55038 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

§ 72.214 List of approved spent fuel 

storage casks. 

* * * * * 

Certificate Number: 1004. 

Initial Certificate Effective Date: 

January 23, 1995. 

Amendment Number 1 Effective Date: 

April 27, 2000. 

Amendment Number 2 Effective Date: 

September 5, 2000. 

Amendment Number 3 Effective Date: 

September 12, 2001. 

Amendment Number 4 Effective Date: 

February 12, 2002. 

Amendment Number 5 Effective Date: 

January 7, 2004. 

Amendment Number 6 Effective Date: 

December 22, 2003. 

Amendment Number 7 Effective Date: 

March 2, 2004. 

Amendment Number 8 Effective Date: 

December 5, 2005. 

SAR Submitted by: Transnuclear, Inc. 

SAR Title: Final Safety Analysis 

Report for the Standardized NUHOMS

Horizontal Modular Storage System for 

Irradiated Nuclear Fuel. 

Docket Number: 72–1004. 

Certificate Expiration Date: January 

23, 2015. 

Model Number: NUHOMS–24P, 

–52B, –61BT, –32PT, –24PHB, and 

–24PTH. 

* * * * * 

Dated at Rockville, Maryland, this 1st day 

of September, 2005. 

For the Nuclear Regulatory Commission. 

Luis A. Reyes, 

Executive Director for Operations. 

[FR Doc. 05–18663 Filed 9–19–05; 8:45 am] 

BILLING CODE 7590–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 210, 211, and 212 

[Docket No. 2004N–0439] 

Current Good Manufacturing Practice 

for Positron Emission Tomography 

Drugs 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is issuing 

proposed regulations on current good 

manufacturing practice (CGMP) for 

positron emission tomography (PET) 

drug products. The regulations are 

intended to ensure that PET drug 

products meet the requirements of the 

Federal Food, Drug, and Cosmetic Act 

(the act) regarding safety, identity, 

strength, quality, and purity. We are 

proposing to establish CGMP 

requirements for approved PET drug 

products. For investigational and 

research PET drugs, the proposed rule 

states that the requirement to follow 

CGMP may be met by producing PET 

drugs in accordance with the United 

States Pharmacopeia (USP) general 

chapter on compounding PET 

radiopharmaceuticals. We are proposing 

to establish these CGMP requirements 

for all PET drugs under the provisions 

of the Food and Drug Administration 

Modernization Act of 1997 (the 

Modernization Act). Elsewhere in this 

issue of the Federal Register, FDA is 

announcing the availability of the draft 

guidance entitled ‘‘PET Drug Products—

Current Good Manufacturing Practice 

(CGMP).’’

DATES: Submit written or electronic 

comments by December 19, 2005. 

Submit written comments on the 

information collection requirements by 

October 20, 2005. See section VII of this 

document for the proposed effective 

date of a final rule based on this 

document. 

ADDRESSES: You may submit comments, 

identified by Docket No. 2004N–0439, 

by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following ways: 

• Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• Agency Web site: http:// 

www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting 

comments on the agency Web site. 

Written Submissions 

Submit written submissions in the 

following ways: 

• FAX: 301–827–6870. 

• Mail/Hand delivery/Courier [For 

paper, disk, or CD–ROM submissions]: 

Division of Dockets Management (HFA–

305), Food and Drug Administration, 

5630 Fishers Lane, rm. 1061, Rockville, 

MD 20852. 

To ensure more timely processing of 

comments, FDA is no longer accepting 

comments submitted to the agency by email. FDA encourages you to continue 

to submit electronic comments by using 

the Federal eRulemaking Portal or the 

agency Web site, as described in the 

Electronic Submissions portion of this 

paragraph. 

Instructions: All submissions received 

must include the agency name and 

Docket No(s). or Regulatory Information 

Number (RIN) for this rulemaking. All 

comments received may be posted 

without change to http://www.fda.gov/ 

ohrms/dockets/default.htm, including 

any personal information provided. For 

detailed instructions on submitting 

comments and additional information 

on the rulemaking process, see the 

‘‘Comments’’ heading of the 

SUPPLEMENTARY INFORMATION section of 

this document. 

Docket: For access to the docket to 

read background documents or 

comments received, go to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm and insert the docket 

number(s), 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: 

Brenda Uratani, Center for Drug 

Evaluation and Research (HFD–320), 

Food and Drug Administration, 11919 

Rockville Pike, Rockville, MD 20852, 

301–827–8941. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Introduction 

A. Background 

B. The Modernization Act and PET 

Drugs 

C. The Nature of PET Drug Production 

and Our Proposed Regulations 

II. Description of the Proposed Rule 

A. Exclusion of PET Drug Products 

From CGMP Regulations in Parts 

210 and 211 

B. Definitions 

C. Describing CGMP Requirements for 

PET Drugs 

D. Applicability of CGMP Regulations 

E. Adequate Personnel and Resources 

F. Quality Assurance 

G. Facilities and Equipment 

H. Control of Components, 

Containers, and Closures 

I. Production and Process Controls 

J. Laboratory Testing Requirements 

K. Stability 

L. Controls and Acceptance Criteria 

for Finished Products 

M. Actions To Be Taken if Product 

Does Not Conform to Specifications 

N. Labeling and Packaging 

O. Distribution Controls 

P. Complaint Handling 

Q. Records 

III. Analysis of Economic Impacts 

A. Regulatory Benefits 

B. Regulatory Costs 

C. Compliance Requirements 

1. Costs to Establish SOPs 

2. Equipment Costs 

3. Process Verification Costs 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55039 

4. Total Costs 

D. Growth of the PET Industry 

E. Regulatory Flexibility Analysis 

1. Objective of the Rule 

2. Definition of Small Entities 

3. Impact on Small Entities 

4. Other Federal Rules 

5. Description of Alternatives 

IV. Environmental Impact 

V. The Paperwork Reduction Act of 

1995 

A. Investigational and Research PET 

Drugs 

B. Batch Production and Control 

Records 

C. Equipment and Facilities Records 

D. Records of Components, 

Containers, and Closures 

E. Process Verification 

F. Laboratory Testing Records 

G. Sterility Test Failure Notices 

H. Conditional Final Releases 

I. Out-of-Specification Investigations 

J. Reprocessing Procedures 

K. Distribution Records 

L. Complaints 

VI. Federalism 

VII. Proposed Effective Date 

VIII. Request for Comments 

I. Introduction 

A. Background 

Positron emission tomography is a 

medical imaging modality involving the 

use of a unique type of 

radiopharmaceutical drug product. The 

majority of PET drug products are 

injected intravenously into patients for 

diagnostic purposes. Most PET drugs are 

produced using cyclotrons and other 

production equipment at locations that 

are close to the patients to whom the 

drugs are administered (e.g., in hospitals 

or academic institutions). Due to their 

short half-lives, PET drugs usually are 

administered to patients within a few 

minutes or hours of production. 

Under section 501(a)(2)(B) of the 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 CGMP to ensure that the drug 

meets the requirements of the act as to 

safety and has the identity and strength, 

and meets the quality and purity 

characteristics, that it purports or is 

represented to possess. Our CGMP 

requirements for non-PET drug products 

are set forth in parts 210 and 211 (21 

CFR parts 210 and 211). 

B. The Modernization Act and PET 

Drugs 

On November 21, 1997, the President 

signed the Modernization Act (Public 

Law 105–115) into law. Section 121 of 

the Modernization Act contains several 

provisions affecting the regulation of 

PET drugs. Section 121(d) directed us to 

terminate the application of the 

following three Federal Register 

documents: 

• A notice entitled ‘‘Regulation of 

Positron Emission Tomography 

Radiopharmaceutical Drug Products; 

Guidance; Public Workshop’’ (60 FR 

10594, February 27, 1995). This notice 

stated that traditional CGMP 

requirements in parts 210 and 211 were 

applicable to PET drugs. 

• A notice that announced the 

availability of a draft guideline on the 

production of PET drugs (60 FR 10593, 

February 27, 1995). 

• A final rule authorizing us to 

approve exceptions or alternatives to the 

application of CGMP requirements to 

the production of PET drugs (62 FR 

19493, April 22, 1997). 

We terminated the application of 

these three documents in a notice (62 

FR 66636) and final rule (62 FR 66522) 

published in the December 19, 1997, 

issue of the Federal Register. 

Section 121(c)(1)(A) of the 

Modernization Act directs us to 

establish appropriate approval 

procedures and CGMP requirements for 

PET drugs. Section 121(c)(2) of the 

Modernization Act provides that FDA 

cannot require the submission of a new 

drug application (NDA) or abbreviated 

new drug application (ANDA) for a PET 

drug product until 2 years after the day 

we publish a final rule establishing 

CGMP requirements for PET drug 

products. 

Section 121(c)(1)(B) of the 

Modernization Act states that, in 

adopting CGMP and approval 

requirements, we must take due account 

of any relevant differences between notfor-profit institutions that compound 

PET drugs for their patients and 

commercial manufacturers of such 

drugs. We discuss the nature of PET 

drug production in section I.C of this 

document. 

Section 121(c)(1)(B) of the 

Modernization Act also directs us, as we 

develop PET drug CGMP requirements 

and approval procedures, to consult 

with patient advocacy groups, 

professional associations, 

manufacturers, and physicians and 

scientists who make or use PET drugs. 

We have taken the following steps in 

developing the PET drug CGMP 

regulations: 

• We presented our initial tentative 

approach to PET drug CGMP 

requirements and responded to 

numerous questions and comments 

about that approach at a public meeting 

on February 19, 1999. 

• In accordance with §§ 10.40(f)(4) 

and 10.80(b)(2) (21 CFR 10.40(f)(4) and 

10.80(b)(2), we announced the 

availability of preliminary draft 

regulations on PET drug CGMP 

requirements in the September 22, 1999, 

issue of the Federal Register (64 FR 

51274). 

• We held a public meeting to discuss 

the preliminary draft regulations on 

September 28, 1999. 

• After considering the comments on 

the preliminary draft regulations, in 

accordance with §§ 10.40(f)(4) and 

10.80(b)(2), we announced the 

availability of a preliminary draft 

proposed rule on PET drug CGMP 

requirements in the April 1, 2002, issue 

of the Federal Register (67 FR 15344). 

• We also announced the availability 

of a draft guidance on ‘‘PET Drug 

Products—Current Good Manufacturing 

Practice for Positron Emission 

Tomography’’ on April 1, 2002 (67 FR 

15404). 

• We held a public meeting to discuss 

the preliminary draft proposed rule and 

draft guidance on April 21, 2002. 

• After considering the comments on 

the preliminary draft proposed rule, we 

are now issuing this proposed rule on 

PET drug CGMP requirements. 

Elsewhere in this issue of the Federal 

Register, we are making available for 

comment a revised draft guidance on 

CGMP for PET drug products. 

C. The Nature of PET Drug Production 

and Our Proposed Regulations 

As directed by Congress in the 

Modernization Act, to aid our 

development of these proposed 

regulations, we closely examined the 

operations of many PET drug producers, 

including not-for-profit institutions and 

commercial manufacturers. Since the 

Modernization Act became law, PET 

drug production in the United States 

has significantly changed. The number 

of PET production facilities has 

increased, as has the number of facilities 

where PET scans are performed. The 

business of PET drug production has 

changed as well. Historically, PET drug 

products were produced by 

academicians and researchers at 

facilities located in universities and 

similar not-for-profit institutions. These 

academically oriented PET production 

facilities usually produce small amounts 

(a few doses per day) of a few PET drug 

products for onsite patient use and a 

larger variety of PET drug products for 

clinical investigation and academic 

research. 

An increasing number of PET 

production facilities are now operated 

55040 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

by large, for-profit corporate entities that 

contract with academic and medical 

institutions (many of which have notfor-profit status) to manage the 

production of PET drugs at those 

institutions. Most of these PET drug 

products are administered onsite, 

although there is some distribution to 

other local or regional hospitals. 

In addition, there are a growing 

number of independent PET production 

facilities that are not affiliated with any 

university or hospital. Typically these 

are for-profit, independently operated 

facilities, although they are often 

contractually managed. These facilities 

generally focus on producing one or two 

PET drug products and distribute them 

to significantly greater numbers of 

patients, sometimes hundreds of miles 

from the production site. 

Our review of PET drug production 

leads us to the following conclusions: 

• A PET drug producer’s status as 

either a not-for-profit or for-profit entity 

does not have a significant bearing on 

the quality of PET drugs that it produces 

and distributes for administration to 

patients, or the methods, facilities, and 

controls that a PET production facility 

needs to ensure product quality. 

• Production and CGMP differences 

among PET drug producers are 

primarily a function of the size, scope, 

and complexity of their production 

operations. 

• Certain production standards and 

controls are necessary to ensure the 

production of quality PET drugs 

regardless of differences in the nature 

and scope of production among 

facilities. 

While this proposed rule and the draft 

guidance primarily reflect our 

familiarity with the current approved 

PET drugs (fludeoxyglucose (FDG) F 18 

injection and ammonia N 13 injection), 

we intend both the proposed rule and 

the draft guidance to apply to future 

PET drug products. We also recognize 

that the development of new PET drug 

products may require us to amend 

regulations or guidance to accommodate 

the new products. 

This proposed rule on CGMP 

requirements contains the minimum 

standards needed for PET drug 

production at all types of PET 

production facilities. We have designed 

the CGMP regulations to be sufficiently 

flexible to accommodate not-for-profit, 

academically oriented institutions as 

well as larger commercial producers. 

In consideration of the unique nature 

of PET drugs and PET drug production, 

the proposed CGMP requirements for 

PET drug products differ in many 

significant ways from the CGMP 

requirements for non-PET drug products 

found in our regulations in part 211. 

The proposed PET CGMP requirements 

include the following differences: 

• Fewer required personnel with 

fewer organizational restrictions 

consistent with the scope and 

complexity of operations; 

• Allowance for multiple operations 

(or storage) in the same area as long as 

organization and other controls are 

adequate; 

• Streamlined requirements for 

aseptic processing consistent with the 

nature of the production process; 

• Streamlined quality control 

requirements for components; 

• Self-verification of significant steps 

in PET drug production consistent with 

the scope and complexity of operations; 

• Same-person oversight of 

production, review of batch records, and 

authorization of product release 

consistent with the scope and 

complexity of operations; 

• Specialized quality control 

requirements for PET drugs produced in 

multiple sub-batches; and 

• Simplified labeling requirements 

consistent with the scope and 

complexity of operations. 

These and other proposed PET CGMP 

provisions, designed to reflect the 

unique characteristics of PET drug 

production, should make it easier for 

PET production facilities to achieve 

compliance with CGMP requirements. 

This proposed rule incorporates 

principles from Chapter <823>, 

‘‘Radiopharmaceuticals for Positron 

Emission Tomography—

Compounding,’’ of the 28th edition of 

the USP (2005) (USP 28). The USP 

contains standards that are of significant 

regulatory importance for PET drugs. 

Under section 501(a)(2)(C) of the act, a 

compounded PET drug is adulterated 

unless it is produced in compliance 

with the USP’s PET drug compounding 

standards and the official monograph 

for the particular PET drug. Section 

121(b) of the Modernization Act added 

this provision as a safety net while we 

develop this rule. Under section 121(b) 

of the Modernization Act, however, 

section 501(a)(2)(C) of the act will 

expire 2 years after the date on which 

we establish final approval procedures 

and CGMP requirements for PET drugs. 

At that time, compliance with the final 

version of this rule will be required. The 

USP 28 general chapter on PET drug 

compounding largely reflects the 

consensus views of the PET community 

and FDA on how to properly produce 

PET drug products. Consequently, we 

believe it is appropriate to incorporate 

many of the principles and concepts in 

the USP general chapter into these 

proposed CGMP requirements. 

Moreover, as discussed in section II.D 

of this document, we believe that it is 

appropriate to designate the provisions 

of USP 28, Chapter <823> as the CGMP 

requirements for investigational PET 

drugs produced under an investigational 

new drug application (IND) and 

research PET drugs produced with the 

approval of a Radioactive Drug Research 

Committee (RDRC) under § 361.1 (21 

CFR 361.1). Thus, under the proposed 

rule, investigational and research PET 

drugs produced in accordance with 

Chapter <823> would be deemed to 

meet CGMP requirements; they would 

not have to meet the more specific 

requirements in proposed part 212. 

Because most PET drugs currently are 

produced under an IND or RDRC 

review, adopting USP 28, Chapter 

<823> as the standard for CGMP for 

investigational PET drugs should make 

it easier for PET drug producers to 

comply with the proposed CGMP 

requirements. 

To further assist PET production 

facilities in complying with the 

requirements in the rule, we have 

revised the draft guidance document 

entitled ‘‘PET Drug Products—Current 

Good Manufacturing Practice (CGMP).’’

For many aspects of CGMP (such as 

resources, controls, and 

documentation), the draft guidance 

makes different recommendations 

depending on the size, scope, and 

complexity of a PET production 

facility’s operations. The draft guidance 

provides practical examples of methods 

and procedures that different types of 

PET production facilities might use to 

comply with the CGMP requirements. 

II. Description of the Proposed Rule 

We are proposing to establish CGMP 

regulations for PET drug products by 

creating 21 CFR part 212. These 

regulations are intended to ensure that 

every PET drug product meets the 

requirements of the act as to safety and 

has the identity and strength, and meets 

the quality and purity characteristics, 

that it is represented to possess. 

