Guidance 
 
PET Drugs  Current Good 
Manufacturing Practice (CGMP)  
 
(Small Entity Compliance Guide) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2011 
Compliance 
   
 
Guidance  
 
PET Drugs  Current Good 
Manufacturing Practice (CGMP)  
(Small Entity Compliance Guide) 
 
 
 
 
 
 
Additional copies are available from: 
 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Avenue 
Silver Spring, MD  20993-0002 
Phone:  301-796-3400; Fax:  301-847-8714 
druginfo@fda.hhs.gov 
 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2011 
Compliance 
 
  Contents Are Only Recommendations 
 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................1 
A.  Current Status of PET Drug Production.....................................................................................2 
B.  PET CGMP Requirements............................................................................................................2 
III.  PET DRUGS AND CGMP REQUIREMENTS.............................................................4 
A.  What Is a PET Drug?....................................................................................................................4 
B.  What Is CGMP?.............................................................................................................................4 
C.  Distinguishing Between PET Drug Production and the Practice of Pharmacy.......................5 
IV.  PERSONNEL RESOURCES...........................................................................................5 
A.  Regulatory Requirements.............................................................................................................5 
B.  Organization and Staffing.............................................................................................................5 
C.  Personnel Qualifications................................................................................................................6 
V.  QUALITY ASSURANCE................................................................................................6 
A.  Regulatory Requirements.............................................................................................................6 
B.  The Activity and Responsibility of the Quality Assurance Function........................................7 
VI.  FACILITIES AND EQUIPMENT..................................................................................8 
A.  Regulatory Requirements.............................................................................................................8 
B.  Facilities..........................................................................................................................................8 
1. General............................................................................................................................................8 
2. Aseptic Processing Area..................................................................................................................9 
C.  Equipment....................................................................................................................................10 
1. Production Equipment...................................................................................................................10 
2. Quality Control Equipment............................................................................................................13 
VII.  CONTROL OF COMPONENTS, CONTAINERS, AND CLOSURES....................14 
A.  Regulatory Requirements...........................................................................................................15 
B.  Control of Components, Containers, and Closures..................................................................15 
1. Vendor Selection............................................................................................................................15 
2. Receipt of Materials.......................................................................................................................15 
3. Acceptance, Release, and Storage of Materials.............................................................................16 
4. Acceptance Testing........................................................................................................................16 
5. Handling of Components, Containers, and Closures....................................................................17 
6. Records..........................................................................................................................................18 
VIII.  PRODUCTION AND PROCESS CONTROLS...........................................................18 
A.  Regulatory Requirements...........................................................................................................18 
B.  Master Production and Control Records/Batch Production and Control Records...............18 
C.  Microbiological Control on Aseptic Processing and Sterilizing Filtration.............................21 
  Contents Are Only Recommendations 
 
1. Water..............................................................................................................................................22 
2. Glassware......................................................................................................................................22 
3. Transfer Lines................................................................................................................................22 
4. Resin Columns...............................................................................................................................22 
5. Components...................................................................................................................................23 
6. Qualification for Aseptic Processing.............................................................................................23 
7. Sterilizing Filtration.......................................................................................................................23 
8. Environmental and Personnel Monitoring....................................................................................23 
D.  Process Verification and Computer Control.............................................................................24 
1. Process Verification Under  212.50(f)(2)....................................................................................24 
2. Computer Control..........................................................................................................................24 
IX.  LABORATORY CONTROLS......................................................................................25 
A.  Regulatory Requirements...........................................................................................................25 
B.  Laboratory Controls....................................................................................................................26 
X.  STABILITY TESTING..................................................................................................27 
A.  Regulatory Requirements...........................................................................................................27 
B.  Guidance on Stability..................................................................................................................27 
XI.  FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA...27 
A.  Regulatory Requirements...........................................................................................................27 
B.  Finished-Product Testing............................................................................................................28 
C.  Microbiological Tests for Sterile PET Drug Products..............................................................29 
D.  Accepting and Releasing a Batch (Lot)......................................................................................30 
E.  Conditional Final Release............................................................................................................30 
F.  Rejection and Reprocessing........................................................................................................31 
XII.  LABELING AND PACKAGING..................................................................................31 
A.  Regulatory Requirements...........................................................................................................31 
B.  Recommendations on Labeling and Packaging.........................................................................31 
XIII.  DISTRIBUTION.............................................................................................................32 
A.  Regulatory Requirements...........................................................................................................32 
B.  Recommendations........................................................................................................................32 
XIV.  COMPLAINT HANDLING...........................................................................................33 
A.  Regulatory Requirements...........................................................................................................33 
B.  Recommendations........................................................................................................................33 
XV.  RECORDS.......................................................................................................................33 
A.  Regulatory Requirements...........................................................................................................33 
B.  Recommendations........................................................................................................................33 
REFERENCES............................................................................................................................35 
  Contents Are Only Recommendations 
 
 
 
1
Guidance  
 
PET Drugs  Current Good Manufacturing Practice (CGMP) 
 
(Small Entity Compliance Guide) 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
 
 
 
 
I.  INTRODUCTION   
 
This guidance is intended to help small businesses better understand and comply with the 
regulations issued by the Food and Drug Administration (FDA) concerning current good 
manufacturing practice (CGMP) for positron emission tomography (PET) drugs. The guidance 
addresses resources, procedures, and documentation for all PET drug production facilities.  In 
some cases, the guidance provides practical examples of methods or procedures that PET drug 
production facilities can use to comply with the CGMP requirements.  FDA has prepared this 
guidance in accordance with section 212 of the Small Business Regulatory Enforcement Fairness 
Act (Public Law 104-121). 
 
FDAs guidance documents, including this guidance, should not be viewed as establishing 
legally enforceable responsibilities.  Instead, guidances describe the Agencys current thinking 
on a topic and should be viewed only as recommendations.  The use of the word should in 
Agency guidances means that something is suggested or recommended, but not required. 
 
 
II.  BACKGROUND 
 
Section 121(c)(1)(A) of the Food and Drug Administration Modernization Act of 1997 (the 
Modernization Act) directed FDA to establish CGMP requirements for PET drugs.  FDA 
established these requirements in 21 CFR part 212.   
 
                                                 
1 This guidance has been prepared by the PET Steering Committee in the Center for Drug Evaluation and Research 
(CDER) at the Food and Drug Administration (FDA). 
  1 Contents Are Only Recommendations 
 
 
A.  Current Status of PET Drug Production 
 
As directed by Congress in the Modernization Act, to help in developing the PET CGMP 
regulations and this guidance, we closely examined the operations of many PET drug producers, 
including not-for-profit institutions and commercial manufacturers.  Since the Modernization Act 
became law, significant changes have occurred in PET drug production in the United States.  The 
number of PET drug 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 drugs were produced by academicians and researchers at PET drug production 
facilities located in universities and similar not-for-profit institutions.  An academically oriented 
PET drug production facility usually produces small amounts (a few doses per day) of a few PET 
drugs for on-site patient use and a larger variety of PET drugs for clinical investigation and 
academic research.  
 
An increasing number of PET drug production facilities are now operated by for-profit corporate 
entities that contract with academic and medical institutions (many of which have not-for-profit 
status) to manage the production of PET drugs at those institutions.  Most of these PET drugs are 
administered on site, although often there is some distribution to other local or regional hospitals.  
In addition, a growing number of independent PET drug production facilities are not affiliated 
with any university or hospital.  These for-profit, often contractually managed, and 
independently operated PET drug production facilities distribute PET drugs to significantly 
greater numbers of patients, sometimes hundreds of miles from the production site.   
 
Our review of PET drug production has led to the conclusion that a PET drug producers status 
as either a not-for-profit or for-profit entity has little bearing on the quality of PET drugs that it 
produces and distributes for administration to patients, or on the methods, facilities, and controls 
that a PET drug production facility needs to ensure product quality.  Instead, production and 
CGMP differences among PET drug producers are primarily a function of the size, scope, and 
complexity of their production operations.  We have also found that implementing certain 
production standards and controls can ensure the production of quality PET drugs, regardless of 
differences among the various PET drug production facilities.  The Agency believes that the 
welfare of a patient undergoing a PET scan should not depend on where a particular PET drug 
was produced.  
 
B.  PET CGMP Requirements 
 
The PET CGMP regulations contain what we believe are the minimum standards for quality 
production of PET drugs at all types of PET drug production facilities.  We have designed the 
CGMP regulations to be sufficiently flexible to accommodate not-for-profit, academically 
oriented institutions as well as commercial producers.  
 
The CGMP regulations also incorporate principles from the United States Pharmacopeia (USP) 
general chapter on PET drug compounding.  The USP contains standards that are of significant 
regulatory importance for PET drugs.  The Modernization Act added section 501(a)(2)(C) of the 
Federal Food, Drug, and Cosmetic Act (the Act), which provides that a compounded PET drug is 
adulterated unless it is produced in compliance with USP compounding standards and official 
  2 Contents Are Only Recommendations 
 
 
monographs for PET drugs.  Section 501(a)(2)(C) is to expire 2 years after the date on which we 
establish approval procedures and CGMP requirements for PET drugs. The approval procedures 
were established previously.  The CGMP requirements for PET drugs were established 
December 10, 2009.  On December 12, 2011, compliance with the PET CGMP regulations will 
be required (except for investigational and research PET drugs, as discussed below).  However, 
the USP general chapter on PET drug compounding largely reflects the consensus views of the 
PET community and FDA on how to properly produce PET drugs.  Consequently, it is 
appropriate to incorporate many of the principles and concepts in the USP general chapter into 
the CGMP requirements. 
 
Section 212.5 of the PET CGMP regulations specifies the particular CGMP requirements for 
investigational, research, and approved PET drugs.   
 
  Section 212.5(a) states that the regulations in part 212 apply only to the production, 
quality control, holding, and distribution of PET drugs; human drugs that do not meet 
the definition of a PET drug must be manufactured in accordance with the CGMP 
requirements in parts 210 and 211.    
 
