2015-32685. Agency Information Collection Activities: Proposed Collection; Comment Request; Current Good Manufacturing Practice for Positron Emission Tomography Drugs

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice.

SUMMARY:

The Food and Drug Administration (FDA) is announcing an opportunity for public comment on the proposed collection of certain information by the Agency. Under the Paperwork Reduction Act of 1995 (the PRA), Federal Agencies are required to publish notice in the Federal Register concerning each proposed collection of information, including each proposed extension of an existing collection of information, and to allow 60 days for public comment in response to the notice. This notice solicits comments on the information collection contained in FDA's regulations on current good manufacturing practice (CGMP) for positron emission tomography (PET) drugs.

DATES:

Submit either electronic or written comments on the collection of information by February 29, 2016.

ADDRESSES:

You may submit comments as follows:

Electronic Submissions

Submit electronic comments in the following way:

• Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to http://www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on http://www.regulations.gov.
• If you want to submit a comment with confidential information that you do not wish to be made available to the public, submit the comment as a written/paper submission and in the manner detailed (see “Written/Paper Submissions” and “Instructions”).

Written/Paper Submissions

Submit written/paper submissions as follows:

• Mail/Hand delivery/Courier (for written/paper submissions): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments submitted to the Division of Dockets Management, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in “Instructions.”

Instructions: All submissions received must include the Docket No. FDA-2013-N-0242 for “Agency Information Collection Activities: Proposed Collection; Comment Request; Current Good Manufacturing Practice for Positron Emission Tomography Drugs.” Received comments will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

• Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION”. The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on http://www.regulations.gov. Submit both copies to the Division of Dockets Management. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469, September 18, 2015, or access the information at: http://www.fda.gov/​regulatoryinformation/​dockets/​default.htm.

Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to http://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

FDA PRA Staff, Office of Operations, Food and Drug Administration, 8455 Colesville Rd., COLE-14526, Silver Spring, MD 20993-0002, [e-mail].

SUPPLEMENTARY INFORMATION:

Under the PRA (44 U.S.C. 3501-3520) Federal Agencies must obtain approval from the Office of Management and Budget (OMB) for each collection of information they conduct or sponsor. “Collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes Agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to provide a 60-day notice in the Federal Register concerning each proposed collection of information, including each proposed extension of an existing collection of information, before submitting the collection to OMB for approval. To comply with this requirement, FDA is publishing notice of the proposed collection of information set forth in this document.

With respect to the following collection of information, FDA invites comments on these topics: (1) Whether the proposed collection of information is necessary for the proper performance of FDA's functions, including whether the information will have practical utility; (2) the accuracy of FDA's estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.

Current Good Manufacturing Practice for Positron Emission Tomography Drugs (OMB Control Number 0910-0667)—Extension

Positron emission tomography is a medical imaging modality involving the use of a unique type of radiopharmaceutical drug product. FDA's CGMP regulations at 21 CFR part 212 are intended to ensure that PET drug products meet the requirements of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) regarding safety, identity, strength, quality, and purity. The CGMP requirements for PET drugs are issued under the provisions of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). These CGMP requirements are designed to take into account the unique characteristics of PET drugs, including their short half-lives and the fact that most PET drugs are produced at locations that are very close to the patients to whom the drugs are administered.

The CGMP regulations are intended to ensure that approved PET drugs meet the requirements of the FD&C Act as to safety, identity, strength, quality, and purity. The regulations address the following matters: Personnel and resources; quality assurance; facilities and equipment; control of components, in-process materials, and finished products; production and process controls; laboratory controls; acceptance criteria; labeling and packaging controls; distribution controls; complaint handling; and recordkeeping.

The CGMP regulations establish several recordkeeping requirements and a third-party disclosure requirement for the production of PET drugs. In making our estimates of the time spent in complying with these information collection requirements, we relied on communications we have had with PET producers, visits by our staff to PET facilities, and our familiarity with both PET and general pharmaceutical manufacturing practices. The estimated annual recordkeeping and third-party disclosure burden is based on there being approximately 129 PET drug production facilities.