We describe our proposed CGMP 

regulations for PET drug production in 

the following sections of this document. 

The format of the proposed regulations, 

including the use of questions in section 

headings, is in accordance with the 

Presidential Memorandum of June 1, 

1998, promoting the use of plain 

language in regulatory writing. 

A. Exclusion of PET Drug Products 

From CGMP Regulations in Parts 210 

and 211 

We propose revising certain sections 

of parts 210 (CGMP for the 

manufacturing, processing, packing, or 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55041 

holding of drugs) and 211 (CGMP for 

finished pharmaceuticals) to make clear 

that the regulations in those parts do not 

apply to PET drug products. The 

revisions are in § 210.1 (status of CGMP 

regulations), § 210.2 (applicability of 

CGMP regulations), and § 210.3 

(definitions). We propose revising the 

text of each of these sections so that the 

provisions will only apply to parts 210, 

211, 225, and 226, rather than part 210 

and parts 211 through 226. The 

revisions would exclude part 212, 

which will address PET drug products, 

from the scope of §§ 210.1, 210.2, and 

210.3. Similarly, we propose to revise 

§ 211.1(a) (scope of CGMP for finished 

pharmaceuticals) to clarify that the 

regulations in part 211 do not apply to 

PET drug products. 

B. Definitions 

Proposed § 212.1 sets forth the 

meaning of several terms used in the 

PET drug CGMP regulations. Most of the 

definitions are self-explanatory and well 

understood by PET producers and the 

pharmaceutical industry. We will 

discuss here a few of the definitions for 

which added comment may help the 

reader better understand the provision. 

• Acceptance criteria. We propose to 

define ‘‘acceptance criteria’’ as 

numerical limits, ranges, or other 

criteria for tests that are used for or in 

making a decision to accept or reject a 

unit, lot, or batch of a PET drug product. 

This varies slightly from the definition 

in part 210, which states that acceptance 

criteria are the ‘‘product specifications 

and acceptance/rejection criteria, such 

as acceptable quality level and 

unacceptable quality level, with an 

associated sampling plan, that are 

necessary for making a decision to 

accept or reject a lot or batch (or any 

other convenient subgroups of 

manufactured units).’’ The proposed 

definition, which does not refer to 

sampling plans, is more appropriate for 

PET drug production. 

• Specifications. We propose a 

separate definition of ‘‘specifications’’ to 

mean the tests, analytical procedures, 

and appropriate acceptance criteria to 

which a PET drug, PET drug product, 

component, container closure system, 

in-process material, or other material 

used in PET drug production must 

conform to be considered acceptable for 

its intended use. Conformance to 

specifications would mean that a PET 

drug, PET drug product, component, 

container closure system, in-process 

material, or other material used in PET 

drug production, when tested according 

to the described analytical procedures, 

meets the listed acceptance criteria. 

The definitions for acceptance criteria 

and specifications are intended to be 

consistent with guidance in ‘‘Q6A 

Specifications: Test Procedures and 

Acceptance Criteria for New Drug 

Substances and New Drug Products,’’

prepared under the auspices of the 

International Conference on 

Harmonisation for Registration of 

Pharmaceuticals for Human Use (ICH). 

ICH works to promote the 

harmonization of technical 

requirements (including definitions, 

procedures, formats, and standards) for 

approval of pharmaceutical products 

among the European Union, Japan, and 

the United States. 

• Active pharmaceutical ingredient. 

We propose to define ‘‘active 

pharmaceutical ingredient’’ (API) for 

purposes of part 212 as a substance 

(excluding intermediates used in the 

synthesis of such substance) that is 

intended for incorporation into a 

finished PET drug product and is 

intended to furnish pharmacological 

activity or other direct effect in the 

diagnosis or monitoring of a disease or 

a manifestation of a disease in humans. 

For example, in the case of FDG F 18 

injection drug product, 2-deoxy-2- 

[18F]fluoro-D-glucose is considered the 

API. In a commonly used production 

method for FDG F 18 injection, 1,3,4,6- 

tetra-O-acetyl-2-O-trifluoromethane 

sulfonyl-b-D-mannopyranose (mannose 

triflate) and O 18 water are considered 

components that yield the API but are 

not part of the API. 

• PET drug. We propose to define 

‘‘PET drug’’ as a radioactive drug that 

exhibits spontaneous disintegration of 

unstable nuclei by the emission of 

positrons and is used for providing dual 

photon positron emission tomographic 

diagnostic images. The definition of PET 

drug includes any nonradioactive 

reagent, reagent kit, ingredient, nuclide 

generator, accelerator, target material, 

electronic synthesizer, or other 

apparatus or computer program to be 

used in the preparation of a PET drug. 

This definition closely parallels the 

statutory definition. 

• PET drug product. We propose to 

define ‘‘PET drug product’’ as a finished 

dosage form that contains a PET drug, 

whether or not in association with one 

or more other ingredients. In other 

words, a PET drug product is the 

finished dosage form of a PET drug, 

with or without an excipient such as a 

diluent. 

• Receiving facility. We propose to 

define ‘‘receiving facility’’ as any 

hospital, institution, nuclear pharmacy, 

imaging facility, or other entity or part 

of an entity that accepts a PET drug 

product that has been given final 

release. A receiving facility may be in 

the same area as or adjacent to the 

production area, in a different area but 

located in the same building as the 

production area, or at a site that is 

completely separate from the 

production area. 

• Material release and final release. 

We propose to define ‘‘material release’’

as the authoritative decision by a 

responsible person in a PET production 

facility to permit the use of a 

component, container and closure, inprocess material, packaging material, or 

labeling in the production of a PET drug 

product. ‘‘Final release,’’ in contrast, is 

defined as the authoritative decision by 

a responsible person in a PET 

production facility to permit the use of 

a batch of a PET drug product in 

humans. 

• Strength. We propose to define 

‘‘strength’’ as the concentration of the 

API (radioactivity amount per volume or 

weight at the time of calibration). This 

proposed definition varies from the 

definition of ‘‘strength’’ in part 210 in 

that it specifies a radioactivity to 

volume (or weight) ratio rather than a 

weight/weight, weight/volume, or unit 

dose/volume ratio. The definition of 

strength for proposed part 212 reflects 

that PET drug products have radioactive 

APIs (quantified in units of 

radioactivity) and generally are 

produced in a solution or gas dosage 

form. 

C. Describing CGMP Requirements for 

PET Drugs 

Proposed § 212.2 answers the 

question ‘‘What is current good 

manufacturing practice for PET drugs?’’

Proposed § 212.2 states that CGMP for 

PET drug products is the minimum 

requirements for the methods to be used 

in, and the facilities and controls used 

for, the production, quality control, 

holding, or distribution of PET drug 

products intended for human use. 

CGMP is intended to ensure that each 

PET drug product meets the 

requirements of the act as to safety and 

has the identity and strength, and meets 

the quality and purity characteristics, 

that it is supposed to have. 

D. Applicability of CGMP Regulations 

Proposed § 212.5 answers the 

question ‘‘To what drugs do the 

regulations in this part apply?’’

Proposed § 212.5(a) states that: 

• Part 212 applies only to the 

production, quality control, holding, 

and distribution of PET drug products. 

• Any human drug product that does 

not meet the definition of a PET drug 

product must be manufactured in 

accordance with the CGMP 

55042 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

requirements in parts 210 and 211 of 

this chapter. 

• Part 212 contains CGMP 

requirements for all PET drug products 

for human use, but proposed § 212.5(b) 

specifies different CGMP requirements 

for investigational and research PET 

drugs. 

We believe that it is appropriate to 

have less detailed CGMP requirements 

for investigational and research PET 

drugs to allow for more flexibility in the 

production of these drugs. We also 

recognize that many investigational PET 

drugs may not have commercial 

potential. Therefore, proposed § 212.5(b) 

states that the regulations in part 212 do 

not apply to investigational PET drugs 

for human use produced under an IND 

in accordance with part 312 and 

research PET drugs produced with the 

approval of an RDRC in accordance with 

§ 361.1. Instead, proposed § 212.5(b) 

states that, for investigational and 

research PET drugs, the requirement 

under the act to follow CGMP is met by 

producing drugs in accordance with 

USP 28 Chapter <823>, which is 

incorporated by reference in accordance 

with 5 U.S.C. 552(a) and 1 CFR part 51. 

Chapter <823> sets forth requirements 

on several aspects of PET drug 

production, including control of 

components, materials, and supplies, 

verification of procedures, stability 

testing and expiration dating, quality 

control, and sterilization and sterility 

assurance. Because most PET drug 

producers are very familiar with the 

requirements in USP 28 Chapter <823>, 

adopting the Chapter <823> provisions 

as the CGMP requirements for 

investigational and research PET drugs 

should greatly facilitate producers’

compliance with those requirements. 

Although the provisions in USP 28 

Chapter <823>, including those on 

documentation, are generally less 

specific and explicit than the 

requirements in proposed part 212, we 

believe that they are adequate to ensure 

that investigational and research PET 

drugs are produced safely under 

appropriate conditions, consistent with 

section 501(a)(2)(B) of the act. We are 

interested in any comments that suggest 

appropriate standards, other than USP 

28 Chapter <823>, for PET drugs and 

drug products produced under an IND 

or with the approval of an RDRC. 

Although we propose that USP 28 

Chapter <823>, rather than part 212, 

would constitute the minimum CGMP 

requirements for investigational and 

research PET drugs, FDA retains the 

authority under section 704 of the act 

(21 U.S.C. 374) to inspect facilities 

where investigational or research PET 

drugs are produced to verify compliance 

with USP 28 Chapter <823>. However, 

as with inspection of investigational 

studies of non-PET drugs, we generally 

would conduct inspections of facilities 

that produce investigational or research 

PET drugs only on a for-cause basis. An 

example of a situation that could lead to 

a for-cause inspection would be when 

we become aware of a potential safety 

concern related to the production of an 

investigational or research PET drug. 

E. Adequate Personnel and Resources 

Proposed § 212.10 answers the 

question ‘‘What personnel and resources 

must I have?’’ The proposal would 

require: 

• A sufficient number of personnel 

with the necessary education, 

background, training, and experience to 

enable those personnel to perform their 

assigned functions, and 

• Adequate resources, including 

facilities and equipment, to enable 

personnel to perform their functions. 

What constitutes ‘‘adequate’’

personnel and resources will depend in 

part on the size and complexity of the 

PET drug producer’s operations. A PET 

production facility having a simple 

operation that produces only one or two 

doses each day (or week) of a single PET 

drug would need fewer personnel and 

other resources than a facility having a 

more complex operation that produces 

multiple PET drug products or a facility 

producing larger amounts of a PET drug 

product. 

F. Quality Assurance 

Proposed § 212.20 answers the 

question ‘‘What activities must I 

perform to ensure product quality?’’

Under proposed § 212.20, PET drug 

product producers would be required to: 

• Oversee production operations to 

ensure that each PET drug product 

meets the requirements of the act as to 

safety and has the identity and strength, 

and meets the quality and purity 

characteristics, that it is supposed to 

have (proposed § 212.20(a)). Each PET 

drug producer will determine what 

personnel should perform the quality 

assurance function; at some PET 

production facilities, it may be 

reasonable for the same personnel to be 

involved in both production and quality 

assurance. 

• Examine and approve or reject 

components, containers, closures, inprocess materials, packaging materials, 

labeling, and finished dosage forms to 

ensure compliance with procedures and 

specifications affecting the identity, 

strength, quality, or purity of a PET drug 

product (proposed § 212.20(b)). 

• Approve or reject, before 

implementation, any initial 

specifications, methods, processes, or 

procedures, and any proposed changes 

to existing specifications, methods, 

processes, or procedures, to ensure that 

they maintain the identity, strength, 

quality, and purity of the PET drug 

product when they are implemented. 

PET drug producers must demonstrate 

that any change does not adversely 

affect the identity, strength, quality, or 

purity of any PET drug product 

(proposed § 212.20(c)). 

• Review production records to 

determine whether errors have 

occurred. If errors have occurred or a 

production batch or any of its 

components fails to meet any of its 

specifications, the producer must 

determine the need for an investigation, 

conduct investigations when necessary, 

and take appropriate corrective action 

(proposed § 212.20(d)). Possible errors 

include miscalculating yield, omitting a 

production step, or transcription 

mistakes. 

• Establish and follow written quality 

assurance procedures to ensure that 

quality assurance responsibilities are 

known to all personnel involved in PET 

drug product production (proposed 

§ 212.20(e)). 

G. Facilities and Equipment 

Proposed § 212.30 answers the 

question ‘‘What requirements must my 

facilities and equipment meet?’’ Under 

proposed § 212.30, a PET drug producer 

would be required to: 

• Provide adequate facilities to ensure 

the orderly handling of materials and 

equipment, the prevention of mixups, 

and the prevention of contamination of 

equipment or product by substances, 

personnel, or environmental conditions 

that could reasonably be expected to 

have an adverse effect on product 

quality (proposed § 212.30(a)). 

• Implement procedures to ensure that 

all equipment that could reasonably be 

expected to adversely affect the 

strength, quality, or purity of a PET drug 

product (such as a laminar airflow 

workbench or sterilizing filters) or give 

erroneous or invalid test results when 

improperly used or maintained (such as 

high pressure liquid chromatography 

(HPLC) devices) is clean, suitable for its 

intended purposes, properly installed, 

maintained, and capable of repeatedly 

producing valid results. PET production 

facilities must document their activities 

in accordance with these procedures 

(proposed § 212.30(b)). 

• Ensure that equipment is 

constructed and maintained so that 

surfaces that contact components, in 

process materials, or PET drug products 

are not reactive, additive, or absorptive 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55043 

so as to alter the quality of PET drug 

products (proposed § 212.30(c)). 

H. Control of Components, Containers, 

and Closures 

Proposed § 212.40 answers the 

question ‘‘How must I control the 

components I use to produce PET drugs 

and the containers and closures I 

package them in?’’ Under proposed 

§ 212.40, PET drug producers would be 

required to: 

• Establish, maintain, and follow 

written procedures describing the 

receipt, login, identification, storage, 

handling, testing, approval, and 

rejection of components and drug 

product containers and closures. The 

procedures must be adequate to ensure 

that the components, containers, and 

closures are suitable for their intended 

use (proposed § 212.40(a)). 

• Establish appropriate written 

specifications for the identity, quality, 

and purity of components and for the 

identity and quality of drug product 

containers and closures (proposed 

§ 212.40(b)). 

Proposed § 212.40(c) specifies that: 

• Upon receipt, each lot of 

components and containers and 

closures must be uniquely identified 

and tested or examined to determine 

whether it complies with the PET 

production facility’s specifications. 

• Any lot that does not meet its 

specifications, including any expiration 

date if applicable, or that has not yet 

received its material release, must not 

be used in PET drug production. 

• Any incoming lot must be 

appropriately designated as either 

quarantined, accepted, or rejected. 

• PET drug producers must use a 

reliable supplier as a source of each lot 

of each component, container, and 

closure. 

We are proposing to establish 

different requirements for examination 

and testing of components required 

under proposed § 212.40(c) depending 

on whether a PET drug producer 

conducts finished-product testing that 

includes testing to ensure that the 

correct components have been used: 

• When the finished-product testing of 

a PET drug product includes testing to 

ensure that the correct components have 

been used, the PET drug producer need 

only determine that each lot of 

incoming components complies with 

written specifications by examining a 

certificate of analysis provided by the 

supplier (proposed § 212.40(c)(1)(i)). We 

believe that the use of this type of 

finished-product testing makes specific 

identity testing of components 

redundant and unnecessary. For 

example, when identity of the F 18 

radionuclide is established as part of the 

finished-product testing and the method 

of production used is well-documented 

and understood (e.g., as in the 18O (p,n) 18F nuclear reaction), it can be 

reasonably argued that the component 

that yields this radionuclide is likely to 

be O 18 water. In this case, a specific 

identity test for O 18 water is not 

necessary before the lot is used in 

production. Similarly, a specific 

identity test before using a lot of 

mannose triflate may be redundant and 

unnecessary when: (1) A wellunderstood method of synthesis of FDG 

F 18 is used, (2) a test to confirm the 

radiochemical identity is performed in 

the finished drug product, and (3) the 

mannose triflate was obtained from a 

reliable supplier with whom a 

relationship has been previously 

established. 

• If the finished-product testing of a 

PET drug product does not include 

testing to ensure that the correct 

components have been used, the 

following provisions (proposed 

§ 212.40(c)(1)(ii)) would apply: 

—The PET drug producer would be 

required to conduct identity testing, 

using a test that is specific to the 

component, on each lot of a component 

that yields an active ingredient and each 

lot of an inactive ingredient. 

—For any other component, such as 

solvents or reagents, the PET drug 

producer would determine that each lot 

complies with written specifications by 

examining a certificate of analysis 

provided by the supplier. 

—If the PET drug producer prepares 

an inactive ingredient on site, the 

producer would be required to perform 

an identity test on the components used 

to make the inactive ingredient before 

those components could be released for 

use. 

However, if the PET drug producer 

uses as an inactive ingredient a product 

that is marketed as a finished drug 

product intended for intravenous 

administration, the producer would not 

need to perform a specific identity test 

on that ingredient. 

We are also proposing that PET drug 

producers would be required to do the 

following: 

• Examine a representative sample of 

each lot of containers and closures for 

conformity to its written specifications 

(proposed § 212.40(c)(2)). 