   Section 212.5(b) gives producers of investigational PET drugs2 and research PET 
drugs3 the option of following the CGMP regulations in part 212 or producing PET 
drugs in accordance with Chapter <823> of the 32nd edition of the USP (2009).  We 
believe that it is appropriate to have less detailed CGMP requirements for 
investigational and research PET drugs to allow more flexibility during the 
development of these drugs.  We also recognize that many investigational PET drugs 
may not have commercial potential. 
 
USP Chapter <823> sets forth requirements for 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 Chapter <823>, allowing producers to meet 
the CGMP requirements for investigational and research PET drugs by following Chapter <823> 
should greatly facilitate producers compliance with the CGMP requirements.  Although the 
provisions in Chapter <823>, including those on documentation, are generally less specific and 
explicit than the requirements in 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, and are appropriate CGMP requirements for the 
investigational and research stage of development. 
 
Although USP Chapter <823>, rather than part 212, constitutes the minimum CGMP 
requirements for investigational and research PET drugs, we retain the authority to inspect 
facilities where investigational and research PET drugs are produced to verify compliance with 
either Chapter <823> or part 212.  However, as with inspection of production facilities for non-
                                                 
2 Investigational PET drugs or drug products for human use produced under an investigational new drug application 
(IND) in accordance with part 312. 
3 Research PET drugs or drug products produced with the approval of a Radioactive Drug Research Committee 
(RDRC) in accordance with 21 CFR 361.1. 
  3 Contents Are Only Recommendations 
 
 
PET investigational drugs, we generally will conduct inspections of facilities that produce 
investigational or research PET drugs only on a for-cause basis (i.e., when we become aware of a 
potential safety concern related to the production of an investigational or research drug). 
 
PET drugs, other than investigational and research PET drugs, must meet the requirements of 
part 212.  PET drugs that must be marketed under an approved new drug application (NDA) or 
an approved abbreviated new drug application (ANDA) must be produced in accordance with 
part 212, which delineates the appropriate CGMP requirements for that stage of development. 
 
 
III.  PET DRUGS AND CGMP REQUIREMENTS 
 
A.  What Is a PET Drug? 
 
PET is a medical imaging modality that requires the use of a unique type of radiopharmaceutical 
drug.  A PET drug exhibits spontaneous disintegration of unstable nuclei by the emission of 
positrons (+).  PET drugs are used to provide dual photon positron emission tomographic 
images.  The radionuclide is generally produced by a particle accelerator (e.g., a cyclotron) and 
has a short half-life.  As defined in  212.1 of the regulations, a PET drug includes a PET drug 
product (i.e., a finished dosage form of a PET drug, whether or not in association with one or 
more other ingredients). 
 
Currently, a batch or lot of a PET drug typically consists of one multiple-dose vial containing the 
PET drug in a sterile solution.  A sample from the vial, which is representative of all doses to be 
administered, is tested to verify that the batch or the lot conforms to all established 
specifications. 
 
A PET drug product is typically administered to patients within a few minutes to a few hours 
following preparation.  Because of the short half-life of the radionuclide and the mode of 
production, PET drug products have unique storage, shipping, and handling concerns.   
  
B.  What Is CGMP? 
 
Current good manufacturing practice (CGMP) is a minimum standard that ensures that a drug 
meets the requirements of safety and has the identity, strength, quality, and purity characteristics 
it is represented to possess.  CGMP is demonstrated through written documentation of 
procedures and practices.  The documents and practices may be similar or identical to documents 
and practices requested by other oversight bodies (e.g., the Nuclear Regulatory Commission and 
State and local agencies).  Documents produced for others, where appropriate, can be used to 
provide the documentation of compliance with CGMP requirements.  However, because of 
institutional, local, or State differences, some of these documents may not be sufficient to 
achieve compliance with FDA CGMP regulations.  Therefore, to ensure uniformity for all 
patients and human subjects, we recommend that PET drug producers review their documents 
and practices and, when necessary, develop supplemental documentation.  
 
 
  4 Contents Are Only Recommendations 
 
 
C.  Distinguishing Between PET Drug Production and the Practice of Pharmacy 
 
FDA regulates the production of PET drugs.  Section 121 of the Modernization Act directs FDA 
to establish appropriate approval procedures for PET drugs pursuant to section 505 of the Act as 
well as appropriate CGMP requirements.  In the course of developing these approval procedures 
and CGMP requirements, a question has been raised concerning how to distinguish PET drug 
production from the practice of pharmacy (regulation of which FDA has traditionally deferred to 
State and local authorities). 
 
FDA has determined that the production of a PET drug includes all operations to the point of 
final release of a finished dosage form, and these activities will be subject to CGMP.  A PET 
drug product may be released to a hospital, institution, imaging facility, nuclear pharmacy (e.g., 
pharmacy bulk packages for use in accordance with USP <1> Injections), or other entity or part 
of an entity.  After a finally released PET drug product is received by the receiving facility, FDA 
generally regards subsequent dispensing of a patient-specific dose and use of the drug product to 
be part of the practice of medicine and pharmacy.  FDA generally will defer to State and local 
authorities concerning regulation of these activities.  In general, a routine FDA inspection to 
ensure compliance with CGMP would focus on activities up to and including the point of final 
release of a PET drug product.   
 
In the following sections of the guidance, each section is introduced by a statement of the 
relevant requirements from the PET CGMP regulations.   The section then provides more 
detailed current thinking.  Certain CGMP requirements in the regulations are self-explanatory 
and are not further addressed in this guidance. 
 
 
IV.  PERSONNEL RESOURCES 
 
A.  Regulatory Requirements 
 
Section 212.10 requires a PET drug production facility to have a sufficient number of personnel 
with the necessary education, background, training, and experience to enable them to perform 
their assigned functions correctly.  Each center also must provide adequate resources, including 
equipment and facilities, to enable their personnel to perform their functions. 
 
The following section of the guidance addresses personnel.  Guidance on resources (facilities and 
equipment) is provided in section VI. 
 
B.  Organization and Staffing 
We recommend that staffing levels correspond to the size and complexity of the operation of the 
PET drug production facility and enable the facility to satisfactorily complete all intended tasks 
in a timely manner before administration of a finished PET drug product to humans.  We 
recommend that the responsibilities and assigned duties of all staff be clearly identified in written 
policies. 
 
  5 Contents Are Only Recommendations 
 
 
For a PET drug production facility that typically produces one or two batches of a product daily 
(or weekly), it may be adequate to employ only a few employees (typically at least two persons) 
to accomplish all production and quality assurance functions.  We recommend the PET facility 
demonstrate that the production and quality assurance functions can be consistently 
accomplished in a timely and appropriate manner before administration of a drug to humans.  
One individual can be designated to perform the production as well as quality assurance 
functions, provided he or she is highly qualified in the performance of all such functions (i.e., has 
appropriate education, documented training, and significant experience in the technical area). 
 
Under current CGMP regulations for conventional drug products in part 211, FDA normally 
requires second-person checks at various stages of production as well as test verification.  In a 
PET drug production facility with only one person assigned to perform production and quality 
assurance tasks, it is recommended that that person recheck his or her own work.  Self-checks 
involve the confirmation of the operators own action and would be documented.  Examples of 
self-check activities include reviewing batch records (e.g., review the batch record to ensure that 
all finished-product test results are within the acceptance criteria) before release of the drug 
product for distribution and verifying calculations in analytical tests.  
 
At a PET production facility that produces multiple PET drugs, we recommend the staffing level 
be adequate to perform all quality assurance functions and to prevent mix-ups and cross-
contamination.   
 
C.  Personnel Qualifications 
 
As mentioned above, each person performing an activity or a function in the production and 
quality assurance of a PET drug must have the appropriate education, training, and experience 
related to that function and should be trained in CGMP relevant to their assigned tasks.  We 
recommend that PET drug production facilities have adequate ongoing programs or plans in 
place for training employees in new procedures and operations and in the areas where 
deficiencies have occurred.   
 
We recommend PET drug production facilities maintain an updated file (e.g., curriculum vitae, 
copies of degree certificates, certificates of training) for each employee. 
 
 
V.  QUALITY ASSURANCE 
 
A.  Regulatory Requirements 
 
Section 212.20 requires PET drug production facilities to have a quality assurance function.  In 
the regulations, the following activities are defined as the responsibilities of the quality assurance 
function: 
 
  Oversee production operations to ensure that PET drugs have adequately defined 
identity, strength, quality, and purity.  
 
  6 Contents Are Only Recommendations 
 
 
  Examine and approve or reject components, containers, closures, in-process 
materials, packaging materials, labeling, and finished dosage forms to ensure that all 
these meet their current specifications. 
 
  Approve or reject specifications, methods, processes, and procedures, and any 
proposed changes.  
 
   Review production records to determine whether errors occurred.  If errors have 
occurred or specifications have not been met, determine the need for an investigation 
and take appropriate corrective action. 
 
B.  The Activity and Responsibility of the Quality Assurance Function 
 
The quality assurance function in a PET drug production facility typically consists of execution 
and oversight activities.  
 
We recommend that the execution of quality assurance functions include the following: 
 
  Examine and evaluate each lot of incoming material before use to ensure that the material 
meets its established specifications. 
  
  Review the production batch records and laboratory control records for accuracy, 
completeness, and conformance to established specifications before authorizing the final 
release or rejection of a batch or lot of a PET drug. 
 
  Ensure that deviations from normal procedures are documented and justified. 
 
We recommend that the oversight of quality assurance functions include the following: 
 
  Approve procedures, specifications, process, and methods. 
 
  Ensure that personnel are properly trained and qualified, as appropriate. 
 
  Ensure that PET drugs have adequately defined identity, strength, quality, and purity. 
 
