Draft  Not for implementation 
 
Attachment I 
 
Sample Formats 
 
Chemistry, Manufacturing, and Controls (CMC) Section 
 
 Ammonia N 13 Injection 
Fludeoxyglucose F 18 Injection (FDG F 18) 
and 
Sodium Fluoride F 18 Injection  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: August 2011 
 
These sample formats for the chemistry, manufacturing, and controls section have been prepared by the PET 
Steering Committee in the Center for Drug Evaluation and Research at the Food and Drug Administration.  This 
document represents the Agencys current thinking on the production of these positron emission tomography (PET) 
drug products.  It does not create or confer any rights for or on any person and does not operate to bind FDA or the 
public. An alternative approach may be used if such approach satisfies the requirements of the applicable statues, 
regulations, or both. 
 
 
  Draft  Not for implementation 
Table of Contents 
 
 
 
 
Ammonia N 13 Injection..................................................................................................1 
Fludeoxyglucose F 18 Injection.....................................................................................15 
Sodium Fluoride F 18 Injection......................................................................................33 
 
 
 
 
 
 
 
INSTRUCTIONS 
 
 
 
1.  At a number of places, the sample format contains text that provides guidance to 
assist you in the preparation of the CMC section of your NDA or ANDA. Such text is 
in italics, and may be omitted in the submitted NDA or ANDA. 
 
2.  Where necessary, the CMC section may be expanded or contracted to include 
additional or less information, respectively. Ammonia N 13 Injection 
CMC Sections  
  Draft  Not for Implementation 
 
Ammonia N 13 Injection 
 
1.  DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION 
 
     
       Component  Composition/mL  Composition/ 
sub-batch vial 
     
Drug Substance  ____ to ____ mCi @ EOS1 ____ to ____ mCi @ EOS1
Ammonia N 13  (____ to ____ MBq @EOS)  (____ to ____ MBq @EOS) 
   
 
Inactive ingredient(s)2            
 
   
1.    ____________________       ____________________      
      (e.g., Sodium chloride       (e.g., 1 mL)  _________________mL  
       injection, USP)     
    
1.  EOS = End of synthesis calibration time 
2.  Provide all inactive ingredients used in drug product. Examples of inactive ingredients include 
diluents, buffers, stabilizers, and preservatives. 
 
2.  CONTROLS FOR COMPONENTS AND OTHER RAW MATERIALS 
 
A.  TARGET MATERIAL (Starting material) 
 
The following target material will be used for the production of ammonia N13: 
[Note: If multiple components are used in the target, include the one(s) that undergoes nuclear 
reaction to produce drug substance.] 
 
   
 
1.  Name of the target material 
   
 
2.  Name and address of the target 
 
material manufacturer 
   
     
3.  Specifications  TEST              ACCEPTANCE                   TEST 
[Specifications to control identity,                           CRITERION               PROCEDURE
purity, relevant quality should be   
proposed]   
   
 
Attachment ______, page ______. 
     
4.  Identity test performed to release  TEST     PROCEDURE     ACCEPTANCE                   
each lot for production use                                                  CRITERION 
  _____              _______        ____________________ 
 
 
The procedure is provided in attachment ________, 
page_____. 
 
Certificate of analysis (COA)  Copy of representative COA is provided in attachment 
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5.  ______, page_______.  
     
6.  Is the target material recycled?  ______ Yes ______ No. 
If yes, its reprocessing procedures are described in 
attachment _______, page______. 
 
Data to support that the reprocessed material 
conforms to the acceptance criteria for the target 
material are provided in attachment ______, 
page____. 
 
 
We intend to use additional suppliers for this target material: _____Yes _____No. 
 
If yes, for each additional supplier, the target material information specifically identified in items 1, 2, 
and 5 above is provided in attachment ______, page______. 
 
B.  INACTIVE INGREDIENTS 
 
The following inactive ingredients are used in the ammonia N 13 injection drug product: 
 
       
Name  Function of  Name and address  Specifications, 
the inactive  of the manufacturer  representative COA and 
ingredient  acceptance procedures for 
each lot are included 
       
        Attachment _____, page 
  ____. 
       
      Attachment _____, page 
  ____. 
[Note: COA need not be provided if the inactive ingredient used is a marketed finished drug product.] 
 
Additional inactive ingredients (if any) are listed and the information is provided in attachment______, 
page ______. 
 
C.  REAGENTS, SOLVENTS, GASES, PURIFICATION COLUMNS, AND OTHER AUXILIARY 
MATERIALS 
 
Provide following information for each reagent, solvent, gas, purification column, and other auxiliary 
material that is used in the production of ammonia N 13 injection: 
 
     
                   Name  Name and address of the  Quality grade (e.g., ACS, USP, 
supplier  etc.) or specifications, 
representative COA, and 
acceptance procedures for 
each lot are included 
 
    
 
  Attachment _____, page ____. 
1 
   
   
2   
  Attachment _____, page ____. 
 
    
  3 Draft  Not for Implementation 
    Attachment _____, page ____. 
3 
       
       
4    Attachment _____, page ____. 
 
       
       
5    Attachment _____, page ____. 
   
       
       
6    Attachment _____, page ____. 
 
   
[Note: The above table can be extended, if needed, to include additional raw materials, and 
information provided in an attachment] 
 
 
3.  REFERENCE STANDARDS 
 
The following reference standards are used in the quality control test methods of ammonia N 13 
injection: 
[Note: If a reference standard is obtained from USP, it should be so stated. If a reference standard is 
not  obtained from USP, data to support that the reference standard has the desired structure must be 
submitted in the indicated attachment. Purity of the reference standard lot should be provided.] 
 
     
Name of reference standard  Name and address of the  Specifications, representative 
supplier  COA, and acceptance 
procedures for each lot are 
included 
     
 
     
Ammonium chloride 
1    Attachment _____, page____ 
 
 
 
4  PRODUCTION AND TESTING FACILITIES 
 
Name of PET drug production facility:  __________________________________________ 
  Address:           __________________________________________ 
              __________________________________________ 
__________________________________________ 
  Name of contact person:      __________________________________________   
  Phone number of contact person:    __________________________________________  
   
  Additional production and/or testing facilities (if any), including their function, are listed in  
  attachment ________, page  ____  
 
 
5.  PRODUCTION OF DRUG SUBSTANCE 
 
A.  BATCH FORMULA 
 
The following components and quantities are used in the production of each batch of ammonia N 13 
  4 Draft  Not for Implementation 
drug substance: 
[Provide the name of each component (include all reactants, solutions, solvents, and reagents used in 
the chemical synthesis and purification operation) used in the production of ammonia N 13, whether or 
not it appears in the final product, its function, and the amount (mass or volume) used in each batch] 
 
     
Name of component   Components function  Amount used 
   
 
   
     
     
     
     
     
     
     
     
 
B.  PRODUCTION OF RADIONUCLIDE  
 
(i)  Particle Accelerator (e.g., Cyclotron) Used 
 
The following particle accelerator is used for the production of ammonia N 13: 
 
MAKE:   ____________________________________ 
MODEL:  ____________________________________ 
   
Information concerning additional particle accelerators, if any, is provided in attachment _______, 
page ______. 
 
(ii)  Operating Parameters 
 
  During irradiation a beam current of _____A  +  ____A is used. 
  Irradiation times of _____ minutes to _____ minutes are used (identify for batch or sub-
portion, as appropriate) 
  We use/do not use high-pressure targets. When high-pressure targets are used, irradiations 
are performed under ____ psi pressure.   
 
(iii) Specifications for Target Body  
 
  Volume of the target body is ____________ l or ml.    
  The target body used in production operation is composed of  _____________________. 
  The target windows used in target body are ___________ (state thickness) and are 
composed of ____________________________________________________________. 
  The schedule for the replacement of target windows is ___________________________. 
  The acceptance criteria for the target body and the target windows (that come in contact with 
target material) are provided in attachment _________, page  _______. 
 
If multiple target bodies of different types are used, the above information concerning each is 
provided in attachment ________, page ______. 
 
C.  SYNTHESIS AND PURIFICATION OF THE DRUG SUBSTANCE 
 
(i)  Description of Synthesis and Purification Equipment 
 
A description of the synthesis and purification equipment, including a complete schematic flow 
  5 Draft  Not for Implementation 
diagram, is provided in attachment ______, page _______.  
 
The following information should be provided if a commercial unit is used: 
 
MAKE:   ____________________________________ 
MODEL:  ____________________________________ 
 
(ii)   Description of Synthesis and Purification Operation 
 
A step-wise description of the synthesis and purification procedure, including the amount of each 
reactant, reagent, solvent used, and radiochemical yield(s) obtained is provided in attachment 
_______, page _____. 
 
   [Note: Description should also include pr eparation and manipulation of sub-batches] 
 
(iii)  In-Process Controls 
 
The synthesis and purification procedure is controlled by monitoring the process controls and 
parameters described in attachment ______, page_____. 
 
[Note: We recommend that the applicant have adequate process controls to ensure continued 
quality of the product.  The specified process controls should be monitored and documented in the 
master production and control records]  
 
(iv)  Post-Synthesis Procedures 
 
Description of procedures used to prepare the production equipment, including any cleaning and 
purging procedures, for a subsequent batch is provided in attachment _______, page _____. 
 