• Perform at least a visual 

identification of each lot of containers 

and closures (proposed § 212.40(c)(2)). 

• Handle and store components, 

containers, and closures in a manner 

that prevents contamination, mixups, 

and deterioration and ensures that these 

items are and remain suitable for their 

intended use (proposed § 212.40(d)). 

• Keep a record of each shipment of 

each lot of components, containers, and 

closures they receive (proposed 

§ 212.40(e)), including the following 

information: 

—Identity and quantity of each 

shipment, 

—Supplier’s name and lot number, 

—Date of receipt, 

—Results of any testing performed, 

—Disposition of rejected material, and 

—Expiration date, where applicable. 

(Some components may not have 

expiration dates.) 

I. Production and Process Controls 

Proposed § 212.50 answers the 

question ‘‘What production and process 

controls must I have?’’ Proposed 

§ 212.50 states that PET drug producers 

must have adequate production and 

process controls to ensure the consistent 

production of a PET drug product that 

meets the applicable standards of 

identity, strength, quality, and purity. 

Proposed § 212.50 would require PET 

drug producers to have the following 

controls: 

• Written production and process 

control procedures, 

• Master production and control 

records, 

• Batch and production control 

records, 

• Production area and equipment 

checks, 

• In-process materials controls, and 

• Depending on finished-product 

testing, process verification. 

The proposed written production and 

process control procedures would 

ensure and document that all key 

process parameters are controlled and 

that any deviations from the procedures 

are justified (proposed § 212.50(a)). 

The proposed master production and 

control records would document all 

steps in the PET drug product 

production and would include the 

following information (proposed 

§ 212.50(b)): 

• The name and strength of the PET 

drug product; 

• If applicable, the name and 

radioactivity or other measurement of 

each API and each inactive ingredient 

per batch or per unit of radioactivity or 

other measurement of the drug product, 

and a statement of the total radioactivity 

or other measurement of any dosage 

unit; 

• A complete list of components 

designated by names and codes 

sufficiently specific to indicate any 

special quality characteristic; 

• Identification of all major pieces of 

equipment used in production; 

55044 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

• An accurate statement of the weight 

or measurement of each component, 

using the same weight system (metric, 

avoirdupois, or apothecary) for each 

component (with reasonable variations 

permitted in the amount of component 

necessary if specified in the master 

production and control records); 

• A statement of acceptance criteria 

on radiochemical yield, i.e., the 

minimum percentage of yield beyond 

which investigation and corrective 

action are required; 

• Complete production and control 

instructions, sampling and testing 

procedures, specifications, special 

notations, and precautions to be 

followed; and 

• A description of the PET drug 

product containers, closures, and 

packaging materials, including a 

specimen or copy of each label and all 

other labeling. 

The creation of a unique batch and 

production control record would be 

required each time a batch of a PET drug 

product is produced (proposed 

§ 212.50(c)), including the following 

information: 

• The name and strength of the PET 

drug product, 

• An identification number or other 

unique identifier of the specific batch 

that was produced, 

• The name and radioactivity or other 

measure of each API and each inactive 

ingredient per batch or per unit of 

radioactivity or other measurement of 

the drug product, 

• Each major production step 

(obtained from the approved 

appropriate master production and 

control record), 

• Weights and identification codes of 

components, 

• Dates and time of production steps, 

• Identification of major pieces of 

equipment used in production of the 

batch, 

• Testing results, 

• Labeling, 

• Initials or signatures of persons 

performing or checking each significant 

step in the operation, and 

• Results of any investigations 

conducted. 

Proposed § 212.50(d) would require 

production area and equipment checks 

to ensure cleanliness and suitability 

immediately before use, and a record of 

the checks. 

Proposed § 212.50(e) specifies that 

process controls for PET production 

facilities include control of in-process 

materials to ensure that the materials are 

controlled until required tests or other 

verification activities have been 

completed or necessary approvals are 

received and documented. 

Proposed § 212.50(f) would establish 

different requirements for process 

verification depending on whether a 

PET drug producer conducts full 

finished-product testing on a particular 

PET drug product: 

• Proposed § 212.50(f)(1) would 

exempt a PET drug product from these 

process verification requirements if each 

batch of that PET drug product, prior to 

human administration, undergoes full 

finished-product testing to ensure that 

the product meets all specifications. For 

example, process verification under 

proposed § 212.50(f)(2) would not be 

required for the production of FDG F 18 

where: (1) The entire batch is made in 

a single vial, (2) a sample from the vial 

is withdrawn for full finished-product 

testing, and (3) the finished product 

passes all established specifications 

(except for sterility) prior to human 

administration. 

• When the results of the production 

of an entire batch of a PET drug product 

are not fully verified through finishedproduct testing or when only the initial 

sub-batch in a series is tested, process 

verification would be required. The PET 

drug producer would be required to 

demonstrate that the process for 

producing the PET drug product is 

reproducible and is capable of 

producing a drug product that meets the 

predetermined acceptance criteria 

(proposed § 212.50(f)(2)). While 

currently most, if not all, batches of PET 

drug products are fully verified through 

finished-product testing, future PET 

drug products may not be suitable for 

finished-product testing of an entire 

batch due to the short half-life of the 

radionuclide, and process verification 

would be required. 

• When process verification activities 

are conducted, the PET drug producer 

would be required to document 

activities and results, including the date 

and signature of the individual(s) 

performing the verification, the 

monitoring and control methods and 

data, and the major equipment qualified 

(proposed § 212.50(f)(2)). 

For a PET facility that has an 

established history of producing a 

particular PET drug product, 

verification of that production process 

may be conducted retrospectively 

provided that the process has not 

changed and has not resulted in 

process-related failures. However, when 

a PET drug product is not fully verified 

through finished-product testing or 

when only the initial sub-batch in a 

series is tested, process verification 

would be required for any new 

production process and after any 

significant change to a qualified process. 

J. Laboratory Testing Requirements 

Proposed § 212.60 answers the 

question ‘‘What requirements apply to 

the laboratories where I test 

components, in process materials, and 

finished PET drug products?’’ Under 

proposed § 212.60, the following 

requirements would apply to 

laboratories used to conduct testing of 

components, in process materials, and 

finished PET drug products: 

• Each laboratory must have and 

follow written procedures for the 

conduct of each test and for the 

documentation of the results (proposed 

§ 212.60(a)). 

• Each laboratory must have sampling 

and testing procedures designed to 

ensure that components, in process 

materials, and PET drug products 

conform to appropriate standards, 

including established standards of 

identity, strength, quality, and purity 

(proposed § 212.60(b)). 

• Laboratory analytical methods must 

be suitable for their intended use and 

must be sufficiently sensitive, specific, 

accurate, and reproducible (proposed 

§ 212.60(c)). 

If a compendial test is used, the 

testing laboratory should verify that the 

method works under the actual 

conditions of use and that the drug 

product as formulated can be analyzed 

using the compendial method. This 

verification is recommended because 

many compendial methods for PET drug 

products lack specific information (for 

example, they do not describe specific 

equipment used), the method may not 

have been developed in the context of 

the production method actually being 

used, and the PET production facility 

may not be using the same equipment 

that was used in the compendial 

method. 

• The identity, purity, and quality of 

reagents, solutions, and supplies used in 

testing must be adequately controlled, 

and all solutions prepared by the PET 

production facility must be labeled with 

their identity and expiration date 

(proposed § 212.60(d)). 

• All testing equipment must be 

suitable for its intended purposes and 

capable of producing valid results 

(proposed § 212.60(e)). 

• Each laboratory must have and 

follow written procedures to ensure that 

equipment is routinely calibrated, 

inspected, checked, and maintained, 

and these activities must be 

documented (proposed § 212.60(f)). 

• Each laboratory performing tests 

related to the production of a PET drug 

product must keep complete records of 

all tests performed to ensure compliance 

with established specifications and 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55045 

standards, including examinations and 

assays (proposed § 212.60(g)). 

The records required under proposed 

§ 212.60(g) would include the following: 

• A description of the sample received 

for testing, including its source, the 

quantity, the batch or lot number, the 

date (and time, if appropriate) the 

sample was taken, and the date (and 

time, if appropriate) the sample was 

received for testing; 

• A description of each method used 

in the testing of the sample, a record of 

all calculations performed in connection 

with each test, and a statement of the 

weight or measurement of the sample 

used for each test; 

• A complete record of all data 

obtained in the course of each test, 

including all graphs, charts, and spectra 

from laboratory instrumentation, 

properly identified to show the specific 

component, in-process material, or drug 

product for each lot tested; 

• A statement of the results of tests 

and how the results compare with 

established acceptance criteria; and 

• The initials or signature of the 

person performing the test and the date 

on which the test was performed. 

K. Stability 

Proposed § 212.61 answers the 

question ‘‘What must I do to ensure the 

stability of my PET drug products 

through expiry?’’ Proposed § 212.61 

would provide the following 

requirements to ensure the stability of 

PET drug products: 

• PET production facilities must 

establish, follow, and maintain a written 

testing program to assess the stability 

characteristics of their PET drug 

products (proposed § 212.61(a)). 

• Test methods must be reliable, 

meaningful, and specific (i.e., they must 

be capable of determining the stability 

characteristics of the PET drug product) 

(proposed § 212.61(a)). 

• Samples tested for stability must be 

representative of the lot or batch from 

which they were obtained and must be 

stored under suitable conditions 

(proposed § 212.61(a)). 

• Results of the stability testing must 

be documented and used in determining 

appropriate storage conditions and 

expiration dates and times for each PET 

drug product (proposed § 212.61(b)). 

L. Controls and Acceptance Criteria for 

Finished Products 

Proposed § 212.70 answers the 

question ‘‘What controls and acceptance 

criteria must I have for my finished PET 

drug products?’’ These controls and 

acceptance criteria are the requirements 

that must be met before a PET 

production facility may give final 

release to a finished PET drug product. 

We propose to establish the following 

requirements regarding controls and 

acceptance criteria: 

• PET production facilities would be 

required to establish specifications for 

each batch of a PET drug product, 

including criteria for identity, strength, 

quality, purity, and, if appropriate, 

sterility and pyrogenicity (proposed 

§ 212.70(a)). Most, but not all, PET drugs 

are sterile injectable products, and such 

products would be required to have 

specifications for sterility and 

pyrogenicity. 

• Before a PET drug producer 

implements a test procedure in a 

specification, the producer would be 

required to establish and document the 

accuracy, sensitivity, specificity, and 

reproducibility of the procedure 

(proposed § 212.70(b)). 

• If the PET drug producer uses an 

established compendial test procedure 

in a specification, the producer would 

be required to first verify and document 

that the test works under the conditions 

of actual use (proposed § 212.70(b)). 

• PET drug producers would be 

required to conduct laboratory testing of 

a representative sample of each batch of 

a PET drug product before final release 

to ensure that the batch conforms to its 

specifications, except for sterility. For a 

PET drug product produced in subbatches (e.g., ammonia N 13 injection), 

at least each initial sub-batch that is 

representative of the entire batch must 

conform to specifications, except for 

sterility, before final release (proposed 

§ 212.70(c)). 

• Under proposed § 212.70(d), 

producers would be required to 

establish and follow procedures to 

ensure that a PET drug product is not 

given final release until: 

—Appropriate laboratory testing 

under paragraph (a) of this section is 

completed, 

—Associated laboratory data and 

documentation are reviewed (review 

may be performed by a second person 

or self-verified in a one-person 

operation) and they demonstrate that 

the PET drug product meets 

specifications, except for sterility, and 

—A designated qualified individual 

authorizes final release by dated 

signature. 

In many cases, the short half-life of a 

PET radionuclide precludes the 

completion and review of all laboratory 

testing before release of the PET drug 

product for distribution to a receiving 

facility. In such cases, release for 

distribution in accordance with 

previously established and documented 

procedures is acceptable as long as all 

testing and review, except for sterility, 

is completed before final release of the 

drug product. The PET production 

facility should document the 

communication of this authoritative 

decision to the receiving facility. 

We are proposing special 

requirements for sterility testing because 

of the short half-lives of PET 

radionuclides. Proposed § 212.70(e) 

provides that: 

• Sterility testing need not be 

completed before final release but must 

be performed within 30 hours after 

completion of production. Sterility 

testing should normally be started 

within 24 hours after production. We 

propose the additional 6 hours in 

response to the concerns of some PET 

drug producers that a 24-hour test 

initiation period would coincide with 

the peak activity for PET production the 

following day. Proposed § 212.70(e) 

would allow the 30-hour period to be 

exceeded in certain cases, such as 

weekends or holidays, provided it is 

shown that the extended period will not 

affect the stability or viability of the 

contaminants in the product or 

otherwise yield a potentially inaccurate 

result. 

• Product samples must be tested 

individually and must not be pooled. 

• If the product fails the sterility test, 

all receiving facilities must be notified 

of the results immediately. 

• The notification must include any 

appropriate recommendations and must 

be documented. 

We are also including in this proposal 

a provision to allow the conditional 

final release of PET drug products under 

certain conditions. At the September 28, 

1999, public meeting on PET drug 

product CGMP, some comments stated 

that the regulations should allow PET 

drug producers to release a PET drug 

product if they experience an 

unanticipated, temporary failure of 

analytical equipment that prevents them 

from completing final release testing. 

The comments maintained that having 

duplicative equipment was difficult for 

smaller PET production facilities. They 

stated that having to cancel scheduled 

PET scans because of analytical 

equipment failure would inconvenience 

physicians and patients, some of whom 

may have traveled long distances to 

undergo the diagnostic procedure. 

In our preliminary draft proposed 

rule, we requested comments on 

whether the regulations should allow 

the conditional final release of PET drug 

products in case of equipment 

breakdown and, if so, what conditions 

should apply to such release. Nearly all 

the comments that we received on this 

matter requested that conditional final 

release be permitted. After 

55046 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

consideration of the comments, we 

propose to allow the conditional final 

release of PET drug products under 

certain conditions. 

Under proposed § 212.70(f), a PET 

drug producer that cannot complete one 

of the required finished product tests for 

a PET drug product because of a 

breakdown of analytical equipment may 

approve the conditional final release of 

the product if the conditions in 

proposed § 212.70(f)(1) through (f)(7) are 

met. These conditions would require the 

PET drug producer to do the following: 

• Have data to document that 

preceding consecutive batches, 

produced using the same method of 

production as the conditionally released 

batch, demonstrate that the 

conditionally released batch will likely 

meet the established specifications, 

• Determine that all other acceptance 

criteria are met, 

• Notify the receiving facility of the 

incomplete testing, 

• Retain a reserve sample of the 

conditionally released batch of drug 

product, 

• Complete the omitted test using the 

reserve sample after the analytical 

equipment is repaired and document 

that reasonable efforts have been made 

to ensure that the problem does not 

recur, 

• Immediately notify the receiving 

facility if an out-of-specification result 

is obtained when testing the reserve 

sample, and 

• Document all actions regarding the 

conditional final release of the drug 

product, including the justification for 

the release, all followup actions, results 

of completed testing, all notifications, 

and corrective actions to ensure that the 

equipment breakdown does not recur. 

Conditional final release should be a 

rare occurrence. In general, we believe 

that a PET drug producer should be 

prepared for equipment failures. 

Conditional final release would not be 

permissible when certain types of 

equipment fail. If a PET drug producer 

could not perform a radiochemical 

identity/purity test on the API of a PET 

drug product, conditional final release 

of a PET drug product would not be 

allowed. There are, however, certain 

tests, such as the gas chromatography 

(GC)-based residual solvent 

determination in FDG F 18, where an 

equipment failure could result in the 

authorization of a conditional final 

release if all the criteria in proposed 

§ 212.70(f) were met. Conditional final 

release would not generally be 

appropriate for certain tests where it is 

difficult to envision equipment failing 

or where equipment should be very easy 

to replace (for example, in the case of 

FDG F 18, the hydrogen-ion 

concentration (pH) test, test for 

kryptofix, thin layer chromatography 

based radiochemical identity and purity 

tests). Alternate test methods can be 

developed and used when these 

problems occur, so conditional final 

release should not be necessary except 

in very rare circumstances. Repeated 

conditional final releases based on the 

unavailability of equipment that is 

difficult to envision failing or that is 

easily replaced could be considered to 

be a failure to take ‘‘reasonable efforts * 

* * to ensure that the problem does not 

recur’’ and could lead to FDA taking 

enforcement action. 

M. Actions To Be Taken if Product Does 

Not Conform to Specifications 

Proposed § 212.71 answers the 

question ‘‘What actions must I take if a 

batch of PET drug product does not 

conform to specifications?’’ Proposed 

§ 212.71(a) states that: 

• If a batch of a PET drug product 

does not conform to specifications, the 

PET drug producer must reject it. 

• The producer must identify and 

segregate the nonconforming product to 

avoid mixups. 

• The producer must have and follow 

procedures to investigate the causes of 

the nonconforming product. 

• The investigation must include 

examination of processes, operations, 

records, complaints, and other relevant 

sources of information concerning the 

nonconforming product. 

Under the proposal, PET drug 

producers also would be required to: 

• Document the investigation of a PET 

drug product that does not conform to 

specifications, including the results of 

the investigation and what happened to 

the rejected PET drug product (proposed 

§ 212.71(b)), and 

• Take action to correct any identified 

problems to prevent recurrence of a 

nonconforming product or other quality 

problem (proposed § 212.71(c)). 