  Ensure that all errors are reviewed.  When it is determined that an investigation is 
appropriate, document the investigation and take corrective action(s) to prevent the 
recurrence of the errors. 
 
  Conduct periodic audits to monitor compliance with established procedures and practices. 
 
For PET drug production facilities currently producing one or two PET drugs, employees located 
at the facility can perform both the daily execution and oversight functions.   
 
On the other hand, a commercial PET firm managing multiple production facilities may choose 
to have an entity located outside the PET drug production facility help to achieve the objective of 
  7 Contents Are Only Recommendations 
 
 
production oversight and more efficient management.  For example, a corporate quality 
assurance/quality control department, or consultants, can provide oversight.  
 
 
VI.  FACILITIES AND EQUIPMENT 
 
A.  Regulatory Requirements 
 
Section 212.30(a) requires that a PET drug production facility have adequate facilities to ensure 
the orderly handling of materials and equipment, the prevention of mix-ups, and the prevention 
of contamination of equipment or product by substances, personnel, or environmental conditions. 
 
Section 212.30(b) and (c) require the implementation of procedures to ensure that all equipment 
that would reasonably be expected to adversely affect the identity, strength, quality, or purity of a 
PET drug, 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.  Activities in accordance with these procedures must be documented.  
Equipment must be constructed so that surfaces that contact components, in-process materials, or 
drug products are not reactive, additive, or absorptive so as to alter the quality of the PET drug.  
 
B.  Facilities 
 
1.  General 
 
The design of the PET drug production facility should promote orderly operations during 
the production process and protect the product from contamination originating from 
personnel and surrounding areas.  To achieve this, a facility should contain adequate 
work areas suitable for the intended tasks (e.g., area for analytical testing, aseptic 
manipulation, chemical production, radiochemical production, and component storage) 
and to allow completion of all production-related tasks in an orderly manner.  Potential 
sources of contamination include particulate matter and chemical and microbiological 
materials. 
 
Sterile PET drugs may be divided into two categories:  those that are manufactured by 
aseptic processing and those that are terminally sterilized.  The facility should maintain 
levels of environmental cleanliness appropriate for the type of operation being performed. 
 
Phases of production for aseptic processing with the potential for microbiological 
contamination should be performed under environmental conditions that minimize the 
possibility of such contamination (e.g., in a laminar airflow workbench (LAFW) or 
barrier isolator system).   
 
The placement of equipment and materials should be carefully evaluated to promote 
efficient operation and eliminate errors, mix-ups, and cross-contamination.  All 
equipment used in production (e.g., particle accelerator, synthesis units, or other 
  8 Contents Are Only Recommendations 
 
 
specialized equipment) should be appropriately located and housed (e.g., with shielding) 
so that all the work areas during the normal course of production are easily accessible. 
 
We recommend that related work areas be organized and proximally located so as to 
promote efficient operation and eliminate the potential for errors in production and 
control operations.  Access to work areas, production and testing equipment, components, 
and containers and closures should be restricted to authorized personnel.      
 
In most PET drug production facilities, the same area or room can be used for multiple 
purposes.  For example, the production (e.g., radiochemical synthesis), laboratory 
operation (e.g., release testing), and storage of approved components, including 
containers and closures, can be located in the same room.  Components that are approved 
for use as well as those that are under quarantine can be stored in the same area or on a 
different shelf in a cabinet, provided each lot is properly labeled as to its status and 
contents and organized in a manner that avoids mix-up or unintended use.  Rejected 
components, containers and closures, and other materials should be kept separate from 
quarantined or approved materials.  
 
As the complexity in a PET drug production facility increases, it is important to develop 
the appropriate level of control required to prevent mix-ups and contamination.  Separate 
and well-defined areas or rooms may be warranted for each independent function of the 
operation, such as production, testing, and storage of components.  It is also important to 
consider what impact a greater number of personnel and activities could have on the 
aseptic processing portion of the process.  When PET production facilities are co-located 
in research institutions, there should be quality assurance oversight to review and approve 
research activities to ensure that they do not compromise the quality of the marketed PET 
drug products. 
 
2.  Aseptic Processing Area  
 
An aseptic work area should be suitable for the assembly of the aseptic components 
required for the preparation of a sterile PET drug.  We recommend that air quality in the 
aseptic processing area be controlled to limit the presence of microorganisms and 
particulate matter.  Critical activities in the production and testing of a PET drug that 
expose the PET drug or the sterile surface of the container/closure system to the 
environment should be conducted within an aseptic workstation (e.g., a LAFW or barrier 
isolator).  Examples of such activities include the aseptic assembly of sterile components 
(syringe, needle, filter, and vial) for sterile filtration of the PET drug, and sterility testing 
of the finished PET drug product.  We recommend that the following precautions be 
taken to help maintain the appropriate air quality of the aseptic workstation: 
 
  Sanitize the aseptic workstation before each operation. 
 
  Keep items within a laminar airflow aseptic workstation to a minimum and do 
not interrupt the airflow.  
 
  9 Contents Are Only Recommendations 
 
 
  Have operators wear clean lab coats and sanitized gloves when conducting an 
aseptic manipulation within the aseptic workstation.  
 
  Frequently sanitize gloved hands or frequently change gloves when working 
in the aseptic workstation.  Examine gloves for damage (tears or holes) and 
replace them if they are damaged.   
 
  Sanitize the surface of nonsterile items (e.g., test tube rack, the overwrap for 
sterile syringes, filters) and wipe with an appropriate disinfectant (e.g., sterile 
70 percent isopropyl alcohol) before placing them in the aseptic workstation. 
  
Conditions in the room where aseptic manipulations are conducted should not present a 
challenge to the operating capability of the aseptic workstation.  For example, the room 
should not be carpeted nor have overhanging pipes or hanging light fixtures.  All areas of 
the production and processing room should be easily accessible for cleaning.  Surfaces of 
the walls, floors, and ceilings in the aseptic work areas should be easily cleaned.  
Cleaning should be performed frequently to ensure consistent control of the 
environmental quality.  In addition, the aseptic processing area (e.g., LAFW) should be 
situated in the section of the room with the lowest traffic and lowest activity.  Cartons 
and boxes should not be stored or opened in the production area to minimize ingress of 
dust and particulate into the aseptic work area. 
 
C.  Equipment 
 
1.  Production Equipment 
 
Equipment used in the production, processing, or packaging of a PET drug should be 
appropriate for the performance of its intended function and not contaminate the product.  
We recommend that each piece of equipment be suitably located to facilitate its use, 
cleaning, and maintenance.  We also recommend that each PET drug production facility 
establish and follow written procedures that address the following issues, where 
applicable: 
 
  Assignment of responsibility and frequency for cleaning and maintenance of 
equipment 
 
  Description of cleaning and maintenance procedures in sufficient detail to include 
disassembly and reassembly of equipment 
   
  Protection of clean equipment from contamination prior to use 
 
  Inspection of equipment and calibration, if indicated, prior to use 
 
We recommend that each PET drug production facility select suitable cleaning agents and 
cleaning techniques and ensure that their cleaning operations not contaminate the drug.  
 
  10 Contents Are Only Recommendations 
 
 
We recommend that newly installed equipment be qualified before first use to verify that 
it was installed correctly and is capable of operating as intended.  Normally, the 
equipment vendor verifies that the equipment is installed correctly (installation 
qualification (IQ)) and operates according to specifications (operational qualification 
(OQ)).  Before the equipment is used for production, personnel in the PET production 
facility should verify that the equipment, when operated under actual production 
parameters or selected method, produces consistent results within established 
specifications (performance qualification (PQ)).  
 
We recommend developing a preventive maintenance schedule with sufficient frequency 
to ensure the correct performance of the equipment.  When needed, calibration should be 
performed prior to the use of the equipment for the intended task.  We recommend that 
facilities follow the schedule for calibration checks recommended by equipment vendors 
unless the PET production facility has determined that more frequent calibrations are 
appropriate.  Major repairs or upgrades in equipment may warrant requalification.  We 
recommend not using malfunctioning or incorrectly operating equipment until repairs or 
corrective action have been made and the equipment has been found to operate correctly.  
All qualification, calibration, and maintenance activities should be properly documented, 
including the date of the activities and who performed them.   
 
FDA recognizes that, after they become subject to the requirements of the final CGMP 
regulations, a number of PET drug production facilities may continue to use existing 
equipment.  If they do, the facilities must make sure that the existing equipment is 
working properly and is being maintained and calibrated according to written procedures. 
 
We recommend that PET production facilities establish procedures to check the correct 
functioning of the equipment that is developed in-house.  Representative equipment is 
discussed below to illustrate how it might be controlled in a PET production facility.   
 
a.  Automated radiochemical synthesis apparatus 
 
The apparatus enables the PET production facility to carry out the production 
process reliably and reproducibly.  The provisions contained in the USP General 
Chapter <1015> Automated Radiochemical Synthesis Apparatus can help ensure 
proper functioning of a synthesis apparatus.  
 
Prior to the production of a PET drug product each day, we recommend that the 
operator conduct a performance check to ensure the following:  
 
  The synthesis apparatus has been cleaned/flushed according to the established 
procedures. 
  
  All appropriate tubing, reaction vessels, purification columns or cartridges, 
and other materials have been replaced and connected as required. 
  
  11 Contents Are Only Recommendations 
 
 
  The monitoring and or recording devices (e.g., temperature, pressure, flow 
rate) are functioning properly. 
 
  When the process is under microprocessor control, the operator ensures that 
the system is functioning and recording correctly and that the correct program 
and operational parameters are used. 
 
b.  Aseptic Workstation  
 
The aseptic workstation should provide an appropriate environment for aseptic 
procedures.  Examples of workstations include a LAFW or barrier isolator 
system.  We recommend that an integrity test be conducted at installation 
(including after each change of the high-efficiency particulate air (HEPA) filter) 
to ensure proper performance.  We recommend that certification (integrity testing 
of the HEPA filter) of the aseptic workstation be performed when the unit is 
initially installed and at least every 6 months thereafter to ensure the desired air 
quality.  More frequent testing may be appropriate if air quality is found to be 
unacceptable, for example, as part of an investigation into a finding of sterility 
failure in a PET drug, or if leakage or decrease in optimal airflow is found.   
 