 
6.  PRODUCTION OF DRUG PRODUCT 
 
A.  PRODUCTION OPERATION 
 
The drug substance obtained following the synthesis and purification procedures is collected in 
the final product vial. The specific procedures used in the formulation and preparation of the 
finished drug product are provided in attachment _____, page _____. 
 
A copy of the master production and control records, which provide the specific procedures used 
in the production of and ensure full traceability / accountability of all components, materials and 
equipment used and the operators for each batch of ammonia N 13 injection, is provided in 
attachment ______, page _____. 
 
B.  REPROCESSING OF PET DRUG PRODUCT 
 
    Check below as appropriate and provide the indicated information. 
 
  A PET drug product batch or lot (or sub-batch thereof) will not be reprocessed. 
  A PET drug product batch or lot (or sub-batch thereof) may be reprocessed under the specific 
conditions (circumstances) described in attachment _____, page _____.  
 
The validated procedures (include SOP) used in reprocessing are described in attachment 
______, page _____. 
 
C.  PACKAGING AND LABELING 
 
  6 Draft  Not for Implementation 
The components used in the packaging of the finished drug product vial and the method of 
labeling are described in the master production and control records on page ______ (attachment 
_____).  
 
The specifications for the packaging components and acceptance procedures for each lot are 
provided in attachment _____, page _____.  
 
 
7.  CONTAINER/CLOSURE 
  
  We use a presterilized, presealed, pyrogen-free container/closure, consisting of USP Type I glass, 
gray butyl rubber stopper, and aluminum crimp seal, from a commercial supplier: _____Yes _____ No. 
 
  If no, information on the container/closure along with its sterilization procedures and sterility assurance 
is provided in attachment ______, page ______. 
 
  If yes, the _____ ml container/closure, consisting of USP Type I glass, gray butyl stopper, and 
aluminum crimp seal, is obtained from the following manufacturer. The specifications and procedures 
used for accepting a lot of container/closure are provided in attachment _____, page _____. 
 
Container/closure catalog #    ___________________________________ 
Name and address of supplier   ___________________________________ 
___________________________________ 
___________________________________ 
    Drug master file number     ___________________________________ 
 
A letter of authorization from the DMF holder, authorizing FDA to refer to the DMF in connection with 
this NDA/ANDA, is provided in attachment _____, page ______. 
 
 
8.  CONTROLS FOR THE FINISHED DOSAGE FORM 
 
A.  SAMPLING PROCEDURES 
 
Each batch of ammonia N 13 injection consists of up to ________ sub-batches, where each sub-
batch is produced in one new vial and the entire batch is produced in multiple vials. 
 
To ensure that each batch (i.e., all sub-batches) meets the finished product acceptance criteria; 
the following vials are tested for the quality control (check as appropriate): 
 
  The first and the last vial (sub-portions) obtained for each batch. 
  The first vial obtained for each batch; we have validated that ______(enter the number) sub-
batches produced in a batch are equivalent. The data to demonstrate equivalency of the 
above number of sub-batches on three production batches (test sample obtained from 
beginning, middle and end) are provided in attachment ______, page _____. 
 
  B.  REGULATORY SPECIFICATIONS  
 
Each batch of the ammonia N 13 injection will meet the following specifications during its entire 
shelf life when tested according to the standard test procedures described in the SOPs submitted 
as part of this NDA / ANDA:   
 
[Note:  The following tests are related to a commonly used production method. In the event that a 
production method does not use a component listed below or uses an alternate method or 
produces additional impurities, appropriate tests, acceptance criteria, procedures, and testing 
  7 Draft  Not for Implementation 
schedules that are more appropriate for such production method should be proposed.] 
 
  
       
TEST  ACCEPTANCE   TEST PROCEDURE  TESTING 
CRITERIA  &   SCHEDULE 
SOP NUMBER 
       
Appearance  Colorless and free from  Visual observation under  Each sub-batch of 
particulate matter    lighted conditions  a batch is tested 
SOP# ______________ 
 
       
Radionuclidic  The measured half-life is  Measurement of  Quality control sub-
identity  between 9.5  10.5  radioactivity for decay of  batch; testing for 
minutes.  a sample over a 10  first sub-batch is 
minute period  completed prior to 
SOP# ______________  preparation of 
  clinical sub-batches 
       
Radiochemical  The retention time (Rt) of  HPLC  Quality control sub-
identity  major peak in test solution    batch; testing for 
corresponds (e.g., + 5%)  SOP#_______________  first sub-batch is 
with the retention time    completed prior to 
peak obtained for the  preparation of 
reference standard  clinical sub-batches 
solution. 
       
Radionuclidic purity  State limit and provide  Gamma spectroscopy of   State schedule and 
  justification in an  decayed sample  provide justification 
attachment.  SOP# _______________  Attachment______ 
Attachment__________    Page___________  
Page_______________ 
       
Radiochemical  NLT1 95.0 %   HPLC  Quality control sub-
purity  Ammonia N 13    batches; testing for 
  SOP#_______________  first sub-batch for 
  first sub-portion 
completed prior to 
 
preparation of 
clinical sub-batches 
       
Assay  ____mCi to ____ mCi / mL  Refer to USP   Each sub-batch 
(radioactivity  @ EOS for each sub- SOP# _______________   
concentration)  batch (vial)     
     
Specific activity 
NLT1 10 Ci / mmol   HPLC  State schedule / 
 
  SOP# _______________  provide justification 
 
 
   
   
pH paper with pH  Quality control sub-
PH  4.5  7.5 (USP) 
reference standards  batch or each sub-
SOP# _______________  batch (depending 
  of production 
  8 Draft  Not for Implementation 
method); testing for 
sub-batch is 
completed prior to 
final release 
       
Membrane filter  Specify limit for the filter  Bubble point  State schedule for 
integrity  being used.  measurement  each sub-batch. 
  SOP# _______________ 
 
       
Bacterial endotoxin  NMT2 175 EU/V, in which  Refer to USP  Quality control sub-
(LAL)  V is the maximum  SOP# _______________  batch; testing for 
recommended total dose    first sub-batch 
in mL, at the expiration  completed prior to 
time.  For intrathecal  release 
administration, please 
contact the review 
division. 
       
Sterility Testing  Sterile  Refer to USP  Quality control sub-
SOP# _______________  batch; test initiated 
  within 24 hours of 
preparation. 
       
Osmolality  Isotonic (specify range)  SOP# _______________  Validate / calculate 
 
       
Chemical purity  State limits for each  State method and provide  Quality control sub-
(provide tests for  SOP.  batch; testing for 
appropriate    first sub-batch is 
chemical impurities  SOP# _______________  completed prior to 
based on the  preparation of 
specific method of    clinical sub-batch 
preparation) 
1.  NLT = No Less Than 
2.  NMT = No More Than 
 
 
 
9.  DESCRIPTION OF ANALYTICAL TEST PROCEDURES 
 
 
Each standard test procedure should be included and its location in the NDA/ANDA identified below: 
 
[Note: Each procedure should include the following: (1) the analytical supplies and their quality used; 
(2) all the equipment and the settings used during the performance of the procedure; (3) the 
preparation of test, standard, and analytical solutions; (4) detailed description of the test procedure; (5) 
exact calculations performed in quantitative procedures; (6) the recording of the results; and (7) the 
system suitability test(s) performed (including performance schedule, system suitability standards 
used, and the acceptance criteria that ensure proper performance of the equipment). Each procedure 
should be reliable and capable of providing valid data. Where applicable, the procedure should be 
specific and stability indicating. For chromatographic, spectroscopic (e.g., gamma) and microbiologic 
procedures, validation data that show suitability of the test procedure for the intended purpose should 
be included in the attachment where the test procedure is included.] 
 
 
  9 Draft  Not for Implementation 
       
Test  Test Procedure  Attachment  Page Number 
Number 
       
Appearance       
       
Radionuclidic identity       
       
Radiochemical identity and       
purity  
       
Radinuclidic purity       
       
Assay (radioactivity       
concentration) 
       
Specific activity       
       
pH       
       
Membrane filter integrity        
       
Bacterial endotoxin (LAL)       
       
Sterility        
       
Osmolality       
       
Chemical purity [identify       
specific test(s)] 
 
[Note: Above list of test procedures should correspond to the tests proposed as part of the 
specifications, and the list may be amended as necessary.] 
 
 
10. MICROBIOLOGICAL VALIDATION 
 
This part describes the information you should submit in Section 10 (microbiological validation) of your 
NDA/ANDA for PET drug product.  At the end of this section, there is a table of contents that you can use 
to list the information submitted in your NDA/ANDA. The indicated information should be submitted in this 
part of the CMC section of your NDA/ANDA and the descriptive guidance provided to assist you in this 
section need not be included. 
 
The microbiological validation section of the CMC section of your NDA/ANDA should be used to describe 
the procedures that ensure sterility of injectable PET radiopharmaceuticals.  Information common to other 
sections should be provided directly, and not by reference, to other sections because the microbiological 
validation attachment is reviewed separately from the chemistry section by microbiology reviewers.  The 
introduction to this section should describe the products container and closure system (size, shape, and 
composition), and the time and maximum volume of product solution that may be administered to a 
patient.  Additionally, each of the following issues should be addressed in the microbiology section: 
 
  Production Site.  The production site (name and complete address) should be identified and 
accompanied by a description of the production area. The description should include the presence of 
environmental controls (e.g., laminar air flow hoods, biosafety cabinets, isolators) that protect product 
components from microbiological sources of contamination.  
 
