liquid filtration used in the 
manufacture, processing, or packing of injectable drug products 
intended for human use must not release fibers into such products.
     Section 211.80(d)--Each container or grouping of 
containers for components or drug product containers or closures must 
be identified with a distinctive code for each lot in each shipment 
received. This code must be used in recording the disposition of each 
lot. Each lot must be appropriately identified as to its status.
     Section 211.100(b)--Written production and process control 
procedures must be followed in the execution of the various production 
and process control functions and must be documented at the time of 
performance. Any deviation from the written procedures must be recorded 
and justified.
     Section 211.105(b)--Major equipment must be identified by 
a distinctive identification number or code that must be recorded in 
the batch production record to show the specific equipment used in the 
manufacture of each batch of a drug product. In cases where only one of 
a particular type of equipment exists in a manufacturing facility, the 
name of the equipment may be used in lieu of a distinctive 
identification number or code.
     Section 211.122(c)--Records must be maintained for each 
shipment received of each different labeling and packaging material 
indicating receipt, examination, or testing.
     Section 211.130(e)--Inspection of packaging and labeling 
facilities must be

[[Page 14863]]

made immediately before use to assure that all drug products have been 
removed from previous operations. Inspection must also be made to 
assure that packaging and labeling materials not suitable for 
subsequent operations have been removed. Results of inspection must be 
documented in the batch production records.
     Section 211.132(c)--Certain retail packages of OTC drug 
products must bear a statement that is prominently placed so consumers 
are alerted to the specific tamper-evident feature of the package. The 
labeling statement is required to be so placed that it will be 
unaffected if the tamper-resistant feature of the package is breached 
or missing. If the tamper-evident feature chosen is one that uses an 
identifying characteristic, that characteristic is required to be 
referred to in the labeling statement.
     Section 211.132(d)--A request for an exemption from 
packaging and labeling requirements by a manufacturer or packer is 
required to be submitted in the form of a citizen petition under 21 CFR 
10.30.
     Section 211.137--Requirements regarding product expiration 
dating and compliance with 21 CFR 201.17.
     Section 211.160(a)--The establishment of any 
specifications, standards, sampling plans, test procedures, or other 
laboratory control mechanisms, including any change in such 
specifications, standards, sampling plans, test procedures, or other 
laboratory control mechanisms, must be drafted by the appropriate 
organizational unit and reviewed and approved by the quality control 
unit. These requirements must be followed and documented at the time of 
performance. Any deviation from the written specifications, standards, 
sampling plans, test procedures, or other laboratory control mechanisms 
must be recorded and justified.
     Section 211.165(e)--The accuracy, sensitivity, 
specificity, and reproducibility of test methods employed by a firm 
must be established and documented. Such validation and documentation 
may be accomplished in accordance with Sec.  211.194(a)(2).
     Section 211.166--Stability testing program for drug 
products.
     Section 211.173--Animals used in testing components, in-
process materials, or drug products for compliance with established 
specifications must be maintained and controlled in a manner that 
assures their suitability for their intended use. They must be 
identified, and adequate records must be maintained showing the history 
of their use.
     Section 211.180(e)--Written records required by part 211 
must be maintained so that data can be used for evaluating, at least 
annually, the quality standards of each drug product to determine the 
need for changes in drug product specifications or manufacturing or 
control procedures. Written procedures must be established and followed 
for such evaluations and must include provisions for a representative 
number of batches, whether approved or unapproved or rejected, and a 
review of complaints, recalls, returned or salvaged drug products, and 
investigations conducted under Sec.  211.192 for each drug product.
     Section 211.180(f)--Procedures must be established to 
assure that the responsible officials of the firm, if they are not 
personally involved in or immediately aware of such actions, are 
notified in writing of any investigations, conducted under Sec.  
211.198, Sec.  211.204, or Sec.  211.208, any recalls, reports of 
inspectional observations issued, or any regulatory actions relating to 
good manufacturing practices brought by FDA.
     Section 211.182--Specifies requirements for equipment 
cleaning records and the use log.
     Section 211.184--Specifies requirements for component, 
drug product container, closure, and labeling records.
     Section 211.186--Specifies master production and control 
records requirements.
     Section 211.188--Specifies batch production and control 
records requirement.
     Section 211.192--Specifies the information that must be 
maintained on the investigation of discrepancies found in the review of 
all drug product production and control records by the quality control 
staff.
     Section 211.194--Explains and describes laboratory records 
that must be retained.
     Section 211.196--Specifies the information that must be 
included in records on the distribution of the drug.
     Section 211.198--Specifies and describes the handling of 
all complaint files received by the applicant.
     Section 211.204--Specifies that records be maintained of 
returned and salvaged drug products and describes the procedures 
involved.
    Written procedures, referred to here as standard operating 
procedures (SOPs), are required for many part 211 records. Current SOP 
requirements were initially provided in a final rule published in the 
Federal Register of September 29, 1978 (43 FR 45014), and are now an 
integral and familiar part of the drug manufacturing process. The major 
information collection impact of SOPs results from their creation. 
Thereafter, SOPs need to be periodically updated. A combined estimate 
for routine maintenance of SOPs is provided in table 1. The 25 SOP 
provisions under part 211 in the combined maintenance estimate include:
     Section 211.22(d)--Responsibilities and procedures of the 
quality control unit;
     Section 211.56(b)--Sanitation procedures;
     Section 211.56(c)--Use of suitable rodenticides, 
insecticides, fungicides, fumigating agents, and cleaning and 
sanitizing agents;
     Section 211.67(b)--Cleaning and maintenance of equipment;
     Section 211.68(a)--Proper performance of automatic, 
mechanical, and electronic equipment;
     Section 211.80(a)--Receipt, identification, storage, 
handling, sampling, testing, and approval or rejection of components 
and drug product containers or closures;
     Section 211.94(d)--Standards or specifications, methods of 
testing, and methods of cleaning, sterilizing, and processing to remove 
pyrogenic properties for drug product containers and closures;
     Section 211.100(a)--Production and process control;
     Section 211.110(a)--Sampling and testing of in-process 
materials and drug products;
     Section 211.113(a)--Prevention of objectionable 
microorganisms in drug products not required to be sterile;
     Section 211.113(b)--Prevention of microbiological 
contamination of drug products purporting to be sterile, including 
validation of any sterilization process;
     Section 211.115(a)--System for reprocessing batches that 
do not conform to standards or specifications to insure that 
reprocessed batches conform with all established standards, 
specifications, and characteristics;
     Section 211.122(a)--Receipt, identification, storage, 
handling, sampling, examination and/or testing of labeling and 
packaging materials;
     Section 211.125(f)--Control procedures for the issuance of 
labeling;
     Section 211.130--Packaging and label operations, 
prevention of mixup and cross contamination, identification and 
handling of filled drug product containers that are set aside and held 
in unlabeled condition, and identification of the drug product with a 
lot or control number that permits determination of