We recommend that a qualified operator change the prefilters in the aseptic 
workstation periodically in accordance with written procedures and preventive 
maintenance schedules.  Some laminar flow hoods are equipped with easily 
readable static pressure gauges that indicate when the pressure builds up behind 
the filter because of the clogging of the filter.  We recommend that the filter be 
changed when clogging is detected. 
 
We recommend laminar airflow velocities be monitored periodically at the work 
surface as well as at the HEPA filter face to ensure adequate uniformity of flow 
throughout the critical area.  We recommend that operators be trained on the 
importance of minimizing objects and equipment within the critical area so 
laminar airflow is not disrupted.  We recommend that microbiological monitoring 
(e.g., using settle plate) in the LAFW be conducted during sterility testing and 
critical aseptic manipulation. 
 
c.  Electronic or analytical weight balance 
 
We recommend that written procedures, if not already available, be developed, 
describing the proper use of the balance, assessment of accuracy, and a schedule 
for calibration.  We recommend that performance be checked by weighing two or 
more standard weights on each day of use.  We recommend that the calibrated 
weights used for assessing daily performance bracket the range of the weights 
being measured.  We also recommend that the balance be fully calibrated 
periodically, or upon failure to meet daily performance checks (see USP <41> 
Weights and Balances).  
 
  12 Contents Are Only Recommendations 
 
 
d.  Dry-heat ovens 
   
If glassware and heat-stable materials used in the production of a PET drug are 
depyrogenated and sterilized on-site, we recommend that the PET drug 
production facility demonstrate and document that the depyrogenation cycle will 
achieve at least a 3-log reduction of an endotoxin challenge, as measured by a 
bacterial endotoxins test.  A suitable challenge study usually involves random 
placement of endotoxin indicators in a representative oven load of materials.  
Suitable endotoxin indicators include glass vials that contain 1,000 to 10,000 
Endotoxin Units.  
 
e.  High performance liquid chromatograph (HPLC)  
 
When an HPLC is used for purification of a PET drug, we recommend the 
operator ensure that the system is working properly and there is no bleeding of 
unintended materials (e.g., column material) into the mobile phase.  If the column 
is to be left idle or stored, we recommend that it be rinsed and stored in a suitable 
solvent that is compatible with the column and will inhibit microbial growth. 
 
f.  Temperature recording device  
 
We recommend that the temperature and humidity (where appropriate) of the dry 
heat oven, refrigerator, freezer, and incubator be recorded on each workday when 
in use.  Automated recording devices are recommended for ease of documentation 
and for recording any deviations.   
 
2.  Quality Control Equipment  
 
We recommend that PET drug production facility have the appropriate equipment to 
adequately perform each quality assurance function that it intends to perform. 
Representative quality control equipment can include: 
 
a.  Gas chromatograph (GC) 
 
Prior to each day of its use, the analyst should make sure that the GC system is 
functioning correctly by conducting system suitability testing.  At least one 
injection of the standard preparation (reference standard or internal standard) 
should be done before the injection of test samples (see USP General Chapter 
<621> Chromatography).  
 
b.  High performance liquid chromatograph (HPLC) 
 
We recommend that the HPLC system have detectors suitable for the intended 
purpose and be of sufficient sensitivity.  Prior to each day of its use, the analyst 
should make sure that the HPLC system is functioning correctly by conducting 
system suitability testing (see USP General Chapter <621> Chromatography and 
  13 Contents Are Only Recommendations 
 
 
FDA reviewer guidance, Validation of Chromatographic Methods).4  At least one 
injection of the standard preparation (reference standard or internal standard) 
should be done before the injection of test samples. 
 
c.  Dose calibrator   
 
We recommend a dose calibrator be used to measure the radioactivity of PET 
drugs.  Accuracy and linearity should be assessed at installation and at appropriate 
intervals thereafter.  The instrument should be calibrated in accordance with 
nationally recognized standards or with a certified dose response factor provided 
for the instrument at commissioning and during routine maintenance.  System 
suitability testing should include a constancy check with a suitable high-energy 
radionuclide standard source. 
 
d.  Radiochromatogram scanner  
 
We recommend that a radiochromatogram scanner (or equivalent equipment that 
provides a radiochromatogram) be used to measure radioactivity distribution in 
the developed thin layer chromatography plate (e.g., instant thin-layer 
chromatography (ITLC), paper or plate).  The scanner should have sufficient 
sensitivity and spatial resolution for the intended discriminatory and quantitative 
objective.  Manufacturer recommended checks and maintenance should be 
performed on the radiochromatogram scanner (see USP General Chapter <821> 
Radioactivity). 
 
e.  Multichannel analyzer (MCA) 
 
A multichannel spectrometer coupled to a calibrated sodium iodide scintillation 
detector (or preferably with the higher resolution germanium lithium 
compensated, Ge (Li) detector) can be useful to determine radionuclidic purity 
and to identify the radionuclide.  The overall system should have sufficient 
sensitivity and resolution for the intended purpose (see USP General Chapter 
<821> Radioactivity).  Adequate calibration using National Institute of Standards 
and Technology (NIST) traceable standards and preventive maintenance should 
be performed at intervals specified in a written procedure and as recommended by 
the equipment manufacturer.  More frequent intervals should be used if problems 
in the operation of the MCA are encountered.   
 
 
VII.  CONTROL OF COMPONENTS, CONTAINERS, AND CLOSURES 
 
                                                 
4 Available on the CDER guidance page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER guidance 
page . 
. 
  14 Contents Are Only Recommendations 
 
 
A.  Regulatory Requirements  
 
Section 212.40(a) and (b) requires PET drug production facilities to establish, maintain, and 
follow written procedures for the control of components, containers, and closures.  There would 
have to be appropriate written specifications for components, containers, and closures.  
  
Section 212.40(c) establishes the minimum standards for controlling components, containers, 
and closures from receipt to consumption.  
 
Section 212.40(d) requires that components, containers, and closures be handled and stored in a 
manner that prevents contamination, mix-ups, and deterioration. 
 
Section 212.40(e) requires that PET drug production facilities keep a record of each shipment of 
each lot of components, containers, and closures that they receive.      
 
B.  Control of Components, Containers, and Closures 
 
The written procedures must specify how each material (components, containers, and closures) 
will be selected and controlled in PET drug production facilities.  Procedures should cover the 
life cycle of a material, from time of receipt to ultimate consumption.  Organizations with more 
than one PET drug production facility could store and perform quality control testing and 
approval of components at a centralized facility.  On receipt of the component, each PET drug 
production facility in such an organization should check the labeling, condition of delivery, and 
the approval status assigned by the central facility.  The process for procurement and use of 
materials by PET drug production facilities should include the following elements, where 
applicable: 
 
1.  Vendor Selection  
 
We recommend only qualified vendors be used.  A vendor is qualified when there is 
evidence to support its ability to supply a material that consistently meets all quality 
specifications.  We also recommend that PET drug production facilities ask the vendor to 
report any major changes in the manufacture of an item.  It is preferable to have more 
than one qualified vendor for a component.  A vendor should be replaced if there is an 
indication that it is supplying unsatisfactory materials.  
 
2.  Receipt of Materials 
 
We recommend that each lot of material be checked upon receipt to determine that the 
order was filled correctly and arrived in good condition.  Each lot should be logged in 
and assigned a new identification code number.  The code number should be used in the 
disposition of that lot.  Sufficient information should be documented to enable the PET 
drug production facility to have full traceability of each lot.  We recommend that before 
release for use, incoming materials be segregated and placed under quarantine and 
labeled as Quarantined.  A lot can then be inspected, sampled, and tested, if applicable. 
  15 Contents Are Only Recommendations 
 
 
 
      3.  Acceptance, Release, and Storage of Materials 
  
Analytical results in the certificate of analysis (COA) for each lot of incoming material 
should be inspected against the PET drug production facilitys current specification sheet 
to ensure that acceptance criteria are met.  Where appropriate, certain components 
described below (see Acceptance Testing) can be tested to confirm their identity before 
they are accepted and released for use in the production of a PET drug.  
 
Materials that meet a PET drug production facilitys specifications can be approved and 
released for use.  The release should be recorded and the examination and testing data 
maintained.  It may be helpful to have a component logbook to record information such 
as receipt date, quantity of the shipment, suppliers name, lot number, expiration date, 
results of any testing performed, and person responsible for release.5  Approved materials 
can be labeled Approved with an identifying code number, storage conditions, and 
expiration date.  We recommend that materials be stored under the proper storage 
conditions and in an area designated for approved materials.  If a lot is rejected, we 
recommend that it be labeled Rejected, segregated, and properly disposed of, and that 
each of these actions be documented.  
 
We recommend that items be stored under the conditions recommended by the vendor 
(e.g., temperature and humidity).  Moisture sensitive materials should be stored in 
desiccated devices in sealed containers.  There should be an expiration date for each item.  
We recommend that PET drug production facilities have a policy that guides the 
expiration dating of items, by category.  Vendor assigned expiration dates can be used 
unless the in-house date is sooner.  
 