As explained in this document, Table 1 provides an estimate of the annual recordkeeping burdens and Table 2 provides an estimate of the annual third-party disclosure burdens associated with this collection.

I. Investigational and Research PET Drugs

Section 212.5(b)(2) provides that for investigational PET drugs produced under an investigational new drug (IND) and research PET drugs produced with approval of a Radioactive Drug Research Committee (RDRC), the requirement under the FD&C Act to follow current good manufacturing practice is met by complying with the regulations in part 212 or with USP 32 Chapter 823. We believe that PET production facilities producing drugs under INDs and RDRCs are currently substantially complying with the recordkeeping requirements of USP 32 Chapter 823 (see section 121(b) of the Modernization Act), and accordingly, we do not estimate any recordkeeping burden for this provision.

II. Batch Production and Control Records

Sections 212.20(c) through (e), 212.50(a) through (c), and 212.80(c) set forth requirements for batch and production records as well as written control records. We estimate that it would take approximately 20 hours annually for each PET production facility to prepare and maintain written production and control procedures and to create and maintain master batch records for each PET drug produced. We also estimate that there will be a total of approximately 221 PET drugs produced, with a total recordkeeping burden of approximately 4,420 hours. We estimate that it would take a PET production facility an average of 30 minutes to complete a batch record for each of approximately 501 batches. Our estimated burden for completing batch records is approximately 32,320 hours.

III. Equipment and Facilities Records

Sections 212.20(c), 212.30(b), 212.50(d), and 212.60(f) contain requirements for records dealing with equipment and physical facilities. We estimate that it would take approximately 1 hour to establish and maintain these records for each piece of equipment in each PET production facility. We estimate that the total burden for establishing procedures for these records would be approximately 1,939 hours. We estimate that recording maintenance and cleaning information would take approximately 5 minutes a day for each piece of equipment, with a total recordkeeping burden of approximately 40,238 hours.

IV. Records of Components, Containers, and Closures

Sections 212.20(c) and 212.40(a), (b), and (e) contain requirements on records regarding receiving and testing of components, containers, and closures. We estimate that the annual burden for establishing these records would be approximately 259 hours. We estimate that each facility would receive approximately 36 shipments annually and would spend approximately 10 minutes per shipment entering records. The annual burden for maintaining these records would be approximately 773 hours.

V. Process Verification

Section 212.50(f)(2) requires that any process verification activities and results be recorded. Because process verification is only required when results of the production of an entire batch are not fully verified through finished-product testing, we believe that process verification will be a very rare occurrence, and we do not estimate any recordkeeping burden for documenting process verification.

VI. Laboratory Testing Records

Sections 212.20(c), 212.60(a), (b), and (g), 212.61(a) through (b), and 212.70(a), (b), and (d) set out requirements for documenting laboratory testing and specifications referred to in laboratory testing, including final release testing and stability testing. Each PET drug production facility will need to establish procedures and create forms for the different tests for each product they produce. We estimate that it will take each facility an average of 1 hour to establish procedures and create forms for one test. The estimated annual burden for establishing procedures and creating forms for these records is approximately 3,232 hours, and the annual burden for recording laboratory test results is approximately 10,730 hours.

VII. Sterility Test Failure Notices

Section 212.70(e) requires PET drug producers to notify all receiving facilities if a batch fails sterility tests. We believe that sterility test failures might occur in only 0.05 percent of the batches of PET drugs produced each year. Therefore, we have estimated in Table 2 that each PET drug producer will need to provide approximately 0.25 sterility test failure notice per year to receiving facilities. The notice would be provided using email or facsimile transmission and should take no more than 1 hour.

VIII. Conditional Final Releases

Section 212.70(f) requires PET drug producers to document any conditional final releases of a product. We believe that conditional final releases will be fairly uncommon, but for purposes of the PRA, we estimated that each PET production facility would have one conditional final release a year and would spend approximately 1 hour documenting the release and notifying receiving facilities. The estimate of one conditional final release per year per facility is an appropriate average number because many facilities may have no conditional final releases while others might have only a few.