PET drug producers would be 

permitted, if appropriate, to reprocess a 

batch of a PET drug product that does 

not conform to specifications (proposed 

§ 212.71(d)). To reprocess material that 

does not meet acceptance criteria: 

• The producer must follow 

preestablished procedures (set forth in 

production and process controls) and 

• The finished product must conform 

to specifications, except for sterility, 

before final release. 

Examples of reprocessing could 

include a second passage through a 

purification column to remove an 

impurity or a second passage through a 

filter if the original filter failed the 

integrity test. 

N. Labeling and Packaging 

Proposed § 212.80 answers the 

question ‘‘What are the requirements 

associated with labeling and packaging 

PET drug products?’’ Under proposed 

§ 212.80, the following requirements 

would apply: 

• PET drug products must be suitably 

labeled and packaged to protect the 

product from alteration, contamination, 

and damage during the established 

conditions of shipping, distribution, 

handling and use (proposed § 212.80(a)). 

• Labels must be legible and applied 

so they will remain legible and affixed 

during the established conditions of 

processing, storage, handling, 

distribution, and use (proposed 

§ 212.80(b)). 

• Information stated on each label 

must also be contained in each batch 

production record (proposed 

§ 212.80(c)). 

• Labeling and packaging operations 

must be controlled to prevent product 

and labeling mixups (proposed 

§ 212.80(d)). 

O. Distribution Controls 

Proposed § 212.90 answers the 

question ‘‘What actions must I take to 

control the distribution of PET drug 

products?’’ This section would 

primarily apply to PET production 

facilities that distribute PET drug 

products beyond the immediate vicinity 

of the production site. Under proposed 

§ 212.90, PET drug producers would be 

required to: 

• Establish, maintain, and follow 

written procedures for the control of 

distribution of PET drug products 

shipped from the PET production 

facility to ensure that shipping will not 

adversely affect the identity, purity, or 

quality of the PET drug product 

(proposed § 212.90(a)). 

• Maintain distribution records for 

each PET drug product (proposed 

§ 212.90(b)), including the following 

information: 

—Name, address, and telephone 

number of the receiving facility that 

received each batch of a PET drug 

product, 

—Name and quantity of the PET drug 

product shipped, 

—Lot number, control number, or 

batch number for the PET drug product 

shipped, and 

—Date and time the PET drug product 

was shipped. 

P. Complaint Handling 

Proposed § 212.100 answers the 

question ‘‘What do I do if I receive a 

complaint about a PET drug product 

produced at my facility?’’ We propose 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55047 

the following requirements regarding 

complaints: 

• PET drug producers must develop 

and follow written procedures for the 

receipt and handling of all complaints 

concerning a PET drug product 

(proposed § 212.100(a)). 

• The procedures must include review 

by a designated person of any complaint 

involving the possible failure of a PET 

drug product to meet any of its 

specifications and an investigation to 

determine the cause of the failure 

(proposed § 212.100(b)). 

• Producers must maintain a written 

record of each complaint in a file 

designated for PET drug product 

complaints (proposed § 212.100(c)), 

including the following information: 

—Name and strength of the PET drug 

product, 

—Batch number, 

—Name of the complainant, 

—Date the complaint was received, 

—Nature of the complaint, 

—Response to the complaint, and 

—Findings of any investigation and 

followup. 

• PET drug products that are returned 

because of a complaint may not be 

reprocessed and must be destroyed in 

accordance with applicable Federal and 

State law (proposed § 212.100(d)). 

Q. Records 

Proposed § 212.110 answers the 

question ‘‘How must I maintain records 

of my production of PET drug 

products?’’ Proposed § 212.110 would 

require that: 

• PET drug producers maintain all 

records at the PET production facility or 

another location that is reasonably 

accessible to responsible officials of the 

production facility and to employees of 

FDA designated to perform inspections 

(proposed § 212.110(a)). A reasonably 

accessible location is one that would 

enable the PET center to make requested 

records available to us in a reasonable 

period of time. 

• All records, including those not 

stored at the inspected establishment, be 

legible, stored to prevent deterioration 

or loss, and readily available for review 

and copying by FDA employees 

(proposed § 212.110(b)). 

• PET drug producers maintain all 

records and documentation referenced 

in part 212 for at least 1 year after the 

final release or conditional final release 

of a PET drug product (proposed 

§ 212.110(c)). 

III. Analysis of Economic Impacts 

We have considered the potential 

economic impact of this proposed rule 

under Executive Order 12866 and the 

Regulatory Flexibility Act (5 U.S.C. 

601–612), and the Unfunded Mandates 

Reform Act of 1995 (Public Law 104–4). 

Executive Order 12866 directs agencies 

to assess all costs and benefits of 

available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

the benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing, ‘‘any rule 

that includes any Federal mandate that 

may result in the expenditure by State, 

local, and tribal governments, in the 

aggregate, or by the private sector, of 

$100,000,000 or more (adjusted 

annually for inflation) in any one year.’’

The current threshold after adjustment 

for inflation is $115 million, using the 

most current (2003) Implicit Price 

Deflator for the Gross Domestic Product. 

FDA does not expect this proposed rule 

to result in any 1-year expenditure that 

would meet or exceed this amount. 

The agency has determined that this 

proposed rule is not an economically 

significant rule as described in the 

Executive order because annual impacts 

on the economy are substantially below 

$100 million. Under the Regulatory 

Flexibility Act, unless an agency 

certifies that a rule will not have a 

significant impact on a substantial 

number of small entities, the agency 

must analyze regulatory options that 

would minimize any significant 

economic impact of a rule on small 

entities. We project that the rule may 

have a significant effect on a substantial 

number of small entities. A regulatory 

flexibility analysis explaining this 

finding is presented in the following 

paragraphs. 

A. Regulatory Benefits 

The Modernization Act requires us to 

establish appropriate good 

manufacturing practices for PET drugs. 

Without minimum manufacturing 

standards, unintentionally inferior PET 

drug products may be produced for 

human use. The short half-life 

characteristic of PET drug products 

often limits extensive and complete 

finished product testing prior to 

administration to humans. Moreover, 

recalls are usually impossible due to 

this short half-life, which can range 

from minutes to hours. Most PET drug 

products are marketed without FDA 

approval, and we have not received any 

official reports of adverse events. 

Official reports that can be relied upon 

to demonstrate or project the actual 

number of adverse events related to 

these products therefore do not exist. 

Tracing infections possibly caused by 

contaminated PET drugs to patients is 

difficult since there are a multitude of 

other factors that can cause infections in 

hospitalized patients, as well as a time 

delay before infection presents itself. 

Lacking this information, we are unable 

to quantify this proposal’s reduction of 

risk of adverse events associated with 

PET drug products and the 

accompanying increase in public health 

benefits. 

This proposed rule would create 

minimum manufacturing standards to 

ensure the safety, identity, strength, 

quality, and purity of PET drug 

products. Although, as discussed in 

section III.B of this document, all PET 

drug producers have adopted some level 

of good manufacturing practices or 

SOPs, not all producers currently are 

fully compliant with all USP standards. 

Therefore, compliance with the 

provisions of the proposed rule would 

ensure that all producers establish and 

implement adequate SOPs for 

production and quality control, 

including internal procedures for 

product quality audits, resulting in 

consistent production of quality 

products. Building quality into the 

production process would permit early 

detection and correction of problems 

and promote continuous improvement. 

Activities such as developing 

specifications may result in increased 

reliability and uniformity of PET drug 

products to patients. Ultimately, this 

rule would be expected to result in a 

reduction in adverse reactions to PET 

drug products and an increase in overall 

benefit to the public health. 

B. Regulatory Costs 

All PET drug producers have already 

adopted some level of good 

manufacturing practices or SOPs, 

although the specificity of the written 

documents may vary. The 

Modernization Act requires that 

compounded PET drugs conform to USP 

compounding standards and official 

monographs for PET drugs until CGMP 

regulations are established for PET 

drugs. For producers already following 

required USP standards, we would 

expect average compliance costs 

associated with this proposal to be 

small. 

The proposed CGMP rule is expected 

to affect all PET drug producers, 

especially those affiliated with hospitals 

and academic medical centers, as well 

as the small number of unaffiliated 

regional producers that produce FDG F 

18. Most of the large corporate PET drug 

55048 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

producers and hospital PET drug 

producers associated with these 

corporate entities are expected to 

already comply to a great degree with 

the proposed CGMP rule. Based on our 

contacts with industry, we have made a 

general assessment of the current 

operational status of PET drug 

producers. 

For this cost analysis, we consulted 

with the PET community, including 

PET drug producers and professional 

associations, through direct contact as 

well as via public comments at public 

meetings and previously published 

preliminary proposed rules (for a full 

description of our interactions with the 

PET community regarding this proposed 

rule, see section I.B of this document). 

We visited six PET drug producers 

affiliated with academic medical centers 

and four commercial (corporate or 

regional) operations. Using the 

knowledge gained from these site visits, 

public meeting comments from industry 

members including the Academy of 

Molecular Imaging (AMI) (a primary 

professional organization for PET), and 

agency employee expertise in PET drug 

manufacturing procedures, we 

estimated the average level of effort 

needed to bring each of the different 

types of PET drug producer into 

compliance with this proposed rule. 

Compliance costs (labor costs) were 

then calculated using these estimated 

levels of effort. In effect, we projected 

compliance costs based on the expected 

additional labor above implicit baseline 

levels (based on information acquired 

through the site visits by FDA officials). 

The estimated number of U.S. 

establishments producing PET drug 

products was created by combining an 

AMI-prepared list of PET centers with 

cyclotrons with a list of PET 

manufacturing facilities from the 

Society of Nuclear Imaging in Drug 

Development (which has since merged 

with the AMI), and adding additional 

facilities that we identified. This 

resulted in the projection that the 

proposed rule would affect 51 producers 

of PET drugs, operating 101 

establishments. Fifteen of these 

producers own or operate 65 

commercial establishments (16 of which 

are associated with academic hospitals). 

Of these 15 producers, 11 are regional 

or local unaffiliated producers that have 

begun to produce PET drug products in 

recent years. The other four commercial 

producers are corporations, each of 

which has multiple establishments. In 

total, these 4 corporate producers 

operate 48 establishments. The 

remaining 36 producers are part of 

academic or hospital institutions (see 

table 1 of this document). 

TABLE 1.—PET DRUG PRODUCERS

Producer 

Type No. of Producers No. of Establishments 

Hospital/Academic1 36 36 

CommercialRegional 11 17 

CommercialCorporate 2 4 48 

Total 51 101 

1Sixteen hospital producers operated by commercial firms are counted under Commercial-Corporate. 

2One producer may not be a corporation but is included here due to its multiple sites and longer history of PET drug production.

C. Compliance Requirements 

The proposed CGMP rule would 

impose compliance requirements 

resulting in two types of costs. From the 

date of publication of the final rule until 

the effective date, PET drug producers 

would incur one-time costs as each 

producer is brought into compliance. In 

succeeding years, each producer would 

be expected to incur only annual costs 

related to maintaining compliance. 

The following proposed sections 

contain the general requirements of the 

rule: 

• Section 212.10: Require qualified 

and trained personnel. 

• Section 212.20: Establish SOPs to 

define quality assurance. 

• Section 212.30: Establish SOPs and 

prepare documents related to 

installation, cleaning, qualification, and 

maintenance of facilities and 

equipment. 

• Section 212.40: Establish SOPs and 

prepare documents on the receipt, 

identification, storage, handling, testing, 

and approval of components and drug 

product containers and closures. 

Establish specifications for the 

components, containers, and closures. 

• Section 212.50: Establish written 

production and process control 

procedures (including in-process 

parameters) for production of a PET 

drug. Prepare master production record 

and batch record. 

• Section 212.60: Establish written 

procedures and schedules for the 

calibration, cleaning, and maintenance 

of laboratory testing equipment. 

Establish testing procedures for 

components, in-process materials and 

finished PET drug products. 

• Section 212.61: Establish written 

procedures to assess the stability 

characteristics of PET drug products. 

• Section 212.70: Establish 

acceptance criteria and written 

procedures to control the release of 

products. Prepare SOPs to establish 

system suitability of each test. Prepare 

documents to record tests performed on 

the PET drug product for final release. 

• Section 212.71: Establish 

procedures to investigate the reason for 

product nonconformance. 

• Section 212.80: Establish templates 

for labeling. 

• Section 212.90: Establish 

procedures and documents for the 

distribution of PET drugs. 

• Section 212.100: Establish 

procedures for the receipt and handling 

of complaints regarding a PET drug 

product. 

We expect some variation in the exact 

SOPs that would need to be created or 

revised to comply with the proposal. We 

expect that the various types of 

producers already comply with the 

proposed rule to different extents. The 

hospital PET drug producers and the 

independent regional commercial 

producers would likely require more 

time and effort to comply than would 

the group of corporate producers. 

Because of this, we estimated average 

compliance efforts for two separate 

groups based on expected current 

compliance levels—the corporate 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55049 

1The document is an attachment to the guidance 

for industry entitled ‘‘PET Drug Applications—

Content and Format for NDAs and ANDAs: 

Fludeoxyglucose F 18 Injection, Ammonia N 13 

Injection, Sodium Fluoride F 18 Injection’’

(available on the Internet at http://www.fda.gov/ 

cder/guidance). 

2Salary represents upper range of estimate 

(intended to not underestimate costs) provided at 

FDA site visit to a commercial PET drug producer 

on October 2, 2001. Although there is uncertainty 

concerning salaries paid by academic/hospital 

producers, we assume they would pay a salary 

similar to those of corporate producers. 

3Labor hour estimate from FDA site visit to a PET 

drug producer on October 2, 2001. 

producers and the hospital and regional 

commercial producers. 

1. Costs to Establish SOPs 

All PET drug producers are expected 

to incur some costs associated with 

interpreting the rule, determining the 

manner of compliance, and 

implementing the compliance method. 

These costs would be included in the 

efforts of a designated individual or 

individuals who would be primarily 

responsible for bringing each center into 

compliance. In this case, we have 

included any general administrative 

efforts in the time required to establish 

and write the SOPs for the previously 

listed requirements and to prepare 

templates for CGMP documentation. 

The document entitled ‘‘Sample 

Formats for Chemistry, Manufacturing, 

and Controls Sections’’1 provides 

guidance that may be helpful in 

preparing master production records, 

finished-product release testing records, 

and in-coming component tracking and 

testing records. PET drug producers 

would have the option of choosing their 

own format (and the amount of detail) 

as long as essential information required 

by the CGMPs is included. We believe 

that the CGMP guidance will aid PET 

drug producers that have little or no 

experience in creating these documents, 

helping to reduce compliance costs. 

We estimate that all hospital and 

regional commercial producers will 

need from 3 to 5 months to establish 

and write detailed SOPs that comply 

with this rule, even with the guidance 

provided and the understanding that 

these establishments currently operate 

under less-detailed SOPs. We assume 

that the employee responsible for 

writing the SOPs would be in a 

management position, either in quality 

assurance or elsewhere, with a salary of 

up to $100,000 per year. Including an 

additional 35 percent for employee 

benefits, the cost of an average 4-month 

effort would amount to $45,000 for each 

hospital and regional commercial PET 

drug producer.2

Although most corporate PET drug 

producers are believed to have a 

complete set of SOPs, we believe each 

would expend some time to verify its 

compliance with this proposal and 

make minor adjustments to their SOPs. 

We estimate that it would take, on 

average, 1 month for an individual to 

complete the same undertaking due to 

the current high compliance rates 

expected at the corporate 

establishments.3 This would result in a 

cost of approximately $11,250 per 

corporate PET drug producer, again 

using an estimated salary of $100,000 

per year plus benefits. We assume that 

corporate producers with multiple 

manufacturing sites would amend a 

single set of SOPs to cover all of their 

production sites. Since there are 

currently four corporate producers of 

PET drug products, the cost of the SOP 

revisions is estimated at $45,000 (4 

times $11,250). 

The SOP establishment or revision 

work could be performed by company 

personnel or an outside consultant or 

contractor. Although we predict that the 

use of an outside consultant or 

contractor would be more likely at the 

hospital and regional commercial PET 

drug producers, we would not expect 

the total cost of this compliance effort 

to vary considerably. 

Producers would also be expected to 

provide some additional training to at 

least one person on revisions made to 

current procedures to comply with the 

CGMP rule. While we do not think 

extensive training would be necessary at 

most establishments, our experience 

with PET drug production procedures 

and our 10 producer site visits leads us 

to believe that one person at each 

establishment could need up to 1 week 

of additional training. The cost of this 

additional training would amount to 

about $262,000 (101 establishments 

times 1 week at $135,000 per year). 

The total cost for initial compliance 

associated with writing the SOPs and 

creating document forms amounts to 

approximately $2.42 million. The 47 

hospital and regional commercial 

producers would incur a total of about 

$2.25 million (47 producers times 

$45,000 plus 53 establishments times 

$2,600). The 4 corporate producers 

would incur a total of about $170,000 (4 

producers times $11,250 plus 48 

establishments times $2,600). 

Annualizing the total one-time cost over 

5 years at a 7-percent discount rate 

results in annualized costs of about 

$591,000 (at a 3-percent discount rate, 

the costs are estimated to be about 

$529,000). 

Once procedures are established and 

documents are in place to record PET 

drug production and events associated 

with routine production of PET drugs, 

we would expect there to be some 

additional costs for the day-to-day 

implementation of the CGMP 

provisions. Periodic audits conducted 

by company personnel to ensure 

compliance with current procedures 

would have to be expanded to include 

any provisions with which the company 

was not already in compliance (for 

example, tracking and recordkeeping of 

incoming components, proper 

documentation of production and 

laboratory testing, tracking, 

investigation and documentation of 

products not meeting specifications). 