4.  Acceptance Testing 
 
a.  Reagents, solvents, gases, purification columns, and other auxiliary 
materials  
 
We recommend that PET drug production facilities have procedures in place to 
ensure that the materials used meet applicable specifications and are from 
approved reliable sources.  The COA and container label for each lot of each 
shipment of incoming materials should be examined to ensure that all 
specifications are met.  
 
b.  Components that yield an active pharmaceutical ingredient (API) and 
inactive ingredients 
 
Under  212.40(c)(1)(i), for the production of PET drugs where finished-product 
testing ensures that the correct components have been used (e.g., production of 
FDG F 18), PET producers may rely on the COA from the suppliers.  The 
                                                 
5 A sample format for record keeping of incoming components is available at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm085783.htm. 
  16 Contents Are Only Recommendations 
 
 
regulation requires that analytical results in the COA for each lot of component be 
examined and compared against the PET drug production facility's current 
specifications to ensure that acceptance criteria are met.  We recommend that PET 
drug producers have a scientific rationale and supporting data to justify why 
identity testing is not needed.  In the case of FDG F 18, when the identity of the F 
18 radionuclide is established as part of the finished-product testing, it is 
appropriate to use the COA without performing identity testing. 
 
Under  212.40(c)(1)(ii), for the production of a PET drug where the finished-
product testing does not ensure that the correct components have been used, 
identity testing must be performed.  When specific identity tests exist, we 
recommend that they be used.  
 
The inactive ingredients in PET drugs usually consist of a diluent, a stabilizer, 
and/or a preservative.  Under  212.40(c)(1)(ii), if a product that is marketed as a 
finished drug product intended for intravenous administration is used as an 
inactive ingredient, it is not necessary to perform a specific identity test for that 
ingredient.  Section 212.40(c)(1)(ii) also states that if an inactive ingredient (e.g., 
0.9 percent sodium chloride solution) was prepared on site from a component that 
is not subject to finished-product testing, an identity test on the components used 
to make the inactive ingredient must be performed before the components are 
released for use.   
  
c.  Commercially available ready-to-use sterile, pyrogen-free, sealed 
container/closure systems for injections, syringes, transfer sets, and filters 
used in aseptic process 
 
Under  212.40(c)(2), a representative sample of each lot of containers and 
closures must be examined for conformity to written specifications.  We 
recommend that PET production facilities use reliable sources for these items. 
Most PET production facilities use sterile and depyrogenated containers (sealed 
vials with stoppers and crimps) that are commercially available.  Also under 
 212.40(c)(2), a visual identification of each lot of containers and closures must 
be conducted.  We recommend that a COA showing conformance with the 
established specifications be obtained before accepting a lot of the 
container/closure system.  We recommend that the container/closure system be 
properly stored under appropriate environmental conditions (e.g., correct 
temperature, humidity, and sterility).   
 
If the sterilization and depyrogenation of the container/closure are performed on 
site, we recommend that the efficacy of each process be demonstrated.  We 
recommend that established procedures shown to be reproducible be used in such 
cases.   
 
5.  Handling of Components, Containers, and Closures 
 
  17 Contents Are Only Recommendations 
 
 
When a lot of material has met all acceptance criteria, the material can be labeled 
Approved.   Under  212.40(d), approved materials must be handled and stored in a 
manner that prevents degradation or contamination.  Unacceptable materials should be 
promptly rejected, identified, and segregated to prevent their use prior to appropriate 
disposal.   
 
6.  Records  
 
Under  212.40(e), records must be kept for each shipment of each lot of components, 
containers, and closures that the PET production facility receives, including results of any 
testing performed.   
 
 
VIII.  PRODUCTION AND PROCESS CONTROLS 
 
A.  Regulatory Requirements 
 
Section 212.50 requires adequate production and process controls to ensure consistent production 
of a PET drug that meets the applicable standards for identity, strength, quality, and purity.  
Under  212.50(a), PET drug production facilities 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.   
 
Section 212.50(b) requires PET drug production facilities to have master production and control 
records that document all steps in the PET drug production process.  Section 212.50(b) also 
specifies what is required in the master production and control records. 
 
Section 212.50(c) requires that a batch production and control record be created for each new 
batch of a PET drug.  Each batch of a PET drug must be uniquely identified, and its batch record 
must include each major production step, weights, and identification codes of components used, 
dates of production steps and times of critical production steps, identification of major 
equipment, testing results, labeling, initials or signatures of persons performing or checking each 
significant step in the operation, and results of any investigations conducted. 
 
Section 212.50(f) requires that when the results of the production of an entire batch of a PET 
drug are not fully verified through finished-product 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 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. 
  
B.  Master Production and Control Records/Batch Production and Control 
Records 
 
  18 Contents Are Only Recommendations 
 
 
Master production and control records are the principal documents describing how a product is 
made.  The master production record, which is used to derive individual batch records, specifies 
how batches are to be produced.  The designated individual should approve the master 
production and control records, or any changes to them, before they are implemented.   
 
We recommend that the master production and control records present logical, chronological 
step-by-step instructions that document how the PET drug is to be produced.6  Production should 
be discussed under headings, where applicable, such as accelerator operation, radiochemical 
synthesis, purification steps, and formulation of the finished product.  We recommend the entire 
production process be pre-established and fully described in the master production and control 
record.  The standard operating procedure (SOP) in performing a specific step can be referenced.  
The master production and control records would include specifications for each critical step.  
Critical steps include the process step, process condition, or other relevant parameters that are 
controlled within predetermined criteria to ensure that the API meets its specification.  Under 
 212.50(b), the master production and control records must include the following: 
 
  The name and strength of the PET drug in MBq/mL or mCi/mL (strength should be 
measured at a calibration time immediately after production). 
  If applicable, the name and radioactivity or other measurement of each API as well as any 
inactive ingredient (e.g., diluent, stabilizer, or preservative) per batch or per unit of 
weight or measure of the drug product and a statement of the total radioactivity or 
measurement of any dosage unit. 
  A complete list of components designated by names and codes (component code) 
sufficiently specific to indicate any special quality characteristic. 
  Identification of all major equipment used in production of the drug. 
  An accurate statement of the weight or measurement of each component (e.g., batch 
formula).  In the process of producing FDG F 18, for example, multiple components are 
weighed or measured by volume.  The radioactive component should be recorded in 
terms of radioactivity units. 
  A statement of the action limit on radiochemical yield (i.e., the minimum percentage of 
yield beyond which investigation and corrective action would be required).  
  Complete instructions (or references) for production, control, and testing of the PET 
drug.  The synthesis of certain PET drugs, such as FDG F 18, involves multiple steps 
including drying, exposure to organic solvents, heating, pH adjustments, passage through 
                                                 
6 In March 2000, FDA issued a draft guidance for industry entitled PET Drug Applications  Content and Format 
for NDAs and ANDAs  With the draft guidance, FDA made available sample formats for submitting the CMC 
section for certain PET drugs; the sample formats describe the nature of information that should be included in the 
batch production and control records.  The draft guidance and sample formats are available at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (under Procedural). 
The draft guidance, when finalized, will represent the FDAs current thinking on PET Drug Applications  Content 
and Format for NDAs and ANDAs. 
  
 
  19 Contents Are Only Recommendations 
 
 
purification media, and sterilizing filtration.  We recommend there be a description of all 
in-process steps and their controls so that the operator can confirm that all steps are 
completed within specified conditions, where feasible.  Controls for movement of liquids 
or gases should also be provided.  For automated radiochemical synthesis equipment, it 
may be sufficient to reference the equipment manufacturers manual that contains a full 
description of the automated production steps and controls. 
  A description of the PET drug product containers, closures, and packaging materials, 
including a specimen or copy of each label and all other labeling.  
 
Section 212.1 defines a batch of a PET drug as a specific quantity of PET drug intended to have 
uniform character and quality.  In the case of FDG F 18, a batch normally consists of the PET 
drug produced in a single synthesis and purification operation.  For ammonia N 13, a batch 
normally consists of multiple sub-batches having uniform character and quality, that are 
produced according to a single preparation order during one succession of multiple irradiation 
using a synthesis and/or purification operation.   
 
Section 212.50(c) requires the use of a batch record to document the production and testing of 
each batch.  The batch records provide complete traceability and accountability for production 
and control of each batch.  We recommend that information in the batch record (paper or 
electronic copy) accurately reflect the information contained in the master production and control 
records.  The control records may be cross-referenced and not be included as part of the batch 
record.  The batch record must contain the information needed for a documented history of the 
batch produced, including: 
 
  Documentation of the execution of each critical production step (e.g., timed events 
occurred within specifications, heating steps occurred at the specified temperature, and 
ingredients were properly transferred into the reaction vessel) where feasible, taking 
radiation exposure concern into consideration.  For an automated radiochemical synthesis 
unit, the printout or electronic record at the end of synthesis documenting the execution 
of the production steps and controls could be used for the chemical synthesis portion of 
the batch record.  
 
  A compilation of tests and printouts that led to acceptance of the final product. 
 
Under  212.50(c), information specific to batch production and control records includes the 
following: 
 
  Name and strength of the PET drug. 
 
  Unique identifier or number for each batch (an identifier or number also can be provided 
for each sub-batch 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. 
 
  Dates of production steps and times of critical production steps. 
  20 Contents Are Only Recommendations 
 
 
 
  Identification of major pieces of equipment where identical equipment in the facility can 
be used.  
 
  Actual weights (or measures) and identification codes of components used. 
 
  Labeling (a description of the finished drug product container label and the outer 
container label should be included). 
 
  Initials or signatures of the person(s) performing and checking each significant step of the 
operation. 
 
  Results of any investigations conducted (this should include documentation of any 
deviations and follow-up investigations).  Reference to the deviation and investigation 
reports can be indicated if stored separately.  
 
  Results of testing. 
 