IX. Out-of-Specification Investigations

Sections 212.20(c) and 212.71(a) and (b) require PET drug producers to establish procedures for investigating products that do not conform to specifications and conduct these investigations as needed. We estimate that it will take approximately 1 hour annually to record and update these procedures for each PET production facility. We also estimate, for purposes of the PRA, that 36 out-of-specification investigations would be conducted at each facility each year and that it would take approximately 1 hour to document the investigation, which results in an annual burden of 4,654 hours.

X. Reprocessing Procedures

Sections 212.20(c) and 212.71(d) require PET drug producers to establish and document procedures for reprocessing PET drugs. We estimate that it will take approximately 1 hour a year to document these procedures for each PET production facility. We do not estimate a separate burden for recording the actual reprocessing, both because we believe it would be an uncommon event and because the recordkeeping burden has been included in our estimate for batch production and control records.

XI. Distribution Records

Sections 212.20(c) and 212.90(a) require that written procedures regarding distribution of PET drug products be established and maintained. We estimate that it will take approximately 1 hour annually to establish and maintain records of these procedures for each PET production facility. Section 212.90(b) requires that distribution records be maintained. We estimate that it will take approximately 15 minutes to create an actual distribution record for each batch of PET drug products, with a total burden of approximately 16,160 hours for all PET producers.

XII. Complaints

Sections 212.20(c) and 212.100 require that PET drug producers establish written procedures for dealing with complaints, as well as document how each complaint is handled. We estimate that establishing and maintaining written procedures for complaints will take approximately 1 hour annually for each PET production facility and that each facility will receive approximately one complaint a year and will spend approximately 30 minutes recording how the complaint was dealt with.

Table 1—Estimated Annual Recordkeeping Burden ¹

21 CFR Section	No. of recordkeepers	No. of records per recordkeeper	Total annual records	Average burden per recordkeeping	Total hours
Batch Production and Control Records 212.20(c), 212.20(e); 212.50(a), 212.50(b)	129	1.71	221	20	4,420
Batch Production and Control Records 212.20(d) and (e); 212.50(c); 212.80(c)	129	501	64,640	0.5 (30 mins.)	32,320
Equipment and Facilities Records 212.20(c); 212.30(b); 212.50(d), 212.60(f)	129	15	1,939	1	1,939
Equipment and Facilities Records 212.30(b), 212.50(d); 212.60(f)	129	3,758	484,800	0.083 (5 mins.)	40,238
Records of Components, Containers, and Closures 212.20(c); 212.40(a), 212.40(b)	129	2	259	1	259
Records of Components, Containers, and Closures 212.40(e)	129	36	4,654	0.166 (10 mins.)	773
Laboratory Testing Records 212.20(c); 212.60(a), 212.60(b), 212.61(a); 212.70(a), 212.70(b), 212.70(d)	129	25	3,232	1	3,232
Laboratory Testing Records 212.60(g); 212.61(b); 212.70(d)(2), 212.70(d)(3)	129	501	64,640	0.166 (10 min.)	10,730
Conditional Final Releases 212.70(f)	129	1	129	1	129
Out-of-Specification Investigations 212.20(c); 212.71(a)	129	36	4,654	1	4,654
Reprocessing Procedures 212.71(b)	129	1	129	1	129
Reprocessing Procedures 212.20(c); 212.71(d)	129	1	129	1	129
Reprocessing Procedures 212.20(c); 212.90(a)	129	1	129	1	129
Distribution Records 212.90(b)	129	501	64,640	0.25 (15 mins.)	16,160
Complaints 212.20(c); 212.100(a)	129	1	129	1	129
Complaints 212.100(b), 212.100(c)	129	1	129	0.5 (30 mins.)	65
Total					115,435
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

Table 2—Estimated Annual Third-Party Disclosure Burden ¹

21 CFR section	No. of respondents	Annual frequency of disclosure	Total annual disclosures	Hours per disclosure	Total hours
Sterility Test Failure Notices 212.70(e)	129	0.25	32	1	32
1 There are no capital costs or operating and maintenance costs associated with this information collection.

Dated: December 22, 2015.

Leslie Kux,

Associate Commissioner for Policy.