[[Page 14864]]

the history of the manufacture and control of the batch;
     Section 211.142--Warehousing;
     Section 211.150--Distribution of drug products;
     Section 211.160--Laboratory controls;
     Section 211.165(c)--Testing and release for distribution;
     Section 211.166(a)--Stability testing;
     Section 211.167--Special testing requirements;
     Section 211.180(f)--Notification of responsible officials 
of investigations, recalls, reports of inspectional observations, and 
any regulatory actions relating to good manufacturing practice;
     Section 211.198(a)--Written and oral complaint procedures, 
including quality control unit review of any complaint involving 
specifications failures, and serious and unexpected adverse drug 
experiences;
     Section 211.204--Holding, testing, and reprocessing of 
returned drug products; and
     Section 211.208--Drug product salvaging.
    In addition, the following regulations in parts 610 and 680 (21 CFR 
parts 610 and 680) reference certain CGMP regulations in part 211: 
Sec. Sec.  610.12(g), 610.13(a)(2), 610.18(d), 680.2(f), and 680.3(f). 
In table 1, the burden associated with the information collection 
requirements in these regulations is included in the burden estimates 
under Sec. Sec.  211.165, 211.167, 211.188, and 211.194, as 
appropriate.
    Although most CGMP provisions covered in this document were created 
many years ago, some existing firms expanding into new manufacturing 
areas and startup firms will need to create SOPs. As provided in table 
1, FDA assumes approximately 50 firms will have to create up to 25 SOPs 
for a total of 1,250 records, estimating 20 hours per recordkeeper to 
create 25 new SOPs for a total of 25,000 hours.
    In the Federal Register of December 14, 2017 (82 FR 58811) we 
published a 60-day notice requesting public comment on the proposed 
collection of information. No comments were received in response to the 
notice and we therefore retain those burden estimates, which are as 
follows:

                                                   Table 1--Estimated Annual Recordkeeping Burden \1\
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                                                               Number of
         21 CFR section/activity              Number of       records per     Total annual   Average burden per recordkeeping (in hours)    Total hours
                                            recordkeepers     recordkeeper       records                         \1\
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SOP Maintenance..........................            3,270  ...............           3,270  25.........................................          81,750
New Startup SOPs.........................               50               25           1,250  20.........................................          25,000
211.34--Consultants......................            3,270             0.25             818  5..........................................           4,090
211.67(c)--Equipment cleaning and                    3,270               50         163,500  0.25 (15 minutes)..........................          40,875
 maintenance.
211.68--Changes in master production and             3,270                2           6,540  1..........................................           6,540
 control records or other records.
211.68(a)--Automatic, mechanical, and                3,270               10          32,700  0.5 (30 minutes)...........................          16,350
 electronic equipment.
211.68(b)--Computer or related systems...            3,270                5          16,350  0.25 (15 minutes)..........................           4,088
211.72--Filters..........................              416             0.25             104  1..........................................             104
211.80(d)--Components and drug product               3,270             0.25             818  0.1 (6 minutes)............................              82
 containers or closures.
211.100(b)--Production and process                   3,270                3           9,810  2..........................................          19,620
 controls.
211.105(b)--Equipment identification.....            3,270             0.25             818  0.25 (15 minutes)..........................             205
211.122(c)--Labeling and packaging                   3,270               50         163,500  0.25 (15 minutes)..........................          40,875
 material.
211.130(e)--Labeling and packaging                   3,270               50         163,500  0.25 (15 minutes)..........................          40,875
 facilities.
211.132(c)--Tamper-evident packaging.....            1,613               20          32,260  0.5 (30 minutes)...........................          16,130
211.132(d)--Tamper-evident packaging.....            1,613              0.2             323  0.5 (30 minutes)...........................             162
211.137--Expiration dating...............            3,270                5          16,350  0.5 (30 minutes)...........................           8,175
211.160(a)--Laboratory controls..........            3,270                2           6,540  1..........................................           6,540
211.165(e)--Test methodology.............            3,270                1           3,270  1..........................................           3,270
211.166--Stability testing...............            3,270                2           6,540  0.5 (30 minutes)...........................           3,270
211.173--Laboratory animals..............               33                1              33  0.25 (15 minutes)..........................               8
211.180(e)--Production, control, and                 3,270              0.2             654  0.25 (15 minutes)..........................             164
 distribution records.
211.180(f)--Procedures for notification              3,270              0.2             654  1..........................................             654
 of regulatory actions.
211.182--Equipment cleaning and use log..            3,270                2           6,540  0.25 (15 minutes)..........................           1,635
211.184--Component, drug product                     3,270                3           9,810  0.5 (30 minutes)...........................           4,905
 container, closure, and labeling records.
211.186--Master production and control               3,270               10          32,700  2..........................................          65,400
 records.
211.188--Batch production and control                3,270               25          81,750  2..........................................         163,500
 records.
211.192--Discrepancies in drug product               3,270                2           6,540  1..........................................           6,540
 production and control records.
211.194--Laboratory records..............            3,270               25          81,750  0.5 (30 minutes)...........................          40,875
211.196--Distribution records............            3,270               25          81,750  0.25 (15 minutes)..........................          20,438
211.198--Compliant files.................            3,270                5          16,350  1..........................................          16,350
211.204--Returned drug products..........            3,270               10          32,700  0.5 (30 minutes)...........................          16,350
                                          --------------------------------------------------------------------------------------------------------------
    Total................................  ...............  ...............  ..............  ...........................................         651,139
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\1\ Burden estimates of less than 1 hour are expressed as a fraction of an hour in the format ``[number of minutes per response]/60''.

    The recordkeeping requirement estimates provided in table 2 are 
specific to medical gases. In particular, on June 29, 2017, FDA 
published a Notice of Availability (NOA) in the Federal Register 
regarding revised draft guidance for industry entitled ``Current Good 
Manufacturing Practice for Medical Gases'' (82 FR 29565). This 
guidance, when finalized, is intended to help medical gas manufacturers 
comply with applicable CGMP regulations found in parts 210 and 211. In 
the NOA for the revised draft guidance, FDA noted the guidance includes 
information collection provisions subject to review by the OMB under 
the PRA and, in accordance with the PRA, before publication of the 
final guidance, FDA intends to solicit public comment and obtain OMB 
approval for any recommended new information collections or material 
modifications to previously approved collections of information found 
in FDA regulations. This notice is intended to solicit such public 
comment.
    The regulations addressed in table 2 are the same as those listed 
in table 1, but the estimated information collection