Batch records should include documentation that each significant step in the production was 
accomplished.  When entries are made in batch records, an entry should be made directly after 
performing the activity (in the order performed) and would have to identify the person (signature 
or initials) making the entry.  Corrections to paper entries would be dated and signed or initialed, 
leaving the original entry still readable.  We recommend that each batch record be reviewed and 
approved for final release (signature/initials and date).  For requirements and information on 
electronic records and signatures, interested persons should refer to part 11 (21 CFR part 11, 
Electronic Records; Electronic Signatures) and the Agency guidance on Part 11, Electronic 
Records; Electronic Signatures  Scope and Application.7 
 
C.  Microbiological Control on Aseptic Processing and Sterilizing Filtration 
 
Most PET drugs are designed for parenteral administration and are produced by aseptic 
processing.  The goal of aseptic processing is to make a product that is free of microorganisms 
and toxic microbial byproducts, most notably bacterial endotoxins.  The use of aseptic technique 
and control of microbiological impurities in components can eliminate microbial and endotoxin 
contamination from PET drugs.  Aseptic processing of PET drugs should involve 
microbiological control over various types of components, as discussed below. 
                                                 
7 Available on the Internet at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  21 Contents Are Only Recommendations 
 
 
1.  Water 
 
Production processes that are relatively free of water or have rigorous chemical processes 
are unlikely to have microbial or endotoxin contaminants.  PET drug production facilities 
often use Water for Injection, USP (WFI), an approved drug product.  Using finished 
packaged WFI eliminates the need for the production facility to verify, maintain, and 
document the existence of a sterile water system.   
 
Nonsterile water can develop significant microbial growth in a matter of hours or days.  
We recommend that production processes that are water-intensive have sufficient 
controls to avoid microbial growth and development of biofilm (bacterial colonization).  
If nonsterile water is allowed to stagnate in a container or tubing, biofilm will develop.  
To minimize their contact with nonsterile water, it is recommended that tubing and 
glassware be washed, rinsed, and promptly dried.  
 
2.  Glassware 
 
Glassware and heat-resistant containers are relatively easy to keep free of microbial 
growth and pyrogens because they can be appropriately wrapped in foil and terminally 
sterilized by a suitable dry-heat cycle (see section VI).  Control procedures for these 
items should include prompt cleaning after use, rinsing with purified or WFI water, 
wrapping in aluminum foil, and depyrogenation by a suitable dry-heat oven cycle. 
 
3.  Transfer Lines 
 
Transfer lines, which are used for synthesis and transfer of solvents or products, are 
usually made of durable plastic and are amenable to reuse.  Prompt cleaning with organic 
solvents after use, rinsing with WFI, flushing with a volatile solvent, and drying with 
nitrogen are measures that help to control microbial contamination.  Organic solvents 
such as ethanol and acetone are useful as a final rinse and are easily dried from containers 
or lines.         
 
For PET drugs with a very short half-life (e.g., ammonia N 13), sometimes a long fluid 
line is used to deliver multiple batches of the product solution to a remote area for further 
processing.  We recommend that procedures be established to ensure that these fluid lines 
are clean and free of pyrogen contamination before each use.  
 
4.  Resin Columns 
 
Resin columns are a potential source of microbes and pyrogens because they can be 
contaminated with microorganisms.  If available, the purchase of low-microbial grade 
resin material may limit bioburden.  Material used for preparing resin columns should be 
suitably processed and rinsed with a large amount of WFI to control contamination.  The 
prepared column should be appropriately flushed.  Refrigerated storage is helpful in 
controlling contamination.  We recommend that wet columns not be stored for a 
prolonged period of time.  
  22 Contents Are Only Recommendations 
 
 
 
5.  Components 
 
The selection of a reliable vendor and high-quality materials are effective ways to limit 
the risk of microbiological contamination.  Components that support microbial growth 
during storage should be kept under controlled conditions and periodically assessed for 
microbial growth/ contamination. 
 
6.  Qualification for Aseptic Processing 
Aseptic processing in PET drug production normally consists of, but is not limited to, 
(1) the aseptic assembly of the container/closure system (syringe, needle, sterilizing filter 
and vial) and (2) sterile filtration of the PET drug.  The ability of personnel to perform 
aseptic processing can be assessed by conducting media fills.  Simulations of aseptic 
manipulations (e.g., the aseptic assembly of the container system, vent connection, and 
sterile filtration) can be carried out by substituting a bacterial growth medium for the 
actual drug product.  Media fills should be conducted in the facility in which the drug 
product is produced.  We recommend that an operator complete three successful media 
fill runs to qualify as a new operator.  Each operator can be requalified annually by 
conducting one media fill run.  Only personnel trained in aseptic techniques should 
conduct aseptic processing.  
 
7.  Sterilizing Filtration 
 
Even if care is taken to minimize microbiological contamination during synthesis, a drug 
is considered to be nonsterile until it is passed through a sterilizing grade filter.  
Generally, PET production facilities can use commercially available, presterilized filters 
to sterilize these solutions, provided that the vendor has been shown to be reliable, the 
filter is certified as compatible for the product, and it meets acceptable specifications.  
 
Integrity testing of membrane filters should always be performed postfiltration.  This is to 
ensure that the filter has performed according to specifications.  Testing can be 
accomplished by performing a validated filter integrity test (e.g., the bubble-point test) to 
show that the integrity of the filter was not compromised during or before use.  
 
8.  Environmental and Personnel Monitoring 
 
Environmental monitoring is crucial to maintaining aseptic conditions.  We recommend 
that microbiological testing of aseptic workstations be performed during sterility testing 
and critical aseptic manipulation.  Methods can include using swabs or contact plates for 
surfaces and settling plates or dynamic air samplers for air quality.  
 
  9.  Parametric Release of Terminally Sterilized Products 
 
Parametric release of a terminally sterilized PET drug product may be appropriate if 
conducted in accordance with the conditions stated in the products approved application. 
 
  23 Contents Are Only Recommendations 
 
 
D.  Process Verification and Computer Control  
 
Section 212.50(f)(1) states that for PET drug production in which every batch undergoes full 
finished-product testing to ensure the PET drug meets all specifications (e.g., FDG F 18), process 
verification is not required. 
 
Section 212.50(f)(2) requires that when the results of the production of an entire batch of a PET 
drug are not fully verified through finished-product 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 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.  
The determination not to conduct process verification for a PET drug should be supported by 
scientific rationale and data. 
 
1.  Process Verification Under  212.50(f)(2) 
 
For a PET drug production facility that has an established history of PET drug 
production, the process verification can be accomplished using historical batch records, 
provided that there is adequate accumulated data to support a conclusion that the current 
process yields batches meeting predetermined acceptance criteria.  We recommend that a 
comprehensive review of accumulated production, testing, and control data be conducted 
according to a written protocol defining the acceptable conditions.  The accumulated data 
should verify that the process used was consistent and should document all changes to 
and failures of the process.   
 
We recommend that new processes or significant changes to existing processes be shown 
to reliably produce PET drugs meeting the predetermined acceptance criteria before any 
batches are distributed.  This verification should be conducted according to a written 
protocol and generally include at least three consecutive acceptable production runs. 
 
Because of the unique characteristics of PET drug production, a PET producer may 
decide to evaluate the reliability of a new process or a significant change to an existing 
process to produce a PET drug by meeting the predetermined acceptance criteria 
concurrently with the distribution of the batch, provided that this approach is consistent 
with 21 CFR 314.70 and is set forth in the products approved application.  Such a 
decision should be justified in writing, subjected to quality assurance procedures, and 
performed according to a written protocol.  Each batch should be processed in strict 
adherence to the written procedures, fully tested (except sterility testing), and found to 
comply with all procedural and quality test requirements prior to final release.  
 
2.  Computer Control 
 
Synthesis of some PET drugs can be executed under automated or computer control.  We 
recommend that the operation of the computer program be verified before first use to 
  24 Contents Are Only Recommendations 
 
 
demonstrate that the program is suitable for its intended purposes and is capable of 
producing results that meet the predetermined acceptance criteria.  We also recommend 
that subsequent changes or upgrades made to the computer program be documented and 
the process demonstrated to be capable of producing a PET drug that meets the 
predetermined acceptance criteria.  PET drug production facilities can rely on a 
certification by the software or system vendor that the specified software was verified 
under its operating conditions.  
 
 
IX.  LABORATORY CONTROLS 
 
A.  Regulatory Requirements  
 
Section 212.60 requires the establishment and implementation of procedures for testing 
components, in-process materials, and finished PET drug products.  All necessary tests of 
materials and products must be documented.   Each laboratory must have sampling and testing 
procedures designed to ensure that components, drug product containers and closures, in-process 
materials, and PET drug products conform to appropriate standards.  Analytical methods and test 
equipment must be suitable for their intended uses.  Reagents, solutions, and supplies used in 
testing procedures must be adequately controlled.  The preventive maintenance, calibration, and 
procedures to make sure that the equipment is functioning properly must be documented.  A 
complete record of all tests related to the production of a PET drug must be kept to ensure 
compliance with established specifications and standards, including examinations and assays, as 
follows: 
 
  A suitable identification of the sample.  
 
  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 (including graphs, charts, and spectra), e.g., a print-out of 
the chromatogram with the calculated amounts of each component analyzed by the test. 
 
  A statement of results of the tests and their relation to acceptance criteria. 
 
  The initials or signature of the analyst and the date of the test. 
  25 Contents Are Only Recommendations 
 
 
 
B.  Laboratory Controls 
 
Under  212.60, a PET drug production facility must have written test procedures that describe 
how to conduct each test of finished products and, where applicable, of components and in-
process materials.  Appropriate testing procedures must be established to ensure that PET drugs 
conform to appropriate standards, including established standards (e.g., relevant USP 
monographs) of identity, strength, quality, and purity.  Analytical tests must be suitable for their 
intended purpose and must be sufficiently sensitive, specific, reproducible, and accurate).   
 
We recommend that any new analytical test method be validated, through documented data, to 
show that it will consistently yield results that accurately reflect the quality characteristics of the 
product tested.  The FDA and USP have published information for determining the appropriate 
analytical parameters (e.g., accuracy, precision, linearity, ruggedness) that should be used to 
validate a new method (see ICH Q2A Text on Validation of Analytical Procedures and USP 
General Chapter <1225> Validation of Compendial Methods).  
 
If a USP analytical test method is used, a PET drug producer should verify that the method 
works under the actual conditions of use.   
 