Additional time would also be spent 

updating the SOPs as the equipment 

and procedures used in the manufacture 

of PET drugs are upgraded and refined. 

We project the day-to-day 

implementation of the CGMP rules 

would require, at most, 1 to 2 additional 

hours per day for an individual at each 

hospital or regional commercial 

producer. Using the midpoint of this 

range would result in 2.25 additional 

months of labor each year. Using the 

same estimated annual salary ($100,000 

plus benefits), 2.25 months of labor 

equates to about $25,300 in annual costs 

to each PET drug production 

establishment, or about $1.34 million 

for all 53 hospital and regional 

commercial producer establishments. 

Our assessment of corporate PET drug 

producers is that they comply 

substantially with the proposed rule. 

For these producers, we project that 1 

production individual may expend an 

additional 1 month of effort over the 

course of each year (about 3 hours per 

week) in order to comply with the 

proposed rule. This month would result 

in each corporate PET center incurring 

about $11,250 in additional annual 

costs, totaling $540,000 for the 48 

corporate PET drug production 

establishments. Some producers would 

probably opt to use an outside 

consultant to manage the 

implementation of the new rules in the 

first year. Although we do not know 

how many producers would hire a 

consultant, we would not expect this to 

affect the total cost considerably, as the 

cost of the consultant would replace the 

cost of the company employee. Total 

annual costs for day-to-day 

implementation are estimated at $1.88 

million. 

Producers would also be expected to 

provide some additional training in 

future years on SOPs that were amended 

to comply with this CGMP rule. We 

would expect that this training (review 

for current employees as well as new 

employees) would be incorporated into 

55050 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

current training programs and therefore 

be less burdensome to producers. 

Nevertheless, we have included the cost 

for annual training for one person per 

establishment for one-half week. The 

cost of this additional training would 

amount to about $131,000 (101 

establishments times one-half week at 

$135,000 per year). 

Total annual costs associated with 

daily implementation and training 

amount to $2.01 million. The 53 

hospital and regional commercial 

establishments would incur a total of 

about $1.41 million (53 establishments 

times ($25,300 plus $1,300)). The 

average cost per facility for these 

provisions is $26,600. The 48 corporate 

production establishments would incur 

a total of about $602,000 (48 

establishments times ($11,250 plus 

$1,300)). The average cost per facility 

for these provisions is $12,600. 

TABLE 2.—CGMP COSTS

Rule Requirement No. of Estab. Labor (Months) Wage (Yr. Sal) 1 Cost 2

One-Time Costs 

Establish/Write SOPs 

Academic PET Producers 47 3 $135,000 $2,115,000 

Commercial PET Producers 4 1 $135,000 $45,000 

Training on SOPs 

Academic PET Producers 53 0.23 $135,000 $138,000 

Commercial PET Producers 48 0.23 $135,000 $125,000 

Total One-Time Costs $2,422,000 

Annual Costs 

Rule Requirement 

Daily Implementation, Audits, Updates 

Academic PET Products 53 2.25 $135,000 $1,342,000 

Commercial PET Products 48 1.0 $135,000 $540,000 

Training 

Academic PET Products 53 0.11 $135,000 $69,000 

Commercial PET Products 48 0.11 $135,000 $62,000 

Total Annual Costs $2,013,000 

1Salary includes 35 percent increase for benefits. 

2 Cost totals may not sum to rounding. 

2. Equipment Costs 

Based on at least 10 site visits to PET 

drug production facilities (both 

commercial and academic) by FDA 

personnel, we believe that the current 

laboratory facilities and equipment 

comply with the requirements of the 

proposed rule. Therefore, additional 

costs for laboratory space or equipment 

would not be incurred in complying 

with this regulation. Further, we believe 

that the qualification procedures for all 

current production equipment already 

occur as a matter of current business 

practice, and further equipment 

qualification procedures would not be 

required. 

3. Process Verification Costs 

In response to public comments to the 

preliminary draft proposed rule, 

modifications have been made to the 

process verification requirements. For 

this proposed rule, all PET drug product 

batches that undergo full finishedproduct testing to ensure that the 

product meets specifications would not 

be required to verify the production 

process. Currently, all NDA-approved 

PET drug products undergo finishedproduct testing. We believe that all PET 

drug products that will receive NDA 

approval in the foreseeable future will 

undergo finished-product testing. This 

is because it would be difficult, using 

current PET drug technology, to 

commercialize a PET drug product with 

a half-life of only minutes (which would 

prevent finished-product testing before 

release). Therefore, the proposed 

finished-product testing requirement 

would not be expected to impose any 

additional burden in the near term. In 

the future, however, it is possible that 

some small percentage of PET drugs 

products with NDA approval may 

submit only the initial sub-batch to 

finished-product testing before release. 

In such cases, producers would have to 

document their process verification 

procedures. Since we do not know how 

many, if any, PET drug products such as 

this would be approved in the future, 

we are unable to estimate any additional 

burden to the industry from process 

verification requirements. Nevertheless, 

we believe current business practice 

includes process verification, so any 

burden to producers would result from 

the need to document and organize the 

verification activities. 

4. Total Costs 

Total one-time costs are estimated at 

about $2.42 million (annualized at 

$591,000 over 5 years at 7 percent, and 

at $529,000 at 3 percent), and annual 

costs at about $2.01 million (see table 3 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55051 

of this document). The 53 hospital and 

regional commercial PET drug 

production establishments would incur 

about $2.25 million in one-time costs 

and $1.41 million in annual costs. The 

annualized (annualized one-time costs 

plus annual costs) cost per facility is 

estimated at about $35,700 at a 7- 

percent discount rate (and at $34,600 at 

3 percent). The 48 corporate PET 

production facilities would incur about 

$170,000 and $602,000 in one-time and 

annual costs, respectively. Total 

annualized (annualized one-time costs 

plus annual costs) costs per corporate 

establishment are estimated at about 

$13,400 at a 7-percent discount rate 

(and at $13,300 at 3 percent). Total 

annualized costs for all producers are 

estimated at $2,603,000 at a 7-percent 

discount rate (and at $2,541,000 at 3 

percent). 

TABLE 3.—PET DRUG PRODUCERS’ COMPLIANCE COSTS

One-Time Cost Annual Cost 

Hospital and Regional 

Commercial Establishments (53) $2,250,000 $1,410,000 

Corporate Establishments 

(48) $170,000 $602,000 

Total Cost 1 $2,420,000 $2,010,000 

Total Annualized Cost 2 2,600,000 

1Sum of costs may not equal total cost due to rounding. 

2Total annualized cost equal to total one-time cost discounted at 7-percent over 5 years plus total annual cost. Using a 3-percent discount rate 

reduces annualized costs by about $60,000. 

D. Growth of the PET Industry 

Although we do not have reliable 

estimates of the annual number of PET 

scans, the number has increased 

dramatically over the last 10 years, due 

at least in part to the increased numbers 

of disease conditions for which both 

public and private insurers have 

extended coverage. The number of 

establishments producing PET drug 

products, and FDG F 18 in particular, 

has also increased over this time period. 

As mentioned previously in this 

document, the majority of this growth in 

establishments reflects commercial 

operations that focus mainly or solely 

on FDG F 18 production. 

As demand for PET scan services and, 

therefore, PET drug products is 

expected to continue to increase, we 

have projected compliance costs over 

the next 10 years. We cannot 

confidently predict the number of 

additional PET drug production runs to 

meet the additional demand for PET 

services because of unknown factors. 

We do not know the number of 

additional diseases for which PET will 

be used and be reimbursable in the 

future or possible increases in size of 

production batches of PET drugs. 

Because PET drug producers are not 

currently producing to capacity, we 

believe that increased demand would be 

partially met by increasing production 

runs and batch sizes at existing 

establishments rather than proportional 

increases in the number of PET 

production establishments. We have 

therefore tentatively projected that 

average annual PET drug production 

establishment increases would range 

from 3 to 7 percent. Assuming this 

growth occurs evenly across producer 

types, this growth rate implies an 

increase in annualized costs from $2.60 

million currently to $3.40 to $4.79 

million in year ten (with a present value 

of $3.37 million at a 7-percent discount 

rate, and $3.64 million at a 3-percent 

discount rate). The PET drug risk 

reduction resulting from this rule would 

also apply to the additional volume of 

PET drug dosages implied by the 3 to 7 

percent annual growth rate in PET drug 

establishments. We request public 

comment and data on the annual 

number of PET scans and the expected 

future growth rate of PET drug products 

and production establishments subject 

to this proposed rule. 

E. Regulatory Flexibility Analysis 

The Regulatory Flexibility Act 

requires agencies to examine regulatory 

alternatives for small entities if that rule 

may have a significant impact on a 

substantial number of small entities. 

1. Objective of the Rule 

The implementation of this proposed 

rule, in accordance with the 

Modernization Act, would help ensure 

the safety, identity, strength, quality, 

and purity of PET drugs by establishing 

CGMP. The objective of the proposal is 

to reduce the risk to public health from 

adverse events that would be more 

likely to occur in the absence of 

adherence to CGMP for PET drug 

products. 

2. Definition of Small Entities 

A regulatory flexibility analysis (RFA) 

is required to estimate the number of 

small entities to which the proposed 

rule would apply. Under the Regulatory 

Flexibility Act (as amended), the 

definition of a small entity would 

include a small business as defined 

under the Small Business 

Administration (SBA) Act, nonprofit 

organizations, and small governmental 

jurisdictions. 

This rule would affect producers of 

PET drug products. These include 

certain hospitals, clinics, colleges and 

universities, and producers of in vivo 

diagnostic substances. According to the 

SBA, pharmaceutical preparation 

manufacturers with 750 or fewer 

employees, electromedical and 

electrotherapeutic apparatus 

manufacturers with 500 or fewer 

employees, drugs and druggists’

sundries wholesalers with 100 or fewer 

employees, and for-profit hospitals, 

clinics, colleges, and universities with 

$29 million or less in revenue are 

considered small businesses or entities. 

As stated earlier in this analysis, we 

identified 101 establishments operated 

by 51 PET drug producers. In over onethird of the cases, the PET drug product 

is produced by a hospital. In other 

instances, a corporate producer manages 

production under contract at one or 

more hospitals with cyclotrons. PET 

drug products are also produced at 

independent establishments by 

corporate producers or small regional 

producers. Total producer numbers 

continue to increase as the current 

corporate producers expand their 

55052 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

4 ‘‘AHA Guide to the Health Care Field, 1997–98 

Edition.’’ Healthcare Infosource, Inc., a subsidiary 

of the American Hospital Association. 

5 ‘‘The Nation: Colleges and Universities,’’ The 

Chronicle of Higher Education, 1999–2000, 

Almanac Issue, volume XVI, no. 1, p. 7, August 27, 

1999.) 

6 ‘‘Hospital Statistics,’’ table 3, pp. 8–9, Health 

Forum, An American Hospital Association 

Company, 1999. 

number of establishments and more 

independent regional producers enter 

the market. 

Using information from the American 

Hospital Association (AHA), we 

characterized 28 of the hospital 

producers as one of the following 

establishment types: 

• Government, non-Federal; 

• Government, Federal; 

• Non-Government not-for-profit; and 

• Investor-owned (for-profit).4

The AHA data did not include 

information for eight hospitals 

associated with large colleges or 

universities, but for this analysis, these 

were assumed to be not-for-profit 

because approximately 93 percent of all 

4-year higher education institutions are 

public or nonprofit institutions.5 Census 

data reports indicate that private 

hospitals (with more than 100 

employees) average gross revenues of 

about $36.8 million in 1997. This figure 

inflates to about $46.0 million using the 

Consumer Price Index (CPI) for medical 

care from 1997 to 2003. Considering that 

hospitals producing PET drug products 

would probably be larger than the 

average private hospital, we consider it 

very likely that the two private hospitals 

producing PET drugs have annual 

revenues over $29 million and would 

therefore not be considered small 

entities.6 In instances where PET drug 

producer information is not available, 

this analysis assumes that the PET drug 

producer is owned by the hospital in 

which it is located. 

Two of the three domestic corporate 

PET drug producers exceed the SBA 

employee limits within their respective 

business classifications to qualify as 

small businesses. Employee data were 

not available for the other domestic 

corporation or any of the 11 regional 

commercial producers, and we therefore 

assume that these may be small 

businesses. 

In total, the 51 identified producers of 

PET drug products are classified as 

follows: 6 Federal, 6 State, 34 small 

entities, and 5 large entities. Most of 

those that were considered small 

entities were classified as such because 

they are not-for-profit organizations, not 

because they met the employee or 

revenue limits for small businesses. It 

should be noted that an entity’s 

identification as small or large in this 

analysis does not necessarily indicate 

the volume of PET drug products it 

produces or the share of the market it 

holds. 

3. Impact on Small Entities 

Another requirement of an RFA is that 

we estimate the reporting, 

recordkeeping, and other compliance 

requirements on small entities. These 

requirements are detailed in the 

regulatory cost section of this preamble. 

Most, if not all, of the PET drug 

producers currently employ individuals 

who possess skills necessary to establish 

written procedures and prepare 

documentation as required by this rule. 

Some may choose, as mentioned above, 

to contract with an outside consultant to 

manage their compliance with the rule. 

At most, a single-establishment PET 

drug producer may incur one-time and 

annual costs of approximately $42,500 

and $25,300 per operating facility, 

respectively. The hospital and regional 

commercial producers would incur 

these higher per-facility costs because 

these establishments are expected to 

require more time to fully comply with 

the written procedure and 

recordkeeping requirements. The total 

of the maximum one-time and annual 

costs per producer equates to 

significantly less than 1 percent of the 

$88 million ($70.8 million inflated by 

the CPI for medical care from 1997 until 

2003) average annual gross revenue per 

nonprofit hospital. In addition, most of 

the hospitals that would be affected by 

this rule are affiliated with large 

universities whose total revenues are 

expected to be much higher than the 

$88 million figure cited. The estimated 

compliance cost would represent an 

even smaller portion of a percent of the 

entire university’s revenues. Revenue 

data were not available for the one 

possibly small corporate producer. This 

company would incur annual costs of 

approximately $62,700 and one-time 

costs of about $24,000. The 11 regional 

commercial producers are expected to 

incur one-time and annual costs of 

approximately $42,500 per producer 

and $25,300 per operating facility, 

respectively. We lack sufficient data to 

estimate the expected compliance costs 

as a percent of revenues for the regional 

commercial producers. Accordingly, it 

is possible that this proposed rule might 

have a significant effect on these small 

entities. We request comment on the 

extent of the effect that this rule will 

have on small entities, as well as 

additional data to profile PET drug 

producers. 

4. Other Federal Rules 

We are not aware of any relevant 

Federal rules that may duplicate, 

overlap, or conflict with the proposed 

rule. We request any information that 

may show otherwise. 

5. Description of Alternatives 

Several alternative provisions were 

considered but not adopted during the 

formulation of this rule. 

Traditional CGMP. We considered 

requiring PET drug producers to follow 

traditional CGMP (parts 210 and 211), 

but because these requirements would 

not allow the flexibility of PET drug 

CGMP detailed in this rule, the 

compliance costs would have been 

much greater under this alternative. The 

increased flexibility provided by this 

proposal is believed to be more 

appropriate because of the special 

characteristics of PET drugs, including 

their short half-life, small-scale 

manufacturing, and limited distribution 

environment. 

Specific identity testing of PET drug 

components. We were also interested in 

preventing contamination of PET drugs 

with components that may present a 

threat to public health. We therefore 

considered an alternative that would 

have required specific identity testing of 

PET drug components. In the May 2002 

preliminary proposed rule, we proposed 

that PET drug producers perform 

identity testing on raw materials that 

yield a drug substance and each inactive 

ingredient that is not a finished drug 

product. For FDG F 18 production, this 

would have required that mannose 

triflate be tested using either infrared 

spectroscopy (IR) or nuclear magnetic 

spectroscopy (NMR). We were unable to 

estimate the current level of compliance 

with this provision and therefore 

assumed the level to be zero, although 

it is possible that some PET drug 

producers currently perform this testing. 

Contact with PET drug producers 

indicated that the most probable method 

of compliance would have been to use 

a private laboratory to perform these 

tests under contract to the PET drug 

producers. Although some producers, 

especially hospital producers, may have 

IR testing equipment or could at least 

acquire these services from other 

departments at their institutions, we 

assumed they would also use the 

services of private laboratories. 

We estimated that producers receive 

from two to six lots of mannose triflate 

annually, and we believe the average 

number is around three. We have 

estimated the costs of the identity 

testing alternative assuming the use of 

NMR. Since testing could be done using 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55053 

either IR or NMR, with IR being 

somewhat less expensive, our estimates 

may overstate actual costs. Sample 

testing using the NMR is expected to 

cost up to $400 including the additional 

consultation and interpretation of the 

results with the technical staff. Testing 

three lots per year would result in a cost 

of $1,200 to each PET drug producer. 

We estimate that the total annual cost of 

identity testing the mannose triflate 

would have been about $121,000 for all 

PET drug producers. 

Identity testing of O 18 water would 

be performed through the cyclotron 

production run and is believed to be 

current practice. Therefore, no 

additional compliance costs would have 

been added for identity testing of the O 

18 water. 