  Processing Equipment and Components.  The methods for preparing equipment and components 
should be summarized in the submission.  When sterile vials, syringes, transfer sets, and filters are 
  10 Draft  Not for Implementation 
obtained from commercial sources and used in the products production, a Certificate of Analysis from 
the suppliers may be substituted where appropriate.  Reusable equipment that contacts the PET drug 
solution during its manufacture should be prepared to eliminate endotoxins and sanitized (or sterilized) 
to control bioburden.  If components are sterilized at the PET facility, their sterilization processes and 
the components aseptic assembly should be verified experimentally and summarized in this section.  
For sterilization done on-site, the performance of a sterilizer should be verified periodically and should 
be described, including a summary of the method and results from the last study.  Drug products for 
parenteral administration must be sterile.  PET solutions are usually filtered and aseptically transferred 
to a sterile, pyrogen-free container (for example, a multiple dose vial). Certain PET products may not 
use a vial for the finished dosage form, and these require special consideration.  Some PET facilities 
may use a long fluid line to deliver multiple batches of the product solution to a remote area for further 
processing.  These delivery lines should be described in the CMC section of your NDA/ANDA, 
including their preparation and the validation of the duration of use.  When special procedures and 
components are used, their impact on sterility assurance should be described. 
 
  Facility Environmental Controls.  A summary of the production process should address control 
systems in the work area used for preparing the finished dosage form.  The work area should be 
clean, and the synthesis unit should be in a location that permits materials to be transferred to the 
aseptic area without adulteration.  It is recommended that batch records indicate that sterile 
components, materials, and equipment are in protective wrapping or containers when transferred into 
the aseptic area.  Also, it is recommended that final containers, filter assembly, sterile fluid lines, vent 
filters, and needles are sterile, disposable, and for single use only.  
 
  The Aseptic Area.  Many facilities have an aseptic area for the transfer of the sterile solution into a 
sterile container for the finished product.  As appropriate, you should include provide descriptions of 
the aseptic hood, isolator, or other suitable environmental system area used when preparing the 
finished product.  The air classification in the aseptic environment should be specified using standard 
nomenclature (e.g., ISO or US Fed. Std 209E). Microbiological testing of the aseptic environment 
should be done periodically, and the microbiological methods (sampling methods and frequency, 
culture media, incubation time and temperature) described.  These methods may include swabs or 
contact plates for surfaces, and settle plates or dynamic air samplers.  Airborne, non-viable particle 
counting should be summarized as part of the testing program, although these tests may be done less 
frequently than microbiological testing.  
 
  Aseptic Technique.  The qualification program for aseptic area operators should be summarized in 
your NDA/ANDA.  The aseptic techniques used to make a sterile product should be evaluated by 
process simulation studies. Simulations should be done 3 times to qualify a new operator.  Each 
operator should repeat one simulation annually, or anytime changes occur in the procedures.  
Microbiological methods, acceptance criteria and results of these simulations (initial studies, or the last 
annual study) should be provided. 
 
  Filtration Process Qualification.  Sterilizing filtration is a critical procedure for removing 
microorganisms from solutions of injectable PET radiopharmaceuticals.  When the filters are made 
and sterilized by a commercial filter manufacturer, the filtration conditions of pressure and flow rate 
are generally provided by the filter manufacturer.  A certificate from the manufacturer is acceptable, 
but the filtration conditions such as pressure or volume should be identified in the batch record and not 
exceeded.  Filter integrity tests to demonstrate that the membrane and housing have not lost the 
ability to retain microorganisms may be done according to the manufacturers recommended method.  
An alternative filter integrity test method may be used if it is demonstrated to be acceptable.  The 
batch record should indicate that after filtering the PET radiopharmaceutical, the sterilizing membrane 
filter is tested for integrity before the product is released.  Filter integrity test methods and acceptance 
criteria should be described in the application.  
 
  Finished Product Microbiological Testing.  PET products for parenteral administration must meet their 
established criteria for sterility and for pyrogens (USP <1>, Injections).  Tests (e.g., sterility and 
endotoxins) should be initiated promptly after preparing the product according to methods described 
  11 Draft  Not for Implementation 
(or provided by a reference) in your NDA/ANDA.  Details of the methods should include sampling 
method, sample sizes, microbiological methods, acceptance criteria and actions following a failure.  
An endotoxins assay is an acceptable demonstration of pyrogenic potential.  An acceptance criterion 
for the endotoxins test should be established and documented in the application using the calculations 
that relate the drug dose to the patient's exposure limit for endotoxins, usually NMT 175 EU/V, where 
V is the maximum recommended dose in mL (see USP <85>, Bacterial Endotoxins Test). For 
intrathecal administration, please contact the review division for limits. 
 
You can use the following as a table of contents for the information you include in Section 10 on 
microbiological validation.  
 
Test or Criterion  Document(s)  Page 
Number(s) 
Product Summary     
Container and Closure System     
Maximum Volume of Patient Dose     
Facility Description     
     
Sterile Equipment and Components     
Single Use  Certificate of Analysis   
Reusable  Sterilization Validation   
     
Environmental Controls     
     
Aseptic Area Environmental Monitoring     
     
Aseptic Process Simulation Methods and     
Results 
     
Sterile Filtration Process     
Microbial Retention Test or Certificate     
Pressure and Flow Rate Limits     
Filter Integrity Test Method     
Post-Use Integrity Test Limits     
     
Sterility Test Methods, Limits and Controls     
Actions if Test Fails     
     
Endotoxins Test Methods, Limits and Controls    
Determination of Endotoxins Limit     
Actions if Test Fails     
 
 
 
11. STABILITY AND BATCH DATA 
 
A.  EXPIRATION DATING PERIOD 
 
We propose an expiration-dating period of ________ minutes/hours from the EOS calibration time 
when ammonia N 13 injection is stored at _____oC +/-____oC. 
  12 Draft  Not for Implementation 
[Note: Refer to USP for controlled room temperature definition.] 
 
B.  STABILITY DATA/BATCH DATA 
 
If the submission is an NDA (under section 505 (b)(2) of the act), complete release and stability 
data on three batches of ammonia N 13 injection, prepared at the upper range of proposed 
radioactivity concentration and stored at _____oC +/- ____oC, are provided in attachment ______, 
page _____. 
 
If the submission is an ANDA (under section 505(j) of the act), complete release data on three 
batches prepared at the upper range of proposed radioactivity concentration along with the 
stability data on one of the three batches of Ammonia N 13 injection, prepared at the upper range 
of proposed radioactivity concentration and stored at _____oC +/- ____oC, are provided in 
attachment ______, page _____ . 
 
    For each stability batch,  
  The batch was stored in the same container/closure as it was produced: _____Yes. 
  The vial was stored in an inverted position: ______Yes. 
  All tests indicated in the specification section were performed at release: _____Yes. 
  The appearance, radiochemical purity, radionuclidic purity, and pH (and stabilizer 
concentration when present) were also evaluated at the end of proposed expiration dating 
period:_____Yes.     
 
[Note: If your NDA/ANDA incorporates multiple production sites, please discuss with the 
reviewing division in advance of submitting your NDA/ANDA concerning the stability and 
batch data that should be submitted. The phone number for the Division of Medical Imaging 
Products is (301) 796-2050] 
 
C.  POSTAPPROVAL COMMITMENTS 
 
We commit that; annually post-approval a minimum of one batch of ammonia N 13 injection will be 
tested according to the protocol described below. The entire content of the batch vial will be stored 
inverted at _____ oC for ______ hours (from EOS), and tested according to the specifications and 
procedures described for finished product testing. The results of such testing will be provided to 
the FDA in the annual report. 
 
 
     
TEST  Test performed at  Test performed at the 
release  end of proposed 
expiry 
     
Appearance  YES  YES 
     
Radionuclidic identity  YES  NO 
     
Radiochemical identity  YES  YES 
and purity 
     
Radionuclidic purity  YES  YES 
     
Assay (radioactivity  YES  NO 
concentration) 
     
pH  YES  YES 
     
Specific activity  YES  YES 
  13 Draft  Not for Implementation 
     
Radiochemical  YES  NO 
impurities 
Chemical purity  YES  NO 
     
Membrane filter  YES  NO 
integrity test 
   
Bacterial endotoxin 
YES  NO 
(LAL) 
   
Sterility test 
YES  NO 
     
Osmolality  YES  NO 
 
Additionally, we commit that any batch or sub-batch thereof of ammonia N 13 injection that fails to 
meet the acceptance criteria will not be released or, if already distributed, will be withdrawn from the 
market.  
 
We also commit that FDA will be notified of any changes to the approved NDA/ANDA, beyond the 
variations already provided for in the NDA/ANDA and that any such change will be implemented 
according to the requirements under section 506A of the Food and Drug Modernization Act and/or 
21CFR 314.70 and 21 CFR 314.71 (for NDA) or under 21CFR 314.97 (for ANDA), as applicable. 
 
 
12. VIAL AND OUTER PACKAGING LABELS 
 
Draft copies of proposed vial and outer packaging labels are provided in attachment ______, page 
______. 
 