Most analyses use reference standards.  We recommend that PET drug production facilities 
establish the reference standards identified in the analytical procedure or SOP.  When a primary 
reference standard is obtained from an officially recognized source (e.g., USP), the material 
usually does not need further testing if it is stored under conditions consistent with the suppliers 
recommendations.  However, where an official standard is not available or if a PET drug 
production facility establishes its own reference standard, we recommend that data to fully 
confirm the materials identity and purity be established and documented.  Documentation such 
as reference spectra or other supporting data to prove the identity and purity of the reference 
standard may be available from the supplier. 
  
Under  212.60(f), equipment must be routinely calibrated and maintained according to the 
established written procedures (see section VI).  We recommend that PET drug production 
facilities verify that the equipment is in good working condition at the time the samples are 
analyzed.  We also recommend that prior to each day of use of the HPLC and GC, a system 
suitability test using reference standards be conducted to verify that the resolution and 
reproducibility of the chromatographic system are adequate for the analysis to be done. 
 
We recommend that any reagent or solution prepared on-site be adequately controlled (including 
temperature control, if applicable) and properly labeled with respect to identity, composition, and 
expiration date.  
 
Raw test data (such as chromatograms, spectra, and printouts) and any calculations performed 
can be documented and become part of the batch production and control record.  Records should 
have information such as the source of the test material, a description of the appearance of the 
material, the amount used, test and acceptance criteria, and an entry for data and interpretation of 
results.  Laboratory controls should be followed and documented at the time of performance.  
  26 Contents Are Only Recommendations 
 
 
We recommend that deviation from written procedures be documented and justified.  Any out-
of-specification results obtained should be investigated and documented. 
 
 
X.  STABILITY TESTING 
 
A.  Regulatory Requirements 
 
Section 212.61 requires the establishment of a written stability testing program for each PET 
drug product.  This program must be used to establish suitable storage conditions as well as 
expiration dates and times. 
 
B.  Guidance on Stability 
 
As with other drug products, PET drug molecules are expected to remain stable during storage.  
Although PET drugs have extremely short shelf lives, because of their short half-lives compared 
to other kinds of drug products, there are stability concerns due to radiation-related radiolysis.  
Certain PET drugs (e.g., F 18 fluorodopa) can undergo very rapid chemical changes.  Therefore, 
appropriate parameters should be evaluated to establish and document the stability of PET drug 
products under proposed storage conditions.  Examples of stability parameters include 
radiochemical identity and purity (including levels of radiochemical impurities), appearance, pH, 
stabilizer or preservative effectiveness, and chemical purity.  We recommend that appropriate 
stability-indicating methods that can distinguish degradation products and impurities be used.  
Stability testing of the PET drug product should be performed at the highest radioactive 
concentration, and the whole batch volume in the intended container/closure should be stored.  
At least three production runs of the final product should be studied for a time period equal to the 
labeled shelf life of the PET drug product.   
 
Although stability studies in support of an expiration dating period are needed for approval of a 
PET drug under  314.50(d)(1)(ii), subsequent changes to the expiration date could be made 
without prior approval (changes would be noted in the annual report for the drug product).  The 
stability studies supporting a changed expiration date should be conducted in accordance with 
the post-approval stability protocol in the drug products approved application. 
 
 
XI.  FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA 
 
A.  Regulatory Requirements 
 
Section 212.70(a) requires that specifications be established for each PET drug product batch, 
including identity, strength, quality, purity, and, if appropriate, sterility and pyrogens.  Section 
212.70(d) requires the implementation of procedures to ensure that a product is not released until 
an appropriate laboratory determination is completed, reviewed, and approved by an appropriate 
releasing authority.   
 
  27 Contents Are Only Recommendations 
 
 
Section 212.70(c) requires that an appropriate laboratory determination be conducted to ensure 
that each batch (or sub-batches, for products produced in sub-batches) of a PET drug product 
conforms to specifications, except for sterility, before final release.  
 
Section 212.71 requires a PET drug production facility to reject PET drug products that do not 
conform to specifications.   Procedures must be established to identify and segregate such 
products.  There must be predetermined procedures for investigating the cause of the problem.  
The investigation must be documented, including the results and what happened to the rejected 
product.  In addition, action must be taken to correct any identified problems and prevent 
recurrence. 
 
B.  Finished-Product Testing 
 
Under  212.70(a), PET drug production facilities must ensure that each batch of PET drug 
product meets its established acceptance criteria, except for sterility (see section XI.C below), 
before it is given final release. 
 
Under  212.70(c), an appropriate laboratory determination is required to ensure that each batch 
of a PET drug product conforms to specifications, which are the measurements of critical quality 
attributes that are indicative of the products safety and effectiveness.  PET drug product 
specifications include radiochemical identity and purity, assay (including radioconcentration), 
specific activity, radioactive and nonradioactive impurities, and sterility.  Because methods of 
PET drug production may differ from site to site, there may be specific impurities to assess 
depending on the method of production at a site, such as kryptofix in FDG F 18. 
 
 An appropriate laboratory determination under  212.70(c) might include the following:   
 
  Finished-product testing  If finished-product testing alone is used, each batch 
should be tested at its conclusion for conformance to specifications. 
 
   In-process testing  In-process testing might involve use of an on-line test to 
measure an attribute that includes an appropriate acceptance criterion, provided that 
the relevant attribute does not change during the production of the finished product. 
 
   Continuous process monitoring of an attribute with statistical process controlsThis 
process involves comprehensive testing of an attribute using on-line monitoring and 
corresponding adjustments to prevent an upward or downward drift in batch-to-batch 
measurements of the attribute. 
 
  Some combination of these approaches.   
 
Depending on the particular PET drug product and specification, any of the approaches 
suggested above might be appropriate for conducting an appropriate laboratory determination to 
ensure that each batch of the product conforms to the specification.  The laboratory 
determination approach for each specification should be set forth in the products marketing 
application. 
  28 Contents Are Only Recommendations 
 
 
 
Although  212.70(c) addresses conformance to specifications, we recognize that there may be 
attributes of a PET drug product that, although not as significant as those included in the 
specifications, are nevertheless important in assessing the quality of the product.  Examples of 
these noncritical attributes might include radionuclidic purity (when potentially contaminating 
radionuclides do not impact the safety or effectiveness of the drug product), as well as certain 
low-level nontoxic impurities and class 3 residual solvents.  For a particular noncritical attribute, 
a PET drug producer might conduct a periodic quality indicator test (PQIT).  A PQIT is a 
noncritical test performed in addition to specification tests.  A PQIT can be performed at 
predetermined intervals rather than on a batch-to-batch basis.  A PET drug producer generally 
establishes and refines tests of noncritical attributes within its internal quality system.  However, 
a PQIT analytical method and limits should also be established in an approved application before 
implementation.  The frequency of PQIT testing will be reviewed during CGMP inspections. 
 
It should be noted that performance of a PQIT on a periodic basis should be contingent upon use 
of a process that is under a state of control (i.e., produces a quality product that consistently 
meets specifications and conforms to an appropriately established facility, equipment, 
processing, and operational control regimen).  If a drug product fails an established PQIT, the 
PET drug producer should immediately revert to full testing (i.e., testing of every batch for the 
attribute specified in the PQIT) until the cause of the failure has been conclusively determined, 
corrective action has been implemented, and the process is again documented to be in a state of 
control. 
 
C.  Microbiological Tests for Sterile PET Drug Products 
 
Section 212.70(e) requires that sterility testing be started within 30 hours after the completion of 
PET drug production; however, the 30-hour requirement may be exceeded due to a weekend or 
holiday.  The regulation states that if the sample for sterility testing is held longer than indicated 
(e.g., over the weekend), the PET drug producer must demonstrate that the longer period does 
not adversely affect the sample and the test results obtained will be equivalent.  The samples 
should be stored appropriately (e.g., under refrigeration).  Verification of equivalent results can 
be accomplished by inoculation of a USP indicator organism (e.g., E. coli) and should 
demonstrate that there is little, if any, loss in viability of the inoculated microorganism.  The 
USP General Chapter <71> Sterility Tests provides information about media and incubation 
conditions. 
 
We recommend that testing be conducted in a controlled area such as an LAFW with clean-room 
apparel.  Aseptic techniques should be used for sterility testing.  The greatest risk of false-
positive results arises in the sampling and transfer of the test aliquot from the vial to the media.  
It may be convenient to apply direct inoculation into commercial media.  We recommend that the 
media be observed on days 3, 7, and 14 after inoculation, but it is prudent to observe the media 
more often during the first week of incubation.  
 
The USP Bacterial Endotoxins Test (BET) (General Chapter <85>) should be performed for a 
sterile PET drug product that is intended for injection.  The BET contains gel-clot and rapid 
photometric methods for endotoxin measurement. 
  29 Contents Are Only Recommendations 
 
 
 
The product can be distributed under control after a pharmacopeial bacterial endotoxin test is 
initiated.  However, the endotoxin results should meet the acceptance criteria before 
administering the product to humans.   
 
If the result of any bacterial endotoxin test exceeds the acceptance limit, or if a sterility test is 
positive for microbial growth, we recommend that a complete investigation be conducted 
immediately and documented.  We recommend that corrective actions based on the results of the 
investigations be implemented promptly. 
 
D.  Accepting and Releasing a Batch (Lot) 
 
We recommend the designated individual review all laboratory testing and documentation from 
the batch record to determine whether or not the PET drug product has met all acceptance 
criteria.  If the product has met acceptance criteria, the designated individual with quality 
assurance function should sign and date the release sections of the batch record and sign a release 
for human administration.   
 