Many of the hospital PET producers 

make a small number of additional PET 

drug products and may use other 

inactive ingredients. Almost all 

excipients and other components are 

marketed as finished drug products and 

would not have required identification 

testing under this alternative policy. We 

do not have enough data to estimate 

confidently the average number of 

additional PET drug products made by 

each establishment, but we 

conservatively project that two 

components would require identity 

testing at each of the 36 hospital PET 

producers as well as the 16 hospital 

producers operated by corporate 

producers. Identity testing of these 

additional components would have 

added an additional $2,400 per PET 

drug producer (2 components times 

$400 per test times 3 lots per year), 

resulting in a total of about $125,000 in 

costs to the industry ($2,400 times 36 

academic and hospital producers plus 

16 hospital producers operated by 

industry). The total cost of identity 

testing of components would have 

amounted to about $246,000 ($121,000 

for mannose triflate and $125,000 for 

the other components). The regional 

commercial PET drug producers and the 

corporate producers (excluding hospital 

producers operated by corporate 

entities) are believed to produce only 

FDG F 18. These producers would have 

incurred no additional costs under this 

alternative. 

PET drug producers commented that 

this alternative requirement would still 

be unnecessary and unduly burdensome 

because components and contaminants 

would be identified in finished-product 

testing and a certificate of analysis is 

provided by the supplier. We are in 

substantial agreement with these 

comments and have removed the 

component identity testing requirement 

from the proposed rule. 

Verification of the certificate of 

analysis. A related alternative, also 

proposed in the preliminary draft 

proposed rule of May 2002, would have 

required producers to verify the 

component specifications as written on 

the certificate of analysis. We believe 

that certificate of analysis verification 

would also be completed by 

independently testing the first three lots 

of each component received. We 

estimate that this would require contract 

testing of about three components for 

the hospital and regional commercial 

producers and about two components 

for the corporate producers. The total 

cost associated with verifying the 

reliability of the component suppliers 

would be a one-time cost of about 

$306,000. This would include $3,600 (3 

lots times 3 components times $400) for 

each hospital and regional commercial 

producer establishment for a total of 

$191,000, and about $2,400 (3 lots times 

2 components times $400) for corporate 

producer establishments for a total of 

about $115,000. Using a discount rate of 

7 percent over 5 years, the annualized 

cost would have amounted to about 

$75,000. 

Several PET drug producers 

commented that a requirement for 

verification of the supplier’s certificate 

of analysis would also be unnecessary 

and unduly burdensome. They stated 

that an established track record with a 

supplier showing no problems in 

finished-product test results should 

adequately establish the reliability of a 

supplier. As with the component 

identity testing alternative, we are in 

substantial agreement with PET drug 

producer comments and have not 

included the certificate of analysis 

verification requirement in the proposed 

rule. 

Validation of production and process 

controls. We also considered a 

requirement that production and 

process controls in every PET drug 

production process be validated 

according to established procedures. 

This provision was included in the 

preliminary draft proposed rule. It 

would have provided for retrospective 

validation in most cases, which would 

have relied on a review of historical 

data to show that each process is 

sufficiently capable of yielding batches 

meeting specifications. PET drug 

producers commented that this 

provision would be unnecessarily 

burdensome for those producers 

without written validation protocols, 

and finished-product testing would 

alleviate the safety concerns. After 

considering these comments, we 

decided not to include this provision in 

the proposed rule. While we did not 

calculate a separate cost for this 

provision, we believe it could have been 

burdensome for some producers. 

Audit trail capabilities. Another 

alternative would have been to require 

audit trail capabilities for all computeroperated systems to ensure the security 

of all production and nonproduction 

records. For nonproduction systems, 

software is available with audit trail 

capabilities and can be run alongside a 

widely used spreadsheet software 

program. This additional software 

system would provide PET producers 

with audit trail capabilities for tracking 

the receipt of drug components and inprocess materials, the distribution of 

finished products, batch records, 

complaint files, personnel training, and 

equipment maintenance. Prices for this 

software, including its base price, a 

validation package, and annual 

maintenance and support, are available 

on the Internet. The entire package 

would amount to about $7,000 in first 

year costs for a PET drug producer. A 

short training course provided by the 

software vendor would increase first 

year costs by about $1,600 for each 

producer. In order to account for some 

uncertainty and regional price 

differences for this or similar software 

programs, we increased the estimated 

costs about 50 percent. Compliance 

costs would therefore be expected to 

total about $12,900 for each PET drug 

producer ($10,400 for the base license, 

validation package, and first year 

maintenance and support plus about 

$2,400 for a short training program). We 

believe there is very little use of 

software providing secure audit trail 

capabilities. Therefore, we assumed that 

to comply with this provision, all PET 

drug producers would have had to 

purchase software providing secure 

audit trail capabilities. The total first 

year cost of this software would have 

been about $1,303,000 for the 101 PET 

drug production establishments. We 

further assumed that 50 percent of the 

producers would need to purchase the 

spreadsheet software at a cost of about 

$150 each, adding $7,600 to the 

software costs. Total one-time software 

costs for non-production equipment 

would have been about $1,310,000. 

The manufacturers of the audit-trail 

capable software would also have been 

expected to provide on-site maintenance 

and support of their systems, as 

mentioned above. PET drug producers 

would have been expected to purchase 

these maintenance and support systems. 

Based on our contact with one such 

software manufacturer, we estimated 

that the annual cost of such a system 

would be about $1,000 per year. In order 

to account for the uncertainty in using 

55054 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

only a single software application in 

estimating costs, we increased this 

amount to about $1,500 for each PET 

drug producer for this analysis. The 

estimated total cost for all 101 

producers would have been about 

$152,000 annually. 

We also considered requiring the 

radiochemical synthesis apparatus, as 

well as the HPLC and GC equipment, to 

have secure audit trail software systems 

with electronic signature capabilities. 

We believe that most of this equipment 

and programming software currently 

provides date, time, and employee 

identification capabilities. However, for 

at least some producers we believe that 

a software update would be required to 

provide, at a minimum, file deletion 

prevention capabilities. While software 

packages are updated regularly in the 

industry, we did not have enough 

information to estimate the incremental 

cost of updating all types of production 

equipment software to include audit 

trail capabilities. Information on 

electronic recordkeeping, which would 

apply to electronic audit trails, may be 

found in 21 CFR part 11; Electronic 

Records; Electronic Signatures and the 

draft guidance document entitled ‘‘PET 

Drug Products—Current Good 

Manufacturing Practice (CGMP).’’ We 

invite public comment and data on the 

scope and cost of creating electronic 

audit trail capability, including data on 

current audit trail capabilities within 

the industry. 

The electronic audit trail 

requirements we have described were 

excluded from the proposed rule 

because we could not determine if the 

additional level of quality assurance 

would justify the additional compliance 

costs. We request public comment and 

data concerning the need for electronic 

audit trail requirements as part of the 

CGMPs for PET drug products. 

IV. Environmental Impact 

We have determined under 21 CFR 

25.30(j) that this action is of a type that 

does not individually or cumulatively 

have a significant effect on the human 

environment. Therefore, neither an 

environmental assessment nor an 

environmental impact statement is 

required. 

V. The Paperwork Reduction Act of 

1995 

This proposed rule contains 

information collection requirements that 

are subject to review by OMB under the 

Paperwork Reduction Act of 1995 (the 

PRA) (44 U.S.C. 3501–3520). The title, 

description, and respondent description 

of the information collection provisions 

are shown below with an estimate of the 

annual reporting and recordkeeping 

burden. Included in the estimate is the 

time for reviewing instructions, 

searching existing data sources, 

gathering and maintaining the data 

needed, and completing and reviewing 

each collection of information. 

We invite comments on these topics: 

(1) Whether the collection of 

information is necessary for the proper 

performance of our functions, including 

whether the information will have 

practical utility; (2) the accuracy of our 

estimate of the burden of the proposed 

collection of information, including the 

validity of the methodology and 

assumptions used; 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. 

Title: Current Good Manufacturing 

Practice for Positron Emission 

Tomography Drugs 

Description: In accordance with the 

Modernization Act, the proposed rule 

would establish CGMP requirements for 

PET drugs. The proposed CGMP 

requirements are designed to take into 

account the unique characteristics of 

PET drugs, including their short halflives 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 estimate is based 

on there being 51 PET drug producers 

operating 36 hospital or academic 

facilities and 65 commercial facilities 

for a total of 101 PET drug production 

facilities. 

The proposed regulations are 

intended to ensure that approved PET 

drug products meet the requirements of 

the act as to safety, identity, strength, 

quality, and purity. The proposed 

regulations address the following 

matters: Personnel and resources; 

quality control; facilities and 

equipment; control of components, inprocess materials, and finished 

products; production and process 

controls; laboratory controls; acceptance 

criteria; labeling and packaging controls; 

distribution controls; complaint 

handling; and recordkeeping. 

The proposed CGMP regulations 

would establish several recordkeeping 

requirements for the production of PET 

drugs. In making our estimates of the 

time spent in complying with these 

proposed 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. 

Description of Respondents: 

Academic institutions, hospitals, 

commercial manufacturers, and other 

entities that produce PET drug products. 

Burden Estimate: Table 4 of this 

document provides an estimate of the 

annual recordkeeping burdens 

associated with the proposed rule. We 

are not proposing any reporting 

requirements. All of our recordkeeping 

burden estimates are based on there 

being 101 PET production facilities, 

with each of the 36 academic or hospital 

facilities producing 3 different PET drug 

products and each of the 65 commercial 

facilities producing 1 PET drug product, 

resulting in an estimated 173 total PET 

drug products. Our estimates are also 

based on a 250-day work year with an 

average yearly production of 500 

batches for each facility. We have also 

taken into account that time spent on 

recording procedures, processes, and 

specifications may be somewhat higher 

in the year in which these records are 

first established and correspondingly 

lower in subsequent years, when only 

updates and revisions would be 

required. 

A. Investigational and Research PET 

Drug Products 

Proposed § 212.5(b)(2) provides that 

for investigational PET drugs or drug 

products produced under an IND and 

research PET drugs or drug products 

produced with approval of an RDRC, the 

requirement under the act to follow 

current good manufacturing practice is 

met by complying with USP 28 Chapter 

<823>. We believe that PET production 

facilities producing drugs under INDs 

and RDRCs are currently substantially 

complying with the recordkeeping 

requirements of USP 28 Chapter <823> 

(see section 121(b) of the Modernization 

Act), and accordingly, we have not 

estimated any recordkeeping burden for 

this provision of this proposed rule. 

B. Batch Production and Control 

Records 

Proposed §§ 212.20(c) through (e), 

212.50(a) through (c), and 212.80(c) set 

out requirements for batch and 

production records as well as written 

control records. We estimate that it 

would take 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 

product produced. We also estimate that 

there will be a total of 173 PET drug 

products produced, with a total 

estimated recordkeeping burden of 

3,460 hours. We estimate that it would 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55055 

take a PET production facility an 

average of 30 minutes to complete a 

batch record for each of 500 batches. 

Our estimated burden for completing 

batch records is 25,250 hours. 

C. Equipment and Facilities Records 

Proposed §§ 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 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 1,515 hours. 

We estimate that recording maintenance 

and cleaning information would take 5 

minutes a day for each piece of 

equipment, with a total recordkeeping 

burden of 31,436 hours. 

D. Records of Components, Containers, 

and Closures 

Proposed §§ 212.20(c), 212.40(a) 

through (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 202 hours. We estimate that 

each facility would receive 36 

shipments annually and would spend 

10 minutes per shipment entering 

records. The annual burden for 

maintaining these records would be 604 

hours. 

E. Process Verification 

Proposed § 212.50(f)(2) would require 

that any process verification activities 

and results be recorded. Because 

process verification would only be 

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 have not 

estimated any recordkeeping burden for 

documenting process verification. 

F. Laboratory Testing Records 

Proposed §§ 212.20(c), 212.60(a) 

through (b) and (g), 212.61(a) through 

(b), and 212.70(a) through (b) and (d) set 

out requirements for documenting 

laboratory testing and specifications 

referred to in laboratory testing, 

including final release testing and 

stability testing. We estimate that each 

commercial PET production facility will 

need to establish procedures and create 

forms for 20 different tests for the 1 

product they produce. Each hospital 

and academic PET drug production 

facility will need to establish 

procedures and create forms for a total 

of 34 different tests for the 3 products 

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 would 

be 2,525 hours, and the annual burden 

for recording laboratory test results 

would be 8,383 hours. 

G. Sterility Test Failure Notices 

Proposed § 212.70(e) would require 

PET drug producers to notify all 

receiving facilities if a batch fails 

sterility tests. We also believe that 

sterility test failures will be a very rare 

occurrence, and we have estimated no 

recordkeeping burden for the notices. If 

such an event were to occur, we believe 

that PET drug producers would use 

e-mail and facsimile transmission to 

notify the receiving facilities of the test 

failure. Providing notice should take 

less than 1 hour per failure. 

H. Conditional Final Releases 

Proposed § 212.70(f) would require 

PET drug producers to document any 

conditional final releases of a product. 

We believe that conditional final 

releases would be fairly uncommon, but 

for purposes of the PRA, we have 

estimated that each PET production 

facility would have one conditional 

final release a year and would spend 1 

hour documenting the release and 

notifying receiving facilities. 

I. Out-of-Specification Investigations 

Proposed §§ 212.20(c) and 212.71(a) 

and (b) would 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 would take 1 hour 

annually to record and update these 

procedures for each PET production 

facility. We also estimate, for purposes 

of the PRA, that one out-of-specification 

investigation would be conducted at 

each facility each year and that it would 

take 1 hour to document the 

investigation. 

J. Reprocessing Procedures 

Proposed §§ 212.20(c) and 212.71(d) 

would require PET drug producers to 

establish and document procedures for 

reprocessing PET drug products. We 

estimate that it would take 1 hour a year 

to document these procedures for each 

PET production facility. We have not 

estimated 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. 

K. Distribution Records 

Proposed §§ 212.20(c) and 212.90(a) 

would require that written procedures 

regarding distribution of PET drug 

products be established and maintained. 

We estimate that it would take 1 hour 

annually to establish and maintain 

records of these procedures for each 

PET production facility. Proposed 

§ 212.90(b) would require that 

distribution records be maintained. We 

estimate that it would take 15 minutes 

to create an actual distribution record 

for each batch of PET drug products, 

with a total burden of 1,375 hours for 

all PET producers. 

L. Complaints 

Proposed §§ 212.20(c) and 212.100 

would 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 would take 1 hour annually 

for each PET production facility and 

that each facility would receive one 

complaint a year and would spend 30 

minutes recording how the complaint 

was dealt with. 

We invite comments on this analysis 

of information collection burdens. 

TABLE 4.—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1

21 CFR Section No. of 

Recordkeepers 

Annual Frequency 

per Recordkeeping Total Annual Records Hours per Recordkeeper Total Hours 

212.20(c) and (e), 

212.50(a) and (b) 

101 1.71 173 20 3,460 

55056 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

TABLE 4.—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1—Continued 

21 CFR Section No. of 

Recordkeepers 

Annual Frequency 

per Recordkeeping Total Annual Records Hours per Recordkeeper Total Hours 

212.20(d) and (e), 

212.50(c), 

212.80(c) 

101 500 50,500 .5 25,250 

212.20(c), 

212.30(b), 

212.50(d), 

212.60(f) 

101 15 1,515 1 1,515 

212.30(b), 

212.50(d), 

212.60(f) 

101 3,750 378,750 .083 31,436 

212.20(c), 

212.40(a) and (b) 

101 2 202 1 202 

212.40(e) 101 36 3,636 .166 604 

212.20(c), 

212.60(a) and (b), 

212.61(a), 

212.70(a), (b), and (d) 

101 25 2,525 1 2,525 

212.60(g), 

212.61(b), 

212.70(d)(2) and (d)(3) 

101 500 50,500 .166 8,383 

212.70(f) 101 1 101 1 101 

212.20(c), 212.71(a) 101 1 101 1 101 

212.71(b) 101 1 101 1 101 

212.20(c), 212.71(d) 101 1 101 1 101 

212.20(c), 212.90(a) 101 1 101 1 101 

212.90(b) 101 500 50,500 .25 12,625 

212.20(c), 212.100(a) 101 1 101 1 101 

212.100(b) and (c) 101 1 101 .5 50 

Total 86,656 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

In compliance with the PRA, we have 

submitted the information collection 

requirements of this proposed rule to 

OMB for review. Interested persons are 

requested to send comments regarding 

information collection to the Office of 

Information and Regulatory Affairs, 

OMB. 

Submit written comments on the 

information collection provisions to the 

Office of Information and Regulatory 

Affairs, OMB. OMB is still experiencing 

significant delays in the regular mail, 

including first class and express mail, 

and messenger deliveries are not being 

accepted. 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: Fumie Yokota, Desk Officer 

for FDA, FAX: 202–395–6974. 

VI. Federalism 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. We 

have tentatively determined that the 

rule does not contain policies that have 

substantial direct effects on the States, 

on the relationship between the 

National Government and the States, or 

on the distribution of power and 

responsibilities among the various 

levels of government. Consequently, we 

do not currently plan to prepare a 

federalism summary impact statement 

for this rulemaking procedure. We 

invite comments on the federalism 

implications of this proposed rule. 

VII. Proposed Effective Date 

In accordance with section 121 of the 

Modernization Act, we propose that any 

final rule that may issue based on this 

proposal become effective 2 years after 

the date on which we issue the final 

rule. 