 
13. ENVIRONMENTAL ASSESSMENT 
 
In accordance with 21 CFR 25.31(b), the (insert name of sponsor) claims a categorical exclusion from 
the environmental assessment requirements of 21 CFR 25.20 for approval of ammonia N 13 Injection 
on the basis that the estimated concentration of ammonia N 13 at the point of entry into the aquatic 
environment will be below 1 part per billion. Additionally, to (name of sponsor)s knowledge no 
extraordinary circumstances exist. 
  14 Draft  Not for Implementation 
 
 
 
 
 
Fludeoxyglucose F 18 Injection 
CMC Sections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  15 Draft  Not for Implementation 
Fludeoxyglucose F 18 Injection 
 
1.  DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION 
 
     
       Component      Composition/mL     Composition/batch 
     
Drug Substance     
2-Deoxy-2[18F]fluoro-D-    _____ to _____ mCi @EOS1    ____ to _____ mCi @EOS1 
glucose  ( ____ to _____ MBq @ EOS)  ( ____ to ____ MBq @ EOS) 
     
Inactive ingredient(s)2              
        
1.          ____________________ 
_________________mL  
____________________       (e.g., 1 mL) 
 
      (e.g., Sodium chloride   
        injection, USP)      _____________________     
2.  ___________________
    
_ 
___________________ 
 
1.  EOS = End of synthesis calibration time. 
2.  Provide all inactive ingredients used in drug product. Examples of inactive ingredients include 
diluents, buffers, stabilizers, and preservatives. 
 
 
2.  CONTROLS FOR COMPONENTS AND OTHER RAW MATERIALS 
  
A.  PRECURSOR [e.g., 1,3,4,6-Tetra-O-acetyl-2-O-trifluoromethanesulfonyl--D-mannopyranose 
(mannose triflate)]  Considered an intermediate and information concerning its manufacture and 
controls, under cGMP,  should be included either in the application or may be referenced to a 
Drug Master File (DMF) from your supplier, filed with FDA.  
   
State the name [e.g., 1,3,4,6-Tetra-O-acetyl-2-O-trifluoromethanesulfonyl--D-mannopyranose 
(mannose triflate)] and provide following information for the precursor used for radiochemical 
synthesis: 
     
1.  Name of the component    
     
2.  Name and address of supplier   
   
 
 
     
3.  Is this raw material further  _______ Yes _______ No. If yes, method of 
purified on site?  purification is provided in attachment _______, 
page_____. 
     
4.  Specifications    TEST                       ACCEPTANCE              TEST 
  (Specifications that control the                                     CRITERION         PROCEDURE
identity, purity and quality of  Appearance               _______ 
 
each lot should be included)  Specific identity          _______ 
    (e.g., IR, NMR) 
    Purity                          _______ 
  (e.g., chromatography) 
 
  16 Draft  Not for Implementation 
   Melting point               _______ 
  Optical rotation          ________ 
 
Attachment ________, Page ________ 
     
5.  Representative certificate of  Copy of representative certificate of analysis is 
analysis (COA) from supplier  provided in attachment _______, page_______. 
 
     
6.  Identity test performed to confirm  TEST     PROCEDURE      ACCEPTANCE                  
structure to release each lot for                                                CRITERION 
production   _____         _______         ___________________ 
 
Detailed test procedure is included in attachment 
_______, page______. 
     
7.  Storage conditions  1. Container/closure _________________________ 
2. Stored at ________________________________ 
3.  This material is stable for _____ months/year, 
when stored in above container/closure under 
described storage conditions: attachment _____, page 
_____. 
 
B.  TARGET MATERIAL (Starting material) / RADIOACTIVE FLUORIDE REAGENT (Key 
intermediate) 
 
We will only produce radioactive fluoride reagent on site at the PET drug production facility? 
_____Yes ____No. 
 
Provide, as appropriate, details in section (i) and / or section (ii) below: 
 
(i) The following target material will be used for the production of radioactive fluoride reagent: 
 
     
1.  Name of the target material  [18O] Water 
   
 
2.  Name and address of the target 
material manufacturer 
 
     
3.  Specifications  TEST          ACCEPTANCE                      TEST 
[Specifications that control                        CRITERION                    PROCEDURE
identity, purity, and quality of  Identity            _______________________ 
each lot should be included]  Enrichment     Provide justified minimum limit 
Conductivity    Provide justified maximum limit 
Fluoride           Provide justified maximum limit 
Content 
Other               Attributes that control purity should be  
                        included 
Attachment _______, Page ________. 
(Justifications should be included in the attachment) 
     
4.  Identity test performed to release  TEST    PROCEDURE     ACCEPTANCE CRITERION 
each lot for production   _____   ___________      ______________________ 
 
Detailed test procedure is included in attachment 
  17 Draft  Not for Implementation 
________, page_____. 
     
5.  Certificate of analysis (COA)  Copy of representative certificate of analysis is 
  provided in attachment ______, page_______.  
   
 
6.  ______ Yes ______ No. 
Is the target material recycled? 
If yes, the reprocessing procedures are described in 
attachment _______, page______. 
 
Data to support that the reprocessed material 
conforms to the acceptance criteria for the target 
material are provided in attachment _______, page 
_____. 
 
 
We intend to use additional suppliers for this target material: _____Yes _____No. 
 
If yes, for each additional supplier, the target material information identified in items 1, 2, and 5 above 
is provided in attachment ______, page______. 
 
(ii)  We will use the radioactive fluoride reagent, obtained from other (e.g., outside) suppliers, for the 
production of 2-deoxy-2[18F]fluoro-D-glucose: ______Yes _______No. 
 
If yes, provide the [18O] Water information as described in (i) above (may be provided in a DMF from 
the supplier or in your NDA/ANDA), and the following information: 
 
     
1.  Name and composition of the   
fluoride reagent solution   
     
2.  Name and address of qualified   
supplier 
 
 
 
     
3.  Method of preparation  (cid:31)1. The fluoride reagent is prepared using a                
(Check the box that applies to          ____MeV particle accelerator utilizing  
your situation)                 18O(p, n)18F reaction on H 18O. 
2
(cid:31)2. The fluoride reagent is reactor produced. 
          If fluoride is produced by methods described in  
          2, or any other method provide description of     
           the method of preparation, purification,              
           specifications and acceptance procedures that 
           are appropriate for such production method.     
           Information is provided in attachment _______, 
           page______. 
 
   
 
Specifications  TEST                   ACCEPTANCE                 TEST 
4. 
(Provide appropriate                                CRITERION             PROCEDURE 
specifications that control the  _______                    ________              _________ 
quality of each lot this material)  _______                    ________              _________  
                               
 
Attachment _______, page _______. 
  18 Draft  Not for Implementation 
 
 
5.  Provide acceptance 
Attachment ______,   page_______. 
procedure(s) used to release 
each lot of the reagent for use in 
production 
     
6.  Certificate of analysis  Copy of representative certificate of analysis is 
provided in attachment _________, page ______. 
 
 
We intend to use additional suppliers for the fluoride reagent: _____Yes _____No. 
 
If yes, for each additional supplier, the fluoride reagent identified in 1,2,3, and 6 above is provided in 
attachment _________, page_____. [Note: Fluoride F18 from different sources must meet the 
sponsors proposed specifications.] 
 
C.  INACTIVE INGREDIENTS 
 
The following inactive ingredient(s) are used in the fludeoxyglucose F 18 injection. 
 
       
Name  Function of  Name and address of the  Specifications, 
the inactive  manufacturer  representative COA and 
ingredient  acceptance procedures for 
each lot are included 
       
        Attachment ___, page ____. 
 
       
      Attachment ___, page ____. 
 
[Note: COA need not be provided if the inactive ingredient used is a marketed finished drug product.] 
 
Additional inactive ingredients (if any) are listed and information provided in attachment ______, page 
______. 
 
D.  REAGENTS, SOLVENTS, GASES, PURIFICATION COLUMNS, AND OTHER AUXILIARY 
MATERIALS 
 
Provide following information for each reagent, solvent, gas, purification column, and other auxiliary 
material that is used in the production of fludeoxyglucose F 18 injection: 
 
 
 
     
                   Name  Name and address of the  Quality grade (e.g., ACS, USP, 
supplier  etc.) or specifications,  
representative COA and 
acceptance procedures for 
each lot are included 
 
     
 
   
1 
 
Attachment _____, page ____. 
   
   
   
 
  19 Draft  Not for Implementation 
2  Attachment _____, page ____. 
     
 
     
 
3     
 
Attachment _____, page ____. 
     
 
     
 
4    Attachment _____, page ____. 
       
       
5    Attachment _____, page ____. 
   
       
       
6    Attachment _____, page ____. 
 
       
7       
  Attachment _____, page ____. 
 
 
[Note: The above table may be extended, if needed, to include additional raw materials, and 
 information provided in an attachment.] 
 
 
3.  REFERENCE STANDARDS 
 
The following reference standards are used in the quality control methods of fludeoxyglucose F18 
injection: 
 
[Note:  Following are presented as an example. Reference standards appropriate for the synthesis 
should be included.  If a reference standard is obtained from USP, it should be so stated. If a 
reference standard is not obtained from USP, data to support that the reference standard lot has the 
desired structure should be submitted in the indicated attachment.  Purity of the reference standard lot 
should be provided.] 
 