[[Page 14865]]

burden differs and is specific to medical gas manufacturing.
    FDA estimates the burden of this collection of information as 
follows:

                                                     Table 2--Estimated Annual Recordkeeping Burden
                                                                   [Medical Gases] \1\
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                                                               Number of
         21 CFR section/activity              Number of       records per     Total annual   Average burden per recordkeeping (in hours)    Total hours
                                            recordkeepers     recordkeeper       records                         \1\
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SOP Maintenance..........................            2,284             0.65           1,485  25.........................................          37,125
New startup SOPs.........................              100               25           2,500  20.........................................          50,000
211.34--Consultants......................            2,284             0.25             571  0.5 (30 minutes)...........................             286
211.67(c)--Equipment cleaning and                    2,284             32.5          74,230  0.25 (15 minutes)..........................          18,558
 maintenance.
211.68--Changes in master production and             2,284                2           4,568  1..........................................           4,568
 control records or other records.
211.68(a)--Automatic, mechanical, and                2,284               10          22,840  0.5 (30 minutes)...........................          11,420
 electronic equipment.
211.68(b)--Computer or related systems...            2,284                5          11,420  0.25 (15 minutes)..........................           2,855
211.72--Filters..........................            2,284              .25             571  1..........................................             571
211.80(d)--Components and drug product               2,284             0.25             571  0.1 (6 minutes)............................              57
 containers or closures.
211.100(b)--Production and process                   2,284                3           6,382  2..........................................          13,704
 controls.
211.105(b)--Equipment identification.....            2,284             0.25             571  0.25 (15 minutes)..........................             143
211.122(c)--Labeling and packaging                   2,284               50         114,200  0.25 (15 minutes)..........................          28,550
 material.
211.130(e)--Labeling and packaging                   2,284               50         114,200  0.25 (15 minutes)..........................          28,550
 facilities.
211.132(c)--Tamper-evident packaging.....            2,284               20          45,680  0.5 (30 minutes)...........................          22,840
211.132(d)--Tamper-evident packaging.....            2,284               .2             457  0.5 (30 minutes)...........................             229
211.137--Expiration dating...............            2,284             3.25           7,423  0.33 (20 minutes)..........................           2,450
211.160(a)--Laboratory controls..........            2,284                2           4,568  1..........................................           4,568
211.165(e)--Test methodology.............            2,284                1           2,284  1..........................................           2,284
211.166--Stability testing...............            2,284              1.3           2,969  0.33 (20 minutes)..........................             980
211.173--Laboratory animals..............            2,284                1           2,284  0.25 (15 minutes)..........................             571
211.180(e)--Production, control, and                 2,284              0.2             457  0.25 (15 minutes)..........................             114
 distribution records.
211.180(f)--Procedures for notification              2,284              0.2             457  1..........................................             457
 of regulatory actions.
211.182--Equipment cleaning and use log..            2,284              1.3           2,969  0.16 (10 minutes)..........................             475
211.184--Component, drug product                     2,284             1.95           4,454  0.33 (20 minutes)..........................           1,470
 container, closure, and labeling records.
211.186--Master production and control               2,284               10          22,840  2..........................................          45,680
 records.
211.188--Batch production and control                2,284            16.25          37,115  1.3........................................          48,250
 records.
211.192--Discrepancies in drug product               2,284                2           4,568  1..........................................           4,568
 production and control records.
211.194--Laboratory records..............            2,284               25          57,100  0.5 (30 minutes)...........................          28,550
211.196--Distribution records............            2,284               25          57,100  0.25 (15 minutes)..........................          14,275
211.198--Complaint files.................            2,284                5          11,420  1..........................................          11,420
211.204--Returned drug products..........            2,284               10          22,840  0.5 (30 minutes)...........................          11,420
    Total................................  ...............  ...............  ..............  ...........................................         396,988
                                          --------------------------------------------------------------------------------------------------------------
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\1\ Burden estimates of less than 1 hour are expressed as a fraction of an hour in the format ``[number of minutes per response]/60''.

    The information collection reflects an increase in the number of 
respondents that results in a corresponding increase to the number of 
annual burden hours. This is consistent with our experience with the 
information collection.

    Dated: April 2, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-07031 Filed 4-5-18; 8:45 am]
 BILLING CODE 4164-01-P