VIII. Comments 

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments regarding this proposal. 

Submit a single copy of electronic 

comments or two paper copies of any 

mailed comments, except that 

individuals may submit one paper copy. 

Comments are to be identified with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55057 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday. 

List of Subjects 

21 CFR Part 210 

Drugs, Packaging and containers. 

21 CFR Part 211 

Drugs, Labeling, Laboratories, 

Packaging and containers, Prescription 

drugs, Reporting and recordkeeping 

requirements, Warehouses. 

21 CFR Part 212 

Current good manufacturing practice, 

Drugs, Incorporation by reference, 

Labeling, Laboratories, Packaging and 

containers, Positron emission 

tomography drugs, Prescription drugs, 

Reporting and recordkeeping 

requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Food and 

Drug Modernization Act of 1997, and 

under authority delegated to the 

Commissioner of Food and Drugs, it is 

proposed that 21 CFR chapter I be 

amended as follows: 

PART 210—CURRENT GOOD 

MANUFACTURING PRACTICE IN 

MANUFACTURING, PROCESSING, 

PACKING, OR HOLDING OF DRUGS; 

GENERAL 

1. The authority citation for 21 CFR 

part 210 continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264. 

§ 210.1 [Amended] 

2. Amend § 210.1(a), (b), and (c) by 

removing the phrase ‘‘211 through 226’’

each time it appears and by adding in 

its place the phrase ‘‘211, 225, and 226’’. 

§ 210.2 [Amended] 

3. Amend § 210.2(a) and (b) by 

removing the phrase ‘‘211 through 226’’

both times it appears and by adding in 

its place the phrase ‘‘211, 225, and 226’’. 

§ 210.3 [Amended] 

4. Amend § 210.3 in paragraphs (a) 

and (b) introductory text by removing 

the phrase ‘‘211 through 226’’ and 

adding in its place the phrase ‘‘211, 225, 

and 226’’. 

PART 211—CURRENT GOOD 

MANUFACTURING PRACTICE FOR 

FINISHED PHARMACEUTICALS 

5. The authority citation for 21 CFR 

part 211 continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264. 

6. Amend § 211.1 by revising 

paragraph (a) to read as follows: 

§ 211.1 Scope. 

(a) The regulations in this part contain 

the minimum current good 

manufacturing practice for preparation 

of drug products (excluding positron 

emission tomography drug products) for 

administration to humans or animals. 

* * * * * 

7. Add part 212 to read as follows: 

PART 212—CURRENT GOOD 

MANUFACTURING PRACTICE FOR 

POSITRON EMISSION TOMOGRAPHY 

DRUGS 

Subpart A—General Provisions 

Sec. 

212.1 What are the meanings of the 

technical terms used in these 

regulations? 

212.2 What is current good 

manufacturing practice for PET drugs? 

212.5 To what drugs do the regulations 

in this part apply? 

Subpart B—Personnel and Resources 

212.10 What personnel and resources 

must I have? 

Subpart C—Quality Assurance 

212.20 What activities must I perform to 

ensure product quality? 

Subpart D—Facilities and Equipment 

212.30 What requirements must my 

facilities and equipment meet? 

Subpart E—Control of Components, 

Containers, and Closures 

212.40 How must I control the 

components I use to produce PET drugs 

and the containers and closures I 

package them in? 

Subpart F—Production and Process 

Controls 

212.50 What production and process 

controls must I have? 

Subpart G—Laboratory Controls 

212.60 What requirements apply to the 

laboratories where I test components, 

in-process materials, and finished PET 

drug products? 

212.61 What must I do to ensure the 

stability of my PET drug products 

through expiry? 

Subpart H—Finished Drug Product 

Controls and Acceptance Criteria 

212.70 What controls and acceptance 

criteria must I have for my finished PET 

drug products? 

212.71 What actions must I take if a 

batch of PET drug product does not 

conform to specifications? 

Subpart I—Packaging and Labeling 

212.80 What are the requirements 

associated with labeling and packaging 

PET drug products? 

Subpart J—Distribution 

212.90 What actions must I take to 

control the distribution of PET drug 

products? 

Subpart K—Complaint Handling 

212.100 What do I do if I receive a 

complaint about a PET drug product 

produced at my facility? 

Subpart L—Records 

212.110 How must I maintain records of 

my production of PET drug products? 

Authority: 21 U.S.C. 321, 351, 352, 355, 

371, 374; Sec. 121, Pub. L. 105–115, 111 Stat. 

2296. 

Subpart A—General Provisions 

§ 212.1 What are the meanings of the 

technical terms used in these regulations? 

The following definitions apply to 

words and phrases as they are used in 

this part. Other definitions of these 

words may apply when they are used in 

other parts of this chapter. 

Acceptance criteria means numerical 

limits, ranges, or other criteria for tests 

that are used for or in making a decision 

to accept or reject a unit, lot, or batch 

of a PET drug product. 

Act means the Federal Food, Drug, 

and Cosmetic Act, as amended (21 

U.S.C. 321 et seq.). 

Active pharmaceutical ingredient 

means a substance that is intended for 

incorporation into a finished PET drug 

product and is intended to furnish 

pharmacological activity or other direct 

effect in the diagnosis or monitoring of 

a disease or a manifestation of a disease 

in humans, but does not include 

intermediates used in the synthesis of 

such substance. 

Batch means a specific quantity of 

PET drug product intended to have 

uniform character and quality, within 

specified limits, that is produced 

according to a single production order 

during the same cycle of production. 

Batch production and control record 

means a unique record that references 

an accepted master production and 

control record and documents specific 

details on production, labeling, and 

quality control for a single batch of a 

PET drug product. 

Component means any ingredient 

intended for use in the production of a 

55058 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

PET drug product, including any 

ingredients that may not appear in the 

final PET drug product. 

Conditional final release means a 

final release made prior to completion 

of a required finished product test 

because of a breakdown of analytical 

equipment. 

Final release means the authoritative 

decision by a responsible person in a 

PET production facility to permit the 

use of a batch of a PET drug product in 

humans. 

Inactive ingredient means any 

intended component of the PET drug 

product other than the active 

pharmaceutical ingredient. 

In-process material means any 

material fabricated, compounded, 

blended, or derived by chemical 

reaction that is produced for, and is 

used in, the preparation of a PET drug 

product. 

Lot means a batch, or a specifically 

identified portion of a batch, having 

uniform character and quality within 

specified limits. In the case of a PET 

drug product produced by continuous 

process, a lot is a specifically identified 

amount produced in a unit of time or 

quantity in a manner that ensures its 

having uniform character and quality 

within specified limits. 

Lot number, control number, or batch 

numbermeans any distinctive 

combination of letters, numbers, or 

symbols from which the complete 

history of the production, processing, 

packing, holding, and distribution of a 

batch or lot of a PET drug product can 

be determined. 

Master production and control record 

means a compilation of records 

containing the procedures and 

specifications for the production of a 

PET drug product. 

Material release means the 

authoritative decision by a responsible 

person in a PET production facility to 

permit the use of a component, 

container and closure, in-process 

material, packaging material, or labeling 

in the production of a PET drug 

product. 

PET means positron emission 

tomography. 

PET drug means a radioactive drug 

that exhibits spontaneous disintegration 

of unstable nuclei by the emission of 

positrons and is used for providing dual 

photon positron emission tomographic 

diagnostic images. The definition 

includes any nonradioactive reagent, 

reagent kit, ingredient, nuclide 

generator, accelerator, target material, 

electronic synthesizer, or other 

apparatus or computer program to be 

used in the preparation of a PET drug. 

PET drug product means a finished 

dosage form that contains a PET drug, 

whether or not in association with one 

or more other ingredients. 

PET production facility means a 

facility that is engaged in the production 

of a PET drug product. 

Productionmeans the manufacturing, 

compounding, processing, packaging, 

labeling, reprocessing, repacking, 

relabeling, and testing of a PET drug 

product. 

Quality control means a system for 

maintaining the quality of active 

ingredients, PET drug products, 

intermediates, components that yield an 

active pharmaceutical ingredient, 

analytical supplies, and other 

components, including containerclosure systems and in-process 

materials, through procedures, tests, 

analytical methods, and acceptance 

criteria. 

Receiving facility means any hospital, 

institution, nuclear pharmacy, imaging 

facility, or other entity or part of an 

entity that accepts a PET drug product 

that has been given final release, but 

does not include a common or contract 

carrier that transports a PET drug 

product from a PET production facility 

to a receiving facility. 

Specifications means the tests, 

analytical procedures, and appropriate 

acceptance criteria to which a PET drug, 

PET drug product, component, 

container closure system, in-process 

material, or other material used in PET 

drug production must conform to be 

considered acceptable for its intended 

use. Conformance to specifications 

means that a PET drug, PET drug 

product, component, container closure 

system, in-process material, or other 

material used in PET drug production, 

when tested according to the described 

analytical procedures, meets the listed 

acceptance criteria. 

Strength means the concentration of 

the active pharmaceutical ingredient 

(radioactivity amount per volume or 

weight at the time of calibration). 

Verification means confirmation that 

an established method, process, or 

system meets predetermined acceptance 

criteria. 

§ 212.2 What is current good 

manufacturing practice for PET drugs? 

Current good manufacturing practice 

for PET drug products is the minimum 

requirements for the methods to be used 

in, and the facilities and controls used 

for, the production, quality control, 

holding, or distribution of PET drug 

products intended for human use. 

Current good manufacturing practice is 

intended to ensure that each PET drug 

product meets the requirements of the 

act as to safety and has the identity and 

strength, and meets the quality and 

purity characteristics, that it is 

supposed to have. 

§ 212.5 To what drugs do the regulations 

in this part apply? 

(a) Application solely to PET drug 

products. The regulations in this part 

apply only to the production, quality 

control, holding, and distribution of 

PET drug products. Any human drug 

product that does not meet the 

definition of a PET drug product must 

be manufactured in accordance with the 

current good manufacturing practice 

requirements in parts 210 and 211 of 

this chapter. The regulations in this part 

apply to all PET drug products for 

human use except for investigational 

and research PET drugs as described in 

paragraph (b) of this section. 

(b) Investigational and research PET 

drugs. The regulations in this part do 

not apply to investigational PET drugs 

or drug products for human use 

produced under an investigational new 

drug application in accordance with 

part 312 of this chapter and PET drugs 

or drug products produced with the 

approval of a Radioactive Drug Research 

Committee in accordance with part 361 

of this chapter. For such investigational 

and research PET drugs or drug 

products, the requirement under the act 

to follow current good manufacturing 

practice is met by producing PET drugs 

or drug products in accordance with 

Chapter 823, ‘‘Radiopharmaceuticals for 

Positron Emission Tomography—

Compounding,’’ of the 28th edition of 

the United States Pharmacopeia (2005), 

which is incorporated by reference. The 

Director of the Office of the Federal 

Register approves this incorporation by 

reference in accordance with 5 U.S.C. 

552(a) and 1 CFR part 51. You may 

obtain copies from the United States 

Pharmacopeial Convention, Inc., 12601 

Twinbrook Pkwy., Rockville, MD 20852, 

or you may examine a copy at the 

Center for Drug Evaluation and 

Research’s Division of Medical Library, 

5600 Fishers Lane, rm. 11B–40, 

Rockville, MD, or at the National 

Archives and Records Administration 

(NARA). For information on the 

availability of this material at NARA, 

call 202–741–6030, or go to: http:// 

www.archives.gov/federallregister/ 

codeloflfederallregulations/ 

ibrllocations.html. 

Subpart B—Personnel and Resources 

§ 212.10 What personnel and resources 

must I have? 

You must have a sufficient number of 

personnel with the necessary education, 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55059 

background, training, and experience to 

perform their assigned functions. You 

must have adequate resources, 

including facilities and equipment, to 

enable your personnel to perform their 

functions. 

Subpart C—Quality Assurance 

§ 212.20 What activities must I perform to 

ensure product quality? 

(a) Production operations. You must 

oversee production operations to ensure 

that each PET drug product meets the 

requirements of the act as to safety and 

has the identity and strength, and meets 

the quality and purity characteristics, 

that it is supposed to have. 

(b) Materials. You must examine and 

approve or reject components, 

containers, closures, in-process 

materials, packaging materials, labeling, 

and finished dosage forms to ensure 

compliance with procedures and 

specifications affecting the identity, 

strength, quality, or purity of a PET drug 

product. 

(c) Specifications and processes. You 

must approve or reject, before 

implementation, any initial 

specifications, methods, processes, or 

procedures, and any proposed changes 

to existing specifications, methods, 

processes, or procedures, to ensure that 

they maintain the identity, strength, 

quality, and purity of a PET drug. You 

must demonstrate that any change does 

not adversely affect the identity, 

strength, quality, or purity of any PET 

drug product. 

(d) Production records. You must 

review production records to determine 

whether errors have occurred. If errors 

have occurred, or a production batch or 

any component of the batch fails to meet 

any of its specifications, you must 

determine the need for an investigation, 

conduct investigations when necessary, 

and take appropriate corrective actions. 

(e) Quality assurance. You must 

establish and follow written quality 

assurance procedures. 

Subpart D—Facilities and Equipment 

§ 212.30 What requirements must my 

facilities and equipment meet? 

(a) Facilities. You must provide 

adequate facilities to ensure the orderly 

handling of materials and equipment, 

the prevention of mixups, and the 

prevention of contamination of 

equipment or product by substances, 

personnel, or environmental conditions 

that could reasonably be expected to 

have an adverse effect on product 

quality. 

(b) Equipment procedures. You must 

implement procedures to ensure that all 

equipment that could reasonably be 

expected to adversely affect the identity, 

strength, quality, or purity of a PET drug 

product, or give erroneous or invalid 

test results when improperly used or 

maintained, is clean, suitable for its 

intended purposes, properly installed, 

maintained, and capable of repeatedly 

producing valid results. You must 

document your activities in accordance 

with these procedures. 

(c) Equipment construction and 

maintenance. Equipment must be 

constructed and maintained so that 

surfaces that contact components, inprocess materials, or PET drug products 

are not reactive, additive, or absorptive 

so as to alter the quality of PET drug 

products. 

Subpart E—Control of Components, 

Containers, and Closures 

§ 212.40 How must I control the 

components I use to produce PET drugs 

and the containers and closures I package 

them in? 

(a) Written procedures. You must 

establish, maintain, and follow written 

procedures describing the receipt, login, 

identification, storage, handling, testing, 

and acceptance and/or rejection of 

components and drug product 

containers and closures. The procedures 

must be adequate to ensure that the 

components, containers, and closures 

are suitable for their intended use. 

(b) Written specifications. You must 

establish appropriate written 

specifications for the identity, quality, 

and purity of components and for the 

identity and quality of drug product 

containers and closures. 

(c) Examination and testing. Upon 

receipt, each lot of components and 

containers and closures must be 

uniquely identified and tested or 

examined to determine whether the lot 

complies with your specifications. You 

must not use in PET drug product 

production any lot that does not meet its 

specifications, including any expiration 

date if applicable, or that has not yet 

received its material release. Any 

incoming lot must be appropriately 

designated as either quarantined, 

accepted, or rejected. You must use a 

reliable supplier as a source of each lot 

of each component, container, and 

closure. 

(1)(i) If you conduct finished-product 

testing of a PET drug product that 

includes testing to ensure that the 

correct components have been used, you 

must determine that each lot of 

incoming components used in that PET 

drug product complies with written 

specifications by examining a certificate 

of analysis provided by the supplier. 

You are not required to perform a 

specific identity test on any of those 

components. 

(ii) If you do not conduct finishedproduct testing of a PET drug product 

that ensures that the correct components 

have been used, you must conduct 

identity testing on each lot of a 

component that yields an active 

ingredient and each lot of an inactive 

ingredient used in that PET drug 

product. This testing must be conducted 

using tests that are specific to each 

component that yields an active 

ingredient and each inactive ingredient. 

For any other component, such as a 

solvent or reagent, that is not the subject 

of finished-product testing, you must 

determine that each lot complies with 

written specifications by examining a 

certificate of analysis provided by the 

supplier; if you use such a component 

to prepare an inactive ingredient on site, 

you must perform an identity test on the 

components used to make the inactive 

ingredient before the components are 

released for use. However, if you use as 

an inactive ingredient a product that is 

approved under section 505 of the act 

(21 U.S.C. 355) and is marketed as a 

finished drug product intended for 

intravenous administration, you need 

not perform a specific identity test on 

that ingredient. 

(2) You must examine a representative 

sample of each lot of containers and 

closures for conformity to its written 

specifications. You must perform at 

least a visual identification of each lot 

of containers and closures. 

(d) Handling and storage. You must 

handle and store components, 

containers, and closures in a manner 

that prevents contamination, mixups, 

and deterioration and ensures that they 

are and remain suitable for their 

intended use. 

(e) Records. You must keep a record 

for each shipment of each lot of 

components, containers, and closures 

that you receive. The record must 

include the identity and quantity of 

each shipment, the supplier’s name and 

lot number, the date of receipt, the 

results of any testing performed, the 

disposition of rejected material, and the 

expiration date (where applicable). 

Subpart F—Production and Process 

Controls 

§ 212.50 What production and process 

controls must I have? 

You must have adequate production 

and process controls to ensure the 

consistent production of a PET drug 

product that meets the applicable 

standards of identity, strength, quality, 

and purity. 