     
Name of reference standard  Name and address of the  Specifications, 
supplier  representative COA and 
acceptance procedures for 
each lot are included  
       
       
1  2-Fluoro-2-deoxy-D-glucose    Attachment __, page____ 
   
     
 
     
2-Chloro-2-deoxy-D-glucose 
2    Attachment___, page____ 
 
 
       
  Kryptofix, 222 (4,7,13,16,21,     
3  24-hexaoxa 1,10diazabicyclo    Attachment___, page____ 
[8.8.8] hexacosane)   
 
 
 
  20 Draft  Not for Implementation 
4.  PRODUCTION AND TESTING FACILITIES 
 
Name of PET drug production facility:  __________________________________________ 
  Address:           __________________________________________ 
              __________________________________________ 
__________________________________________ 
  Name of contact person:      __________________________________________   
  Phone number of contact person:    __________________________________________ 
 
  Additional production and / or testing facilities (if any), including their function, are listed in  
  attachment ________, page ____. 
 
 
5.  PRODUCTION OF DRUG SUBSTANCE 
 
A.  BATCH FORMULA: The following components and their quantities are used in the production of  
  each batch of 2-deoxy-2[18F]fluoro-D-glucose: 
 
Provide the name of each component used in the production of 2-deoxy-2[18F]fluoro-D-glucose, 
whether or not it appears in the final product; its function; and the amount (mass or volume) used in 
each batch (include all reactants, solutions, solvents, and reagents used in the chemical synthesis and 
purification operation). 
 
     
Name of component   Components function  Amount used 
     
[Example: 1,3,4,6-Tetra-O-    
acetyl-2-O-trifluoro         _______ mg + __mg 
methanesulfonyl--D-
mannopyranose] 
     
[18F]Fluoride   Reagent         ______mCi to _____mCi 
     
     
     
     
     
     
     
     
     
     
     
     
   
 
B.  PRODUCTION OF RADIONUCLIDE    
 
We will produce radioactive fluoride reagent only on site at the PET drug production facility? 
____Yes___No. 
 
If the radioactive fluoride reagent is obtained from outside suppliers, the following information (i, ii, & 
iii), may be included in suppliers DMF or provided in your NDA/ANDA: 
 
(i)  Particle Accelerator (e.g., cyclotron) Used 
 
  21 Draft  Not for Implementation 
The following particle accelerator is used for the production of [18F]fluoride radionuclide: 
 
MAKE:   ____________________________________ 
MODEL:  ____________________________________ 
 
Information concerning additional particle accelerators is provided in attachment _______, page 
______. 
 
(ii)  Operating Parameters 
 
  During irradiation a beam current of _____A  +  ____A is used. 
  Irradiation times of _____ minutes to _____ minutes are used. 
  We use / do not use high-pressure targets. When high-pressure targets are used, irradiations 
are performed under ____ psi pressure.   
 
(iii) Specifications for Target Body  
 
  Volume of the target body is____________ l or ml.     
  The target body used in production operation is composed of ______________________. 
  The target windows used in target body are ___________ (state thickness) and are 
composed of_____________________________________________________________. 
  The schedule for the replacement of target windows is _____________________ ______. 
  The acceptance criteria for the target body and the target windows (that come in contact with 
target material) are provided in attachment _________, page _______. 
 
If multiple target bodies of different types are used, the above information concerning each is 
provided in attachment ________, page _____. 
 
C.  SYNTHESIS AND PURIFICATION OF THE DRUG SUBSTANCE 
 
(i)  Description of Radiochemical Synthesis and Purification Equipment 
 
Descriptions of the radiochemical synthesis and purification equipment, including components, 
their acceptance criteria, and a schematic flow diagram are provided in attachment ______, page 
_______. 
 
We use the following synthesis and purification unit(s): 
 
MAKE:   ____________________________________ 
MODEL:  ____________________________________ 
 
If more than one unit is used, and if units are different, provide information for each in attachment 
______, page ______.  
 
(ii)   Description of Radiochemical Synthesis and Purification Operation 
 
A step-wise description of the synthesis and purification procedure, including the amount of each 
reactant, reagent, solvent used, and acceptable radiochemical yields obtained, is provided in 
attachment _______, page _____. 
 
(iii) In-Process Controls 
 
We recommend that the applicant have adequate process controls to ensure continued quality of 
the product.  All controls that are necessary to assure reproducible quality of the drug should be 
described. The following are examples of the process parameters that should be controlled in the 
  22 Draft  Not for Implementation 
synthesis and purification procedure: 
 
  Drying of radioactive fluoride ions during the azeotropic evaporations. 
o  Number of azeotropic evaporations performed:  _____________________. 
o  For evaporation, the vessel is heated between:   ______oC to _____oC for 
_______minutes.  
 
  Temperature and duration of reaction between radioactive fluoride ions and mannose triflate. 
o  The reaction vessel is heated between ______oC to _____oC for _______minutes. 
 
  Temperature and duration of the hydrolysis reaction. 
o  The reaction vessel is heated between ______oC to _____oC for _______minutes.   
 
  The amount of reactants, reagents, solvents, and solutions during each phase of synthesis and 
purification is controlled as described in master production and control records. _____ Yes. 
 
  Flow rate of gas used for movement of materials within the synthesis and purification equipment. 
The flow rate used is _______________. 
 
  Total synthesis and purification time. 
o  The synthesis and purification operation takes a total of ________ minutes. 
 
  Other parameters (provide any additional parameters that are controlled in your individual 
operation): 
o  Attachment ________, page _______ . 
 
All process controls are monitored and documented in the master production and controls 
records: ___ Yes.  
 
(iv) Post-Synthesis Procedures 
 
Descriptions of procedures used to prepare the production equipment, including any cleaning and 
purging procedures, for a subsequent batch are provided in attachment _______, page _____. 
 
 
6.  PRODUCTION OF DRUG PRODUCT 
 
A.  PRODUCTION OPERATION  
 
The drug substance 2-deoxy-2[18F]fluoro-D-glucose is not isolated. The synthesized, purified drug 
substance obtained from the synthesis and purification procedure is collected in the drug product 
vial. The specific procedures used in the formulation and preparation of finished drug product are 
provided in attachment _____, page _____. 
 
The master production and control records which provide the exact procedures used in the 
production of and ensure full traceability / accountability of all components, materials, and 
equipment used and the operators for each batch of fludeoxyglucose F 18 injection, are provided 
in attachment ______, page  _____. 
 
B.  REPROCESSING OF PET DRUG PRODUCT 
 
    Check below as appropriate and provide the indicated information. 
  
  A PET drug product batch or lot will not be reprocessed. 
 
  23 Draft  Not for Implementation 
  A PET drug product batch or lot may be reprocessed under the specific conditions 
(circumstances) described in attachment _____, page _____.  
The validated procedures (include SOP) used in reprocessing are described in attachment 
______, page _____. 
 
C.  PACKAGING AND LABELING  
 
The components used in the packaging of the drug product vial and the method of labeling are 
described in master production and control records on page ______ (attachment _____).  
 
The specifications for the packaging component(s) and the acceptance procedures for each lot 
are provided in attachment ______, page _____.  
 
 
7.  CONTAINER/CLOSURE 
 
  We use a presterilized, presealed, pyrogen-free container/closure, consisting of USP Type I glass, 
gray butyl rubber stopper, and aluminum crimp seal, from a commercial supplier._____Yes _____ 
No. 
 
  If no, information on the container/closure along with its sterilization procedures and sterility 
assurance is provided in attachment ______, page ______. 
 
  If yes, the _____ ml container/closure, consisting of USP Type I glass, gray butyl stopper, and 
aluminum crimp seal, is obtained from the following manufacturer. The specifications and 
procedures used for accepting a lot of the container/closure are provided in attachment ____, 
page _____. 
 
Container/Closure catalog #   ___________________________________ 
Name and address of supplier  ___________________________________ 
___________________________________ 
___________________________________ 
    Drug Master File number    ___________________________________ 
 
A letter of authorization from the DMF holder, authorizing FDA to refer to the DMF in connection with our 
NDA/ANDA, is provided in attachment _____, page ______. 
 
 
8.  CONTROLS FOR THE FINISHED DOSAGE FORM 
 
A.  SAMPLING PROCEDURES 
 
Each batch of fludeoxyglucose F 18 injection will be produced for distribution (check, as appropriate): 
  In a single multidose  vial _____ . 
  In multiple vials (single or multiple dose) _______.  
 
(i)  If each batch is produced in a single vial, a description of how the representative sample is 
obtained (e.g., the amount of volume that is withdrawn from the finished drug product container 
and how it is distributed among individual tests) is provided in attachment _______, page ______.  
 
(ii)  If each batch is produced in multiple vials, a description of sampling techniques that  
assure that the test sample is representative of the entire batch is provided in attachment _____, 
page ______. 
 
B.  REGULATORY SPECIFICATIONS  
  24 Draft  Not for Implementation 
 
Each batch of the fludeoxyglucose F 18 injection will meet the following specifications during its 
entire shelf life when tested according to the standard test procedures submitted in this 
application. 
 
[Note: The following tests are related to a commonly used production method. In the event that the 
production method does not use a component listed below or uses an alternate method or 
produces additional impurities, appropriate tests, acceptance criteria, procedures, and testing 
schedules that are more appropriate for such production method should be proposed.] 
 
       
TEST  ACCEPTANCE    PROCEDURES  TESTING 
CRITERIA  SCHEDULE 
       
Appearance  Colorless and free from  Visual observation under  Test completed 
particulate matter   lighted conditions  prior to release of 
  drug product 
SOP# ______________ 
 
       
Radionuclidic  The measured half-life is  Measurement of  Test completed 
identity  between 105.0  115.0  radioactivity decay of the  prior to release of 
minutes  sample  over a 10  drug product 
minute period  
SOP# ______________ 
 
       
Radiochemical  The Rf of 2-deoxy- TLC, activated silica gel  Test completed 
identity  2[18F]fluoro-D-glucose  plate developed in 95:5 /  prior to release of 
corresponds (e.g., < +10%)  acetonitrile : water (TLC  drug product 
to the Rf (about 0.4) of 2- scanned in a radio-
deoxy-2-fluoro-D-glucose  chromatographic 
reference standard, when  scanner and by 
both are chromatographed  treatment with 
together side by side on the  appropriate reagent) 
same TLC    
SOP#_______________ 
     
 
Radionuclidic purity  State limit and provide  State schedule 
State suitable method of 
  justification in an  and provide 
analysis of  decayed 
attachment.  justification 
sample 
Attachment__________    Attachment____ 
Page_______________  SOP#_______________  Page_________  
       
Radiochemical  NLT1 90.0%   TLC, activated silica gel  Test completed 
purity  2-deoxy-2[18F]fluoro-D- plate developed in 95:5/  prior to release of 
  glucose  acetonitrile : water (TLC  drug product 
scanned in a radio-
chromatographic 
scanner) 
SOP#_______________ 
Radiochemical  State the maximum limit for  Provide test procedure  Test completed 
impurities  fluoride F 18 (free) and    prior to release of 
  provide justification.  SOP# ______________  drug product 
Attachment____________   
Page_________________ 
  25 Draft  Not for Implementation 
   
Assay  ____mCi to ____ mCi / mL 
Refer to USP   Test completed 
(radioactivity  @ EOS ( This should be 
  prior to release of 
concentration)  same as the stated strength 
SOP#_____________  drug product 
of drug product) 
       
Specific activity  No carrier added   None - prepared by no  No testing 
2-deoxy-2[18F]fluoro-D- carrier added method of  performed 
glucose  synthesis 
       
pH  Specify justified limits   pH paper with pH  Test completed 
  reference standards  prior to release of 
  drug product 
Attachment_________ 
SOP# _____________ 
Page______________ 
     
 
The size and intensity of  TLC, comparison of drug  Test completed 
Kryptofix 222 
the  spot in test sample,  product with 50 g / mL  prior to release of 
(if used in 
that corresponds to the  reference standard  drug product 
synthesis) 
50g/ml kryptofix 222  solution 
reference standard spot,   
does not exceed that of the  SOP# _____________ 
standard solution 
       
Residual solvents4    Gas chromatography,  Test completed 
1. Acetonitrile  1. NMT2 0.04% (w/v)  flame ionization  prior to release of 
2. Diethyl Ether  2. NMT2 0.5% (w/v)  detection  drug product 
3. Ethanol  3. NMT2 0.5% (w/v)   
SOP# _____________ 
 
       
2-Chloro-2-deoxy- NMT2 1.0 mg / V3 HPLC  Validation and on 
D-glucose (if it is a    annual batch 
 possibility in  SOP# _____________  thereafter 
synthesis) 
       
Membrane Filter  Specify limit for the filter  Bubble point  Test completed 
Integrity  being used  measurement  prior to release of 
  SOP# _____________  drug product 
 
     
State test procedure 
Bacterial  NMT2 175 EU/V, in which V  Test completed 
SOP# _____________ 
endotoxins  is the maximum  prior to final 
(LAL)  recommended total dose in  release of drug 
mL, at the expiration time.   product 
For intrathecal   
administration, please 
contact the review division. 
       
Sterility testing  Sterile  State test procedure  Test initiated 
SOP# _____________  within 24 hours of 
preparation 
       
Osmolality  Isotonic (specify range)  SOP# _____________  Validate / 
calculate 
     
No test performed 
Glucose  NMT ___ mg/V3 Calculated based 
on the amount of 
  26 Draft  Not for Implementation 
mannose triflate 
used 
1.  NLT = No Less Than 
2.  NMT = No More Than 
  3.  V = Total volume of the batch of fludeoxyglucose F 18 injection produced  
4.    Acceptance criteria should assure that the amount of each residual solvent impurity administered 
to a human subject is within the limits provided in the ICH Guidance on Impurities: residual solvents 
(Federal Register dated December 24, 1997, Vol. 62, No. 247, Pages 67377  67388). 
 
   [Note: If a stabilizer is added, test for the assay of stabilizer should be included in the specifications] 
 
 
9.  DESCRIPTION OF ANALYTICAL TEST PROCEDURES 
 
Each standard test procedure and its location in the NDA / ANDA are identified below: 
 
[Note: Each procedure should include the following: (1) the analytical supplies and their quality used; 
(2) all the equipment and the settings used during the performance of the procedure; (3) the 
preparation of test, standard, and analytical solutions; (4) detailed description of the test procedure; (5) 
exact calculations performed in quantitative procedures; (6) the recording of the results; and (7) the 
system suitability test(s) performed (including performance schedule, system suitability standards 
used, and the acceptance criteria that ensure proper performance of the equipment). Each procedure 
should be reliable and capable of providing valid data. Where applicable, the procedure should be 
specific and stability indicating. For chromatographic, spectroscopic (e.g., gamma) and microbiologic 
procedures, validation data that show suitability of the test procedure for the intended purpose should 
be included in the attachment where the test procedure is included.] 
 
       
Test  Test Procedure  Attachment  Page Number 
Number 
       
Appearance       
       
Radionuclidic identity       
       
Radiochemical identity and       
purity  
       
Radinuclidic purity       
 
     
 
Assay (radioactivity     
concentration) 
       
pH       
       
Test for kryptofix 222 (if used       
in synthesis) 
       
Residual solvents        
       
2-Chloro-2-Deoxy-D-glucose       
       
Membrane filter integrity test       
       
Bacterial endotoxins (LAL)       
Sterility test       
  27 Draft  Not for Implementation 
       
Osmolality       
 
[Note: Above list of test procedures should correspond to the tests proposed as part of the 
specifications, and the list may be amended as necessary] 
 
 
10. MICROBIOLOGICAL VALIDATION 
 
This part describes the information you should submit in Section 10 (microbiological validation) of your 
NDA/ANDA for the PET drug product.  At the end of this section, there is a table of contents that you can 
use to list the information submitted in your NDA/ANDA. Only the indicated information should be 
submitted in this section and the descriptive guidance provided to assist you need not be included.  
 
The microbiological validation section of the application should be used to describe the procedures that 
ensure sterility of injectable PET radiopharmaceuticals.  Information common to other sections should be 
provided directly, and not by reference, to other sections because the microbiological validation 
attachment is reviewed separately from the chemistry section by microbiology reviewers.  The introduction 
to this section should describe the products container and closure system (size, shape, and composition), 
and the time and maximum volume of product solution that may be administered to a patient.  Additionally, 
each of the following issues should be addressed in the microbiology section: 
 
  Production Site.  The production site (name and complete address) should be identified and 
accompanied by a description of the production area. The description should include the presence of 
environmental controls (e.g., laminar airflow hoods, biosafety cabinets, isolators) that protect product 
components from microbiological sources of contamination.  
 
  Processing Equipment and Components.  The methods for preparing equipment and components 
should be summarized in the submission.  When sterile vials, syringes, transfer sets, and filters are 
obtained from commercial sources and used in the products production, a Certificate of Analysis from 
the suppliers may be substituted where appropriate.  Reusable equipment that contacts the PET drug 
solution during its manufacture should be prepared to eliminate endotoxins and sanitized (or sterilized) 
to control bioburden.  If components are sterilized at the PET facility, their sterilization processes and 
the components aseptic assembly should be verified experimentally and summarized in application 
file.  For sterilization done on-site, the performance of a sterilizer should be verified periodically and 
should be described, including a summary of the method and results from the last study.  Drug 
products for parenteral administration must be sterile.  PET solutions are usually filtered and 
aseptically transferred to a sterile, pyrogen-free container (for example, a multiple dose vial). Certain 
PET products may not use a vial for the finished dosage form, and these require special 
consideration.  Some PET facilities may use a long fluid line to deliver multiple batches of the product 
solution to a remote area for further processing.  These delivery lines should be described in the CMC 
section of your NDA/ANDA, including their preparation and the validation of the duration of use.  When 
special procedures and components are used, their impact on sterility assurance should be described. 
 
  Facility Environmental Controls.  A summary of the production process should address control 
systems in the work area used for preparing the finished dosage form.  The work area should be 
clean, and the synthesis unit should be in a location that permits materials to be transferred to the 
aseptic area without adulteration.  It is recommended that batch records indicate that sterile 
components, materials, and equipment are in protective wrapping or containers when transferred into 
the aseptic area.  Also, it is recommended that final containers, filter assembly, sterile fluid lines, vent 
filters, and needles are sterile, disposable, and for single use only.  
 
  The Aseptic Area.  Many facilities have an aseptic area for the transfer of the sterile solution into a 
sterile container for the finished product.  As appropriate, you should provide descriptions of the 
aseptic hood, isolator, or other suitable environmental system area used when preparing the finished 
product.  The air classification in the aseptic environment should be specified using standard 
  28 Draft  Not for Implementation 
nomenclature (e.g., ISO or US Fed. Std 209E). Microbiological testing of the aseptic environment 
should be done periodically, and the microbiological methods (sampling methods and frequency, 
culture media, incubation time and temperature) described.  These methods may include swabs or 
contact plates for surfaces, and settle plates or dynamic air samplers.  Airborne, non-viable particle 
counting should be summarized as part of the testing program, although these tests may be done less 
frequently than microbiological testing.  
 
  Aseptic Technique.  The qualification program for aseptic area operators should be summarized in 
your NDA/ANDA.  The aseptic techniques used to make a sterile product should be evaluated by 
process simulation studies. Simulations should be done 3 times to qualify a new operator.  Each 
operator should repeat one simulation annually, or anytime changes occur in the procedures.  
Microbiological methods, acceptance criteria and results of these simulations (initial studies, or the last 
annual study) should be provided. 
 
  Filtration Process Qualification.  Sterilizing filtration is a critical procedure for removing 
microorganisms from solutions of injectable PET radiopharmaceuticals.  When the filters are made 
and sterilized by a commercial filter manufacturer, the filtration conditions of pressure and flow rate 
are generally provided by the filter manufacturer.  A certificate from the manufacturer is acceptable, 
but the filtration conditions such as pressure or volume should be identified in the batch record and not 
exceeded. Integrity testing by the drug manufacturer is not intended to confirm the filter porosity rating, 
as is the filter manufacturers testing.  However, in-process filter integrity tests to demonstrate that the 
membrane and housing have not lost the ability to retain microorganisms may be done according to 
the manufacturers recommended method or by an alternative filter integrity test method that 
demonstrates the filter membrane is not torn or detached from the housing.  The batch record should 
indicate that after filtering the PET radiopharmaceutical, the sterilizing membrane filter is tested for 
integrity before the product is released.  Filter integrity test methods and acceptance criteria should be 
described in the application. 
 
  Finished Product Microbiological Testing.  All products for parenteral administration, including PET 
radiopharmaceuticals, must be sterile and free of endotoxins (USP <1>, Injections).  Sterility and 
endotoxin tests should be initiated promptly after preparing the product.  Test methods should be 
described (or provided by a reference) in your NDA/ANDA.  Details of the methods should include 
sampling method, sample sizes, microbiological methods, acceptance criteria and actions following a 
failure.  The acceptance limit for endotoxins test results should also include the calculations that relate 
the patient dose to the endotoxins limit.  
 
You can use the following as a table of contents for the information you include in Section 10 on 
microbiological validation.  
 
Test or Criterion  Document(s)  Page 
Number(s) 
Product Summary     
Container and Closure System     
Maximum Volume of Patient Dose     
Facility Description     
     
Sterile Equipment and Components     
Single Use  Certificate of Analysis   
Reusable  Sterilization Validation   
     
Environmental Controls     
     
Aseptic Area Environmental Monitoring     
     
  29 Draft  Not for Implementation 
Aseptic Process Simulation Methods and     
Results 
     
Sterile Filtration Process     
Microbial Retention Test or Certificate     
Pressure and Flow Rate Limits     
Filter Integrity Test Method     
Post-Use Integrity Test Limits     
     
Sterility Test Methods, Limits and Controls     
Actions if Test Fails     
     
Endotoxins Test Methods, Limits and Controls    
Determination of Endotoxins Limit     
Actions if Test Fails     
 
 
11. STABILITY AND BATCH DATA 
 
A.  EXPIRATION DATING PERIOD 
 
We propose an expiration-dating period of ________ hours from the EOS calibration time when 
fludeoxyglucose F 18 injection is stored at _____oC +/- ____oC (or controlled room temperature). 
    (Note: Refer to USP for controlled room temperature definition) 
 
B.  STABILITY DATA/BATCH DATA 
 
If the submission is an NDA (under section 505 (b)(2) of the act), complete release and stability 
data on three batches of fludeoxyglucose F 18 injection prepared at the upper range of proposed 
radioconcentration and stored at _____oC +/- ____oC, are provided in attachment ______, page 
_____ . 
 
If the submission is an ANDA (under section 505(j) of the act), complete release data on three 
batches prepared at the upper range of proposed radioconcentration along with the stability data 
on one of the three batches of fludeoxyglucose F 18 injection prepared at the upper range of 
proposed radioconcentration and stored at _____oC +/- ____oC, are provided in attachment 
______, page _____ . 
 
    Additionally for each stability batch,  
  The entire batch was stored in the same container/closure as it was produced._____Yes. 
  The vial was stored in an inverted position. ______Yes. 
  All tests indicated in the specification section were performed at release. _____Yes. 
  The appearance, radiochemical purity, radionuclidic purity, and pH (and stabilizer 
concentration when present) were also evaluated at the end of proposed expiration dating 
period._____Yes.   
 
[Note: If the application incorporates multiple production sites, please discuss with the reviewing 
division in advance of submitting the application concerning the stability and batch data that 
should be submitted. The phone number for the Division of Medical Imaging Products is (301) 
796-2050.] 
    
  30 Draft  Not for Implementation 
C.  POSTAPPROVAL COMMITMENTS 
 
We commit that; annually post-approval a minimum of one batch of fludeoxyglucose F 18 injection 
will be tested according to the protocol described below. The entire content of the batch vial will be 
stored inverted at _____ oC for ______ hours (from EOS), and tested according to the 
specifications and procedures described in this application for finished product testing. The results 
of such testing will be provided to the FDA in the annual report. 
 
     
Test  Test performed at   Test performed at 
 Release  the end of proposed 
expiry 
     
Appearance  YES  YES 
     
Radionuclidic identity  YES  NO 
     
Radiochemical identity and  YES  YES 
purity 
Radiochemical impurities  YES  YES 
(free 18F fluoride) 
Radionuclidic purity  YES  YES 
     
Assay (radioconcentration)  YES  NO 
   
pH 
YES  YES 
     
Test for kryptofix 222  YES  NO 
(or other catalyst) 
   
Test for residual solvents 
YES  NO 
   
2-Chloro-2-deoxy-D-
YES  NO 
glucose 
     
Membrane filter integrity  YES  NO 
test 
   
Bacterial endotoxins (LAL) 
YES  NO 
     
Sterility test  YES  NO 
     
Osmolality  YES  NO 
      (Note: Include stabilizer at both time intervals, if present) 
 
Additionally, we commit that any batch of fludeoxyglucose F 18 injection that fails to meet the 
acceptance criteria will not be released or, if already distributed, will be withdrawn from the market.  
 
We also commit that FDA will be notified of any changes to the approved application, beyond the 
variations already provided for in the application, and that any such change will be implemented 
according to the requirements under section 506A of the Food and Drug Modernization Act and/or 
21CFR 314.70 and 21 CFR 314.71 (for NDA) or under 21CFR 314.97 (for ANDA), as applicable. 
 
 
 
12. VIAL AND OUTER PACKAGING LABELS 
 
  31 Draft  Not for Implementation 
Draft copies of proposed vial and outer packaging labels are provided in attachment ______, page 
______. 
 
 
13. ENVIRONMENTAL ASSESSMENT 
 
In accordance with 21 CFR 25.31(b), the (insert name of sponsor) claims a categorical exclusion from 
the environmental assessment requirements of 21 CFR 25.20 for approval of fludeoxyglucose F 18 
injection on the basis that the estimated concentration of 2-deoxy-2[18F]fluoro-D-glucose at the point of 
entry into the aquatic environment will be below 1 part per billion. Additionally, to (name of sponsor)s 
knowledge no extraordinary circumstances exist. 
 
 
  32 Draft  Not for Implementation 
 
Sodium Fluoride F 18 Injection 
CMC Sections
  33 Draft  Not for Implementation 
Sodium Fluoride F 18 Injection 
 
1.  DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION 
 
     
       Component      Composition/mL     Composition/batch 
     
Drug Substance  ____ to _____ mCi @ EOS1 _____ to ______ mCi @ EOS1
Sodium Fluoride F 18  ( ____ to _____ MBq @EOS)  ( ____ to _____ MBq @EOS) 
   
 
Inactive Ingredient(s)2            
   _________________mL 
   
 
1.    ____________________       ____________________ 
      (e.g., Sodium chloride          (e.g., 1 mL)     
        injection, USP)   
1.  EOS = End of synthesis calibration time.  
2.  Provide all inactive ingredients used in drug product. Examples of inactive ingredients include 
diluents, buffers, stabilizers, and preservatives. 
 
 
2.  CONTROLS FOR COMPONENTS AND OTHER RAW MATERIALS 
 
A.  TARGET MATERIAL (Starting material) 
 
We will produce the fluoride F 18 drug substance on site at the PET drug production facility? 
_____Yes, ____No. 
 
If yes, provide full details in section (i) below; otherwise proceed to section (ii): 
 
(i) The following target material will be used for production 
 
     
1.  Name of the target material  [18O] Water 
   
 
2.  Name and address of the target 
 
material manufacturer 
   
 
     
3.  Specifications  TEST              ACCEPTANCE                  TEST 
[Specifications that control                             CRITERION               PROCEDURE
identity, purity, and quality of  Identity            ____________              ___________ 
each lot should be included]  Enrichment     Provide justified minimum limit 
Conductivity    Provide justified maximum limit 
Fluoride           Provide justified maximum limit 
Content  
Other               Attributes that control purity should be  
                        included 
Attachment _______, Page ________. 
(Justifications should be included in the attachment) 
 
     
4.  Identity test performed to release  TEST    PROCEDURE     ACCEPTANCE CRITERION 
each lot for production   
  34 Draft  Not for Implementation 
_____          _______        ______________________ 
 
The test procedure is included in attachment 
________, page _____. 
     
5.  Certificate of analysis (COA)  Copy of representative COA is provided in attachment 
  ______, page_______.  
     
6.  Is the target material recycled?  ______ Yes ______ No. 
If yes, its reprocessing procedures are described in 
attachment _______, page______. 
 
Data to support that the reprocessed material 
conforms to the acceptance criteria for the target 
material are provided in attachment ______, 
page_____. 
 
 
We intend to use additional suppliers for this target material: _____Yes _____No. 
 
If yes, for each additional supplier, the target material information identified in items 1, 2, and 5 above 
should be provided in attachment ______, page _____. 
 
(ii)  DRUG SUBSTANCE: We will obtain drug substance from other (e.g., outside) sources, for the 
production sodium fluoride F 18 injection: ______Yes _______No. 
 
If yes, for each source, the following information should provided in a Type-II Drug Master File (DMF). 
The sponsor should refer to the Guideline for Drug Master Files for the administrative information 
that should be included in the DMF.  
 
  Name and composition of the fluoride F 18. 
  Name and address of the manufacturer. 
  Details of the method of manufacture including the controls for the components and raw materials 
used in its manufacture. 
  Specifications for the release of fluoride F 18 drug substance. 
  Information on the container/closure in which the fluoride F18 drug substance is supplied, and the 
copy of the label affixed to it.  
  Representative certificates of analysis (that would be sent to the purchaser with each lot) on three 
representative lots of fluoride F 18 drug substance received by sponsor and used in the 
production of sodium fluoride F 18 Injection. 
  Claim for categorical exclusion from the environmental assessment requirements. 
 
The data and information are provided in DMF # _________. A letter of authorization from the drug 
substance DMF holder, authorizing FDA to refer to the DMF in connection with our application, is 
provided in attachment _____, page ______.  
 
When fluoride f 18 drug substance is obtained from other (e.g., outside) suppliers, the drug application 
should contain the acceptance procedures used by the PET drug product producer to accept and 
release each lot for PET drug product production. Accordingly, following information should be 
supplied in the application: 
 
 
     
1.  Name and composition of the   
fluoride reagent solution 
  35 Draft  Not for Implementation 
     
2.  Name and address of qualified   
supplier 
 
 
 
     
3.  Method of preparation  1. The fluoride F 18 is prepared using a                        
       ____MeV particle accelerator utilizing  
      18O(p, n)18F reaction on H 18O:_____Yes 
2
 
If fluoride reagent is produced by other methods (e.g., 
reactor produced), additional information appropriate 
to such method of production may be necessary. This 
should be discussed in advance with the reviewing 
division. 
 
   
 
Specifications  TEST                ACCEPTANCE                   TEST 
4. 
(Provide specifications that                              CRITERION               PROCEDURE 
control the quality of each lot this  _______                ________                    _____           
material)  _______                ________                    _____          
    
 
                              
 
Attachment _______, page _______. 
 
 
5.  Provide acceptance 
Attachment ______,   page_______. 
procedure(s) used to release 
each lot of the reagent for use in 
production 
     
6.  Certificate of analysis  Copy of representative certificate of analysis is 
provided in attachment _________, page ______. 
 
 
We intend to use additional suppliers for the fluoride F18: _____Yes _____No. 
 
If yes, for each additional supplier, the fluoride F 18 information identified in 1, 2, 3, and 6 above is 
provided in attachment _________, page_____. [Note: Fluoride F18 from different sources must meet 
the sponsors proposed specifications] 
 
B.  INACTIVE INGREDIENTS   
  
The following inactive ingredient(s) are used in sodium fluoride F 18 injection. 
 
       
Name  Function of  Name and address of the  Specifications, representative 
the inactive  manufacturer  COA and acceptance 
ingredient  procedures for each lot are 
included 
       
        Attachment _____, page 
  ____. 
      Attachment _____, page 
____. 
Note: COA need not be provided if the inactive ingredient used is a marketed finished drug product.  
  36 Draft  Not for Implementation 
 
Additional inactive ingredients, if any, are listed and information provided in attachment _____, page 
______. 
 
C.  REAGENTS, SOLVENTS, GASES, PURIFICATION COLUMNS, AND OTHER AUXILIARY 
MATERIALS: 
 
Provide following information for each reagent, solvent, gas, purification columns, and other auxiliary 
materials, which are used in the production of sodium fluoride F 18 injection. 
 
     
                   Name  Name and address of the  Quality grade (e.g., ACS, USP, 
supplier  etc.) or specifications, 
representative COA and  
acceptance procedures for 
each lot are included 
       
       
1    Attachment _____, page ____. 
 
       
       
2    Attachment _____, page ____. 
 
       
       
3      Attachment _____, page ____. 
 
       
       
4    Attachment _____, page ____. 
 
       
       
5    Attachment _____, page ____. 
   
 
[Note: The above table may be extended, if needed, to include additional raw materials, and 
information provided in an attachment] 
 
 
3.  REFERENCE STANDARDS 
 
The following reference standards are used in the quality control methods of sodium fluoride F18 
injection: 
[Note: If a reference standard is obtained from USP, it should be so stated. If a reference standard is 
not obtained from USP, data to support that the reference standard has the desired structure should 
be submitted in the indicated attachment. Purity of the reference standard lot should be provided.] 
 
     
Name of reference standard  Name and address of the  Specifications, representative 
supplier  COA and acceptance 
procedures for each lot are 
included 
      Attachment _____, page ____. 
1  Sodium Fluoride 
  37 Draft  Not for Implementation 
4.  PRODUCTION AND TESTING FACILITIES 
 
Name of PET drug production facility:  __________________________________________ 
  Address:           __________________________________________ 
              __________________________________________ 
__________________________________________ 
  Name of contact person:      __________________________________________   
  Phone number of contact person:    __________________________________________ 
 
Additional manufacturing and / or testing facilities (if any), including their function, are listed in 
attachment ________, page ____ 
 
 
5.   PRODUCTION OF DRUG SUBSTANCE 
 
NOTE: If fluoride F 18 is obtained from external sources, the drug substance manufacturing 
information (item 5) should be provided in the drug master file referenced in 2.A (ii) above. 
 
  A.  BATCH FORMULA:  The following components and their quantities are used in the production of  
  each batch of fluoride F 18: 
 
Provide below the name of each component used in the production of fluoride F 18, whether or not it 
appears in the final product; its function; and the amount (mass or volume) used in each batch 
(include all reactants, solutions, solvents, and reagents used in the chemical synthesis and purification 
operation). 
 
     
Name of component   Components function  Amount used 
     
     
     
     
     
     
     
     
 
 
B.  PRODUCTION OF RADIONUCLIDE    
 
(i)  Particle Accelerator (e.g., Cyclotron) Used 
 
The following particle accelerator is used for the production of fluoride F 18 
 
MAKE:   ____________________________________ 
MODEL:  ____________________________________ 
 
 
Information concerning additional particle accelerators is provided in attachment _______, page 
______. 
 
(ii)  Operating Parameters 
 
  During irradiation a beam current of _____A  +  ____A is used. 
  Irradiation times of _____ minutes to _____ minutes are used. 
  We use/do not use high-pressure targets. When high-pressure targets are used, irradiations 
  38 Draft  Not for Implementation 
are performed under ____ psi pressure.   
 
(iii) Specifications for Target Body  
 
  Volume of the target body is ____________ l or ml.    
  The target body used in production operation is composed of _____________________. 
  The target windows used in target body are ___________(state thickness) and are composed 
of ____________________________________________________________________. 
  The schedule for the replacement of target windows is __________________________. 
  The acceptance criteria for the target body and the target windows (that come in contact with 
target material) are provided in attachment _________, page _______. 
 
If multiple target bodies of different types are used, the above information concerning each is 
provided in attachment _____, page _____. 
 
C.  SYNTHESIS AND PURIFICATION OF THE DRUG SUBSTANCE 
 
(i)  Description of Synthesis and Purification Equipment 
 
Descriptions of the synthesis and purification equipment, including acceptance criteria for the 
components, and a schematic flow diagram are provided in attachment ______, page _____. 
 
(ii)   Description of Synthesis and Purification Operation 
 
A step-wise description of the synthesis and purification procedure is provided in attachment 
_______, page _____. 
 
(iii) In-Process Controls 
 
We recommend that the applicant have adequate process controls to ensure continued quality of 
the product.  The production procedure is controlled by monitoring the process controls and 
parameters described in attachment ______, page___. 
 
All stated process controls are monitored and documented in the master production and controls 
records:  ______ Yes. 
 
(iv) Post-Synthesis Procedures 
 
Descriptions of procedures used to prepare the production equipment, including any cleaning and 
purging procedures, for a subsequent batch are provided in attachment _______, page _____. 
 
 
6.  MANUFACTURE OF DRUG PRODUCT 
 
A.  PRODUCTION OPERATION 
 
The specific procedures used in the formulation and preparation of the finished drug product are 
provided in attachment _____, page _____. 
 
The master production and control records, which provide the