In many cases, modifications to this standard procedure for product release may be appropriate.  
For example, transportation deadlines may justify a prerelease for distribution before all 
elements of testing and review are finalized.  Other than sterility testing, all finished-product 
tests would have to be completed or in progress at the time of shipment or distribution, and PET 
drug products can be released for distribution (but not administration) while some tests are 
pending.  Under  212.70(c)-(d), before final release of a PET drug product for human 
administration, there must be a determination that the product meets specifications, except for 
sterility.  When it is determined that all acceptance criteria have been met, the PET drug 
production facility should then provide a notice of final release to the receiving facility so that 
the dose may be given to the patient.  We recommend the establishment of effective procedures 
for immediate notification of the receiving facility if there is evidence of an out-of-specification 
result, and the notification should be documented. 
 
PET drugs that have a very short half-life (e.g., ammonia N 13) can be produced in multiple sub-
batches on the same day.  Finished-product testing of the initial sub-batch can be conducted, 
provided a sufficient number of sub-batches (beginning, middle, and end) have been 
demonstrated to produce a product meeting the predetermined acceptance criteria.  For routine 
production in this circumstance, the release of subsequent sub-batches can be qualified if the 
initial sub-batch meets all acceptance criteria.  In certain cases, testing each sub-batch for certain 
attributes prior to release may be appropriate (e.g., for pH determination in ammonia N-13 
production method using Devardas alloy catalyst).  
 
E.  Conditional Final Release 
 
When one of the required finished-product tests cannot be completed due to a malfunction 
involving analytical equipment, the product may still be released for human use under the 
conditions stated in  212.70(f).  If equipment is properly maintained, malfunctions should be a 
rare occurrence.  We recommend that PET drug producers determine if the missing testing would 
  30 Contents Are Only Recommendations 
 
 
adversely affect the safety and effectiveness of the PET drug product.  Conditional release 
should be extremely infrequent.  Under  212.70(f)(1), only products that meet all conditional 
release criteria may be released.  Under  212.70(f)(2), conditional release of a PET drug product 
would not be permitted if a PET drug producer could not perform a radiochemical identity/purity 
test on the API of a PET drug product or could not determine the products specific activity.  All 
activities of conditional release must be documented. 
 
F.  Rejection and Reprocessing 
 
Under  212.71(a), a batch of a PET drug product that fails to meet established specifications 
must be rejected, and procedures must be established to identify and segregate the product.  
Section 212.71(b) requires that documentation of the investigation of a nonconforming product 
include the results of the investigation and final disposition of any rejected product. 
 
Under  212.71(d), a drug product can be reprocessed if procedures stated in the products 
approved application are followed and the finished product conforms to specifications (except 
for sterility) before final release.  When the option for reprocessing is exercised, we recommend 
that the event be documented and conditions described in a brief deviation report.  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. 
 
 
XII.  LABELING AND PACKAGING 
 
A.  Regulatory Requirements 
 
Section 212.80 requires that: 
 
  A PET drug product be suitably packaged and labeled to protect the product from 
alteration, contamination, and damage during the established conditions of shipping, 
distribution, handling, and use. 
 
  Labels and packaging operations be controlled to prevent labeling and product mix-ups. 
 
  All information stated on each label be contained in each batch production record.  
 
B.  Recommendations on Labeling and Packaging 
 
Regardless of the scope of operation of a PET drug production facility, under  212.80(d), 
appropriate measures must be taken to handle labels in a way that prevents mix-ups with any 
other labeling materials.  
 
We recommend that PET drug products be labeled with adequate, legible identifying information 
to prevent errors during storage, shipment, and use.  Once an NDA or ANDA is approved for a 
PET drug product, the label approved in the NDA must be used.  Before approval of the NDA or 
  31 Contents Are Only Recommendations 
 
 
ANDA, the label should be approved by persons responsible for quality assurance procedures.  
Labels can be computer generated or handwritten. 
  
Because of radiation exposure concern, it is a common practice to prepare much of the labeling 
in advance.  For example, an empty product vial can be prelabeled with partial information (e.g., 
product name, batch number, date) prior to filtration of the radioactive product, and upon 
completion of a QC test, the outer shielded container can be labeled with the required 
information (e.g., radioactivity).  Alternatively, a string label can be used to label the immediate 
container provided that there is a way to associate the label with the vial if the label were to 
come off.  Different approaches can be used as long as the approach ensures that the required 
information is available on the label.  A label identical to that affixed to the container shield can 
be incorporated into the batch production record.  A final check should be made to verify that the 
correct and complete label has been affixed to the container and the shield. 
 
 
XIII.  DISTRIBUTION 
 
A.  Regulatory Requirements 
 
Section 212.90 requires the development of procedures to ensure that shipment will not 
adversely affect the product.  PET drug production facilities must maintain distribution records 
for PET drug products. 
 
B.  Recommendations 
 
PET drug products should be shipped in accordance with labeled conditions (e.g., temperature) 
to ensure the identity, purity, or quality of the drug product.  For PET drug production facilities 
distributing to outside clients or outside pharmacies, information on the method of shipment and 
the contact person at the final destination should be included in distribution records.  We 
recommend that a system be put in place by which the chain of distribution of each batch of PET 
drug product can be readily determined to permit its recall if necessary.  A recall should consist 
of notifying the receiving facility, the pharmacist, and the patients physician, if known.  When 
the receiving facility disposes of the recalled drug, the PET drug producer can obtain a 
notification from the receiving facility confirming the recalled drug has been disposed of and 
describing the manner in which it was disposed. 
 
When a PET production facility ships a final released PET drug product supplied as a pharmacy 
bulk package (USP<1> Injections) to a nuclear pharmacy for dispensing into individual patient 
doses, FDA generally regards subsequent distribution of the drug product as part of the practice 
of pharmacy. 
 
 
  32 Contents Are Only Recommendations 
 
 
XIV.  COMPLAINT HANDLING 
 
A.  Regulatory Requirements 
 
Section 212.100 requires that procedures be developed and implemented for receipt and handling 
of all complaints pertaining to the quality and labeling of, or possible adverse reactions to, a 
specific PET drug product, including review by a designated individual to determine compliance 
with specifications and to initiate an investigation into the problem.  A written record of each of 
these complaints must be maintained.  The record must contain 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.  The record also must 
include the findings of any investigation and followup.  A PET drug product returned because of 
a complaint or for any other reason may not be reprocessed and must be destroyed in accordance 
with applicable Federal and State law. 
 
B.  Recommendations 
 
We recommend that the designated individual be responsible for collecting as much information 
as possible about the drug and the nature of a complaint and for completing an investigation of 
the matter as soon as possible.  Corrective action should be taken immediately if there is any 
reason to believe that an adulterated drug was implicated in the complaint.  We recommend that 
complaint files reviewed under  212.100(c) be easily retrievable for review and evaluation of 
possible trends. 
 
 
XV.  RECORDS 
 
A.  Regulatory Requirements 
 
Section 212.110(a) requires that all records be maintained at the PET drug production facility or 
another location that is reasonably accessible to responsible officials of the facility and FDA 
investigators.  
 
Section 212.110(c) requires that all records referenced in part 212 be kept for at least 1 year from 
the date of final or conditional final release of a PET drug product. 
 
B.  Recommendations 
 
A reasonably accessible location for the storage of records under  212.110(a) is one that would 
enable the PET drug production facility to make requested records available to an FDA 
investigator in a reasonable period of time during an inspection.  Under  212.110(b), the records 
must be legible and stored in a manner that prevents their deterioration and/or loss. 
 
We recommend that forms for collecting data be kept to a minimum by designing multipurpose 
documents and eliminating redundancy, where possible.  It is prudent to have as much of the 
  33 Contents Are Only Recommendations 
 
 
required information within the batch production record as possible.  Records can be kept 
electronically.  
 
Other records that must be kept include information relating to the composition and quality of 
the PET drug product ( 212.40(e)) and to the operation of production and other processes, such 
as laboratory records ( 212.60(g)), out-of-specification results ( 212.71(b)), master and batch 
records ( 212.50(b) and (c)), distribution records ( 212.90(b)), and complaint files 
( 212.100(c)).  Records relevant to materials and PET drug products must be kept at least 1 year 
from the date of final or conditional final release under  212.110(c).  Verification reports should 
be kept as long as the systems are in use. 
  34 Contents Are Only Recommendations 
 
 
REFERENCES 
 
FDA.  Enforcement Policy:  Electronic Records; Electronic Signatures.  FR Notice (64 FR 
39146, July 21, 1999). 
 
FDA.  Guide to Inspection of Computerized Systems in Drug Processing.  February 1983. 
 
FDA.  General Principles of Process Validation.  May 1987. 
 
FDA.  Part 11, Electronic Records; Electronic Signatures  Scope and Application.  August 
2003. 
 
FDA.  Q2B Validation of Analytical Procedures: Methodology.  May 1997. 
 
FDA.  Q2A Text on Validation of Analytical Procedures.  March 1995. 
 
FDA.  Reviewer Guidance  Validation of Chromatographic Methods.  November 1994. 
 
FDA.  Sterile Drug Products Produced by Aseptic Processing  Current Good Manufacturing 
Practice.  September 2004. 
 
U.S. Pharmacopeia.  <1> Injections.  USP 32, NF 27, 2009. 
 
U.S. Pharmacopeia.  <71> Sterility Tests.  USP 32, NF 27, 2009. 
 
U.S. Pharmacopeia.  <85> Bacterial Endotoxins Test.  USP 32, NF 27, 2009.  
 
U.S. Pharmacopeia.  <621> Chromatography.  USP 32, NF 27, 2009. 
 
U.S. Pharmacopeia.  <821> Radioactivity.  USP 32, NF 27, 2009. 
 
U.S. Pharmacopeia.  <823> Radiopharmaceuticals for Positron Emission Tomography 
Compounding.  USP 32, NF 27, 2009. 
 
U.S. Pharmacopeia.  <1015> Automated Radiochemical Synthesis Apparatus.  USP 32, NF 27, 
2009. 
 
U.S. Pharmacopeia.  <1225> Validation of Compendial Methods.  USP 32, NF 27, 2009. 
 
 
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