55060 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

(a) Written control procedures. You 

must have written production and 

process control procedures to ensure 

and document that all key process 

parameters are controlled and that any 

deviations from the procedures are 

justified. 

(b) Master production and control 

records. You must have master 

production and control records that 

document all steps in the PET drug 

product production process. The master 

production and control records must 

include the following information: 

(1) The name and strength of the PET 

drug product; 

(2) If applicable, the name and 

radioactivity or other measurement of 

each active pharmaceutical ingredient 

and each inactive ingredient per batch 

or per unit of radioactivity or other 

measurement of the drug product, and 

a statement of the total radioactivity or 

other measurement of any dosage unit; 

(3) A complete list of components 

designated by names and codes 

sufficiently specific to indicate any 

special quality characteristic; 

(4) Identification of all major pieces of 

equipment used in production; 

(5) An accurate statement of the 

weight or measurement of each 

component, using the same weight 

system (metric, avoirdupois, or 

apothecary) for each component. 

Reasonable variations are permitted in 

the amount of component necessary if 

they are specified in the master 

production and control records; 

(6) A statement of acceptance criteria 

on radiochemical yield, i.e., the 

minimum percentage of yield beyond 

which investigation and corrective 

action are required; 

(7) Complete production and control 

instructions, sampling and testing 

procedures, specifications, special 

notations, and precautions to be 

followed; and 

(8) A description of the PET drug 

product containers, closures, and 

packaging materials, including a 

specimen or copy of each label and all 

other labeling. 

(c) Batch production and control 

records. Each time a batch of a PET drug 

product is produced, a unique batch 

production and control record must be 

created. The batch production record 

must include the following information: 

(1) Name and strength of the PET drug 

product; 

(2) Identification number or other 

unique identifier of the specific batch 

that was produced; 

(3) The name and radioactivity or 

other measure of each active 

pharmaceutical ingredient and each 

inactive ingredient per batch or per unit 

of radioactivity or other measurement of 

the drug product; 

(4) Each major production step 

(obtained from the approved 

appropriate master production and 

control record); 

(5) Weights (or other measure of 

quantity) and identification codes of 

components; 

(6) Dates and time of production 

steps; 

(7) Identification of major pieces of 

equipment used in production of the 

batch; 

(8) Testing results; 

(9) Labeling; 

(10) Initials or signatures of persons 

performing or checking each significant 

step in the operation; and 

(11) Results of any investigations 

conducted. 

(d) Area and equipment checks. The 

production area and all equipment in 

the production area must be checked to 

ensure cleanliness and suitability 

immediately before use. A record of 

these checks must be kept. 

(e) In-process materials controls. 

Process controls must include control of 

in-process materials to ensure that the 

materials are controlled until required 

tests or other verification activities have 

been completed or necessary approvals 

are received and documented. 

(f) Process verification. (1) For a PET 

drug product for which each entire 

batch undergoes full finished-product 

testing to ensure that the product meets 

all specifications, process verification, 

as described in paragraph (f)(2) of this 

section, is not required. 

(2) When the results of the production 

of an entire batch of a PET drug product 

are not fully verified through finishedproduct testing or when only the initial 

sub-batch in a series is tested, the PET 

drug producer must demonstrate that 

the process for producing the PET drug 

product is reproducible and is capable 

of producing a drug product that meets 

the predetermined acceptance criteria. 

Process verification activities and 

results must be documented. 

Documentation must include the date 

and signature of the individual(s) 

performing the verification, the 

monitoring and control methods and 

data, and the major equipment 

qualified. 

Subpart G—Laboratory Controls 

§ 212.60 What requirements apply to the 

laboratories where I test components, inprocess materials, and finished PET drug 

products? 

(a) Testing procedures. Each 

laboratory used to conduct testing of 

components, in-process materials, and 

finished PET drug products must have 

and follow written procedures for the 

conduct of each test and for the 

documentation of the results. 

(b) Specifications and standards. Each 

laboratory must have sampling and 

testing procedures designed to ensure 

that components, in-process materials, 

and PET drug products conform to 

appropriate standards, including 

established standards of identity, 

strength, quality, and purity. 

(c) Analytical methods. Laboratory 

analytical methods must be suitable for 

their intended use and must be 

sufficiently sensitive, specific, accurate, 

and reproducible. 

(d) Materials. The identity, purity, 

and quality of reagents, solutions, and 

supplies used in testing procedures 

must be adequately controlled. All 

solutions that you prepare must be 

properly labeled to show their identity 

and expiration date. 

(e) Equipment. All equipment used to 

perform the testing must be suitable for 

its intended purposes and capable of 

producing valid results. 

(f) Equipment maintenance. Each 

laboratory must have and follow written 

procedures to ensure that equipment is 

routinely calibrated, inspected, checked, 

and maintained, and that these activities 

are documented. 

(g) Test records. Each laboratory 

performing tests related to the 

production of a PET drug product must 

keep complete records of all tests 

performed to ensure compliance with 

established specifications and 

standards, including examinations and 

assays, as follows: 

(1) A description of the sample 

received for testing, including its 

source, the quantity, the batch or lot 

number, the date (and time, if 

appropriate) the sample was taken, and 

the date (and time, if appropriate) the 

sample was received for testing. 

(2) A description of each method used 

in the testing of the sample, a record of 

all calculations performed in connection 

with each test, and a statement of the 

weight or measurement of the sample 

used for each test. 

(3) A complete record of all data 

obtained in the course of each test, 

including the date and time the test was 

conducted, all graphs, charts, and 

spectra from laboratory instrumentation, 

properly identified to show the specific 

component, in-process material, or drug 

product for each lot tested. 

(4) A statement of the results of tests 

and how the results compare with 

established acceptance criteria. 

(5) The initials or signature of the 

person performing the test and the date 

on which the test was performed. 

Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 55061 

§ 212.61 What must I do to ensure the 

stability of my PET drug products through 

expiry? 

(a) Stability testing program. You 

must establish, follow, and maintain a 

written testing program to assess the 

stability characteristics of your PET 

drug products. The test methods must 

be reliable, meaningful, and specific. 

The samples tested for stability must be 

representative of the lot or batch from 

which they were obtained and must be 

stored under suitable conditions. 

(b) Storage conditions and expiration 

dates. The results of such stability 

testing must be documented and used in 

determining appropriate storage 

conditions and expiration dates and 

times for each PET drug product you 

produce. 

Subpart H—Finished Drug Product 

Controls and Acceptance Criteria 

§ 212.70 What controls and acceptance 

criteria must I have for my finished PET 

drug products? 

(a) Specifications. You must establish 

specifications for each batch of a PET 

drug product, including criteria for 

determining identity, strength, quality, 

purity, and, if appropriate, sterility and 

pyrogenicity. 

(b) Test procedures. Before you 

implement a new test procedure in a 

specification, you must establish and 

document the accuracy, sensitivity, 

specificity, and reproducibility of the 

procedure. If you use an established 

compendial test procedure in a 

specification, you must first verify and 

document that the test works under the 

conditions of actual use. 

(c) Conformance to specifications. 

Before final release, you must conduct 

laboratory testing of a representative 

sample of each batch of a PET drug 

product to ensure that the product 

conforms to specifications, except for 

sterility. For a PET drug product 

produced in sub-batches, at least each 

initial sub-batch that is representative of 

the entire batch must conform to 

specifications, except for sterility, before 

final release. 

(d) Final release procedures. You 

must establish and follow procedures to 

ensure that a PET drug product is not 

given final release until the following is 

done: 

(1) Appropriate laboratory testing 

under paragraph (a) of this section is 

completed; 

(2) Associated laboratory data and 

documentation are reviewed and they 

demonstrate that the PET drug product 

meets specifications, except for sterility; 

and 

(3) A designated qualified individual 

authorizes final release by dated 

signature. 

(e) Sterility testing. Sterility testing 

need not be completed before final 

release but must be started within 30 

hours after completion of production. 

The 30-hour requirement may be 

exceeded due to a weekend or holiday. 

If the sample for sterility testing is held 

longer than indicated, you must 

demonstrate that the longer period does 

not adversely affect the sample and the 

test results obtained will be equivalent 

to test results that would have been 

obtained if the test had been started 

within the 30-hour time period. Product 

samples must be tested individually and 

must not be pooled. If the product fails 

the sterility test, all receiving facilities 

must be notified of the results 

immediately. The notification must 

include any appropriate 

recommendations. The notification 

must be documented. 

(f) Conditional final release. (1) If you 

cannot complete one of the required 

finished product tests for a PET drug 

product because of a breakdown of 

analytical equipment, you may approve 

the conditional final release of the 

product if you meet the following 

conditions: 

(i) You have data documenting that 

preceding consecutive batches, 

produced using the same methods used 

for the conditionally released batch, 

demonstrate that the conditionally 

released batch will likely meet the 

established specifications; 

(ii) You determine that all other 

acceptance criteria are met; 

(iii) You immediately notify the 

receiving facility of the incomplete 

testing; 

(iv) You retain a reserve sample of the 

conditionally released batch of drug 

product; 

(v) You complete the omitted test 

using the reserve sample after the 

analytical equipment is repaired and 

you document that reasonable efforts 

have been made to ensure that the 

problem does not recur; 

(vi) If you obtain an out-ofspecification result when testing the 

reserve sample, you immediately notify 

the receiving facility; and 

(vii) You document all actions 

regarding the conditional final release of 

the drug product, including the 

justification for the release, all followup 

actions, results of completed testing, all 

notifications, and corrective actions to 

ensure that the equipment breakdown 

does not recur. 

(2) Even if the criteria in paragraph 

(f)(1) of this section are met, you may 

not approve the conditional final release 

of the product if the breakdown in 

analytical equipment prevents the 

performance of a radiochemical 

identity/purity test. 

§ 212.71 What actions must I take if a 

batch of PET drug product does not 

conform to specifications? 

(a) Rejection of a nonconforming 

product. You must reject a batch of a 

PET drug product that does not conform 

to specifications. You must have and 

follow procedures to identify and 

segregate the product to avoid mixups. 

You must have and follow procedures to 

investigate the cause(s) of the 

nonconforming product. The 

investigation must include, but is not 

limited to, examination of processes, 

operations, records, complaints, and any 

other relevant sources of information 

concerning the nonconforming product. 

(b) Investigation. You must document 

the investigation of a PET drug product 

that does not meet specifications, 

including the results of the investigation 

and what happened to the rejected PET 

drug product. 

(c) Correction of problems. You must 

take action to correct any identified 

problems to prevent recurrence of a 

nonconforming product or other quality 

problem. 

(d) Reprocessing. If appropriate, you 

may reprocess a batch of a PET drug 

product that does not conform to 

specifications. If material that does not 

meet acceptance criteria is reprocessed, 

you must follow preestablished 

procedures (set forth in production and 

process controls) and the finished 

product must conform to specifications, 

except for sterility, before final release. 

Subpart I—Packaging and Labeling 

§ 212.80 What are the requirements 

associated with labeling and packaging PET 

drug products? 

(a) A PET drug product must be 

suitably labeled and packaged to protect 

the product from alteration, 

contamination, and damage during the 

established conditions of shipping, 

distribution, handling, and use. 

(b) Labels must be legible and applied 

so as to remain legible and affixed 

during the established conditions of 

processing, storage, handling, 

distribution, and use. 

(c) All information stated on each 

label must also be contained in each 

batch production record. 

(d) Labeling and packaging operations 

must be controlled to prevent labeling 

and product mixups. 

55062 Federal Register / Vol. 70, No. 181 / Tuesday, September 20, 2005 / Proposed Rules 

Subpart J—Distribution 

§ 212.90 What actions must I take to 

control the distribution of PET drug 

products? 

(a) Written distribution procedures. 

You must establish, maintain, and 

follow written procedures for the 

control of distribution of PET drug 

products shipped from the PET 

production facility to ensure that the 

method of shipping chosen will not 

adversely affect the identity, purity, or 

quality of the PET drug product. 

(b) Distribution records. You must 

maintain distribution records for each 

PET drug product that include or refer 

to the following: 

(1) The name, address, and telephone 

number of the receiving facility that 

received each batch of a PET drug 

product; 

(2) The name and quantity of the PET 

drug product shipped; 

(3) The lot number, control number, 

or batch number for the PET drug 

product shipped; and 

(4) The date and time you shipped the 

PET drug product. 

Subpart K—Complaint Handling 

§ 212.100 What do I do if I receive a 

complaint about a PET drug product 

produced at my facility? 

(a) Written complaint procedures. You 

must develop and follow written 

procedures for the receipt and handling 

of all complaints concerning a PET drug 

product. 

(b) Complaint review. The procedures 

must include review by a designated 

person of any complaint involving the 

possible failure of a PET drug product 

to meet any of its specifications and an 

investigation to determine the cause of 

the failure. 

(c) Complaint records. A written 

record of each complaint must be 

maintained in a file designated for PET 

drug product complaints. The record 

must include the name and strength of 

the PET drug product, the batch 

number, the name of the complainant, 

the date the complaint was received, the 

nature of the complaint, and the 

response to the complaint. It must also 

include the findings of any investigation 

and followup. 

(d) Returned products. A PET drug 

product that is returned because of a 

complaint may not be reprocessed and 

must be destroyed in accordance with 

applicable Federal and State law. 

Subpart L—Records 

§ 212.110 How must I maintain records of 

my production of PET drug products? 

(a) Record availability. Records must 

be maintained at the PET production 

facility or another location that is 

reasonably accessible to responsible 

officials of the production facility and to 

employees of FDA designated to 

perform inspections. 

(b) Record quality. All records, 

including those not stored at the 

inspected establishment, must be 

legible, stored to prevent deterioration 

or loss, and readily available for review 

and copying by FDA employees. 

(c) Record retention period. You must 

maintain all records and documentation 

referenced in other parts of this 

regulation for a period of at least 1 year 

from the date of final release, including 

conditional final release, of a PET drug 

product. 

Dated: September 1, 2005. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

[FR Doc. 05–18510 Filed 9–15–05; 8:45 am] 

BILLING CODE 4160–01–S 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Part 52 

[R05–OAR–2005–WI–0003; FRL–7970–7] 

Approval and Promulgation of 

Implementation Plans; Wisconsin; 

General and Registration Permit 

Programs 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Proposed rule. 

SUMMARY: EPA is proposing to approve 

revisions to the Wisconsin State 

Implementation Plan (SIP) submitted by 

the State of Wisconsin on July 28, 2005. 

These revisions include General and 

Registration permit programs that 

provide for the issuance of general and 

registration permits as part of the State’s 

construction permit and operation 

permit programs. In addition, these 

permit programs may include the 

regulation of hazardous air pollutants 

(HAPs) which may be regulated under 

section 112 of the Clean Air Act (the 

Act). Thus, EPA is also proposing 

approval of Wisconsin’s general and 

registration permit program under 

section 112(l) of the Act. 

These SIP revisions also contain 

changes to definitions related to 

Wisconsin’s air permit program, as well 

as a minor technical change to provide 

correct references to the recently 

updated chapter NR 445, which was 

inadvertently omitted in the processing 

of that rule package. Additionally, these 

revisions clarify an existing 

construction permit exemption and 

operation permit exemption for certain 

grain storage and drying operations. 

This clarification is necessary to ensure 

that column dryers and rack dryers are 

included in the exemption criteria. 

DATES: Written comments must be 

received on or before October 20, 2005. 

ADDRESSES: Submit comments, 

identified by Regional Material in 

EDocket (RME) ID No. R05–OAR–2005–

WI–0003, by one of the following 

methods: 

Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the on-line 

instructions for submitting comments. 

Agency Web site: http:// 

docket.epa.gov/rmepub/. RME, EPA’s 

electronic public docket and comments 

system, is EPA’s preferred method for 

receiving comments. Once in the 

system, select ‘‘quick search,’’ then key 

in the appropriate RME Docket 

identification number. Follow the online instructions for submitting 

comments. 

E-mail: blakley.pamela@epa.gov. 

Fax: (312) 886–5824. 

Mail: You may send written 

comments to: Pamela Blakley, Chief, Air 

Permit Section, (AR–18J), U.S. 

Environmental Protection Agency, 

Region 5, 77 West Jackson Boulevard, 

Chicago, Illinois 60604. 

Hand Delivery or Courier: Deliver 

your comments to: Pamela Blakley, 

Chief, Air Permit Section, (AR–18J), 

U.S. Environmental Protection Agency, 

Region 5, 77 West Jackson Boulevard, 

18th floor, Chicago, Illinois 60604. Such 

deliveries are only accepted during the 

Regional Office’s normal hours of 

operation. The Regional Office’s official 

hours of business are Monday through 

Friday, 8:30 a.m. to 4:30 p.m. excluding 

Federal holidays. 

Instructions: Direct your comments to 

RME ID No. R05–OAR–2005–WI–0003. 

EPA’s policy is that all comments 

received will be included in the public 

docket without change and may be 

made available online at http:// 

docket.epa.gov/rmepub/, including any 

personal information provided, unless 

the comment includes information 

claimed to be Confidential Business 

Information (CBI) or other information 

whose disclosure is restricted by statute. 

Do not submit information that you 

consider to be CBI or otherwise 

protected through RME, regulations.gov, 

or e-mail. The EPA RME website and 

the federal regulations.gov Web site are 

‘‘anonymous access’’ systems, which 

means EPA will not know your identity 

or contact information unless you 

provide it in the body of your comment. 

If you send an e-mail comment directly 

to EPA without going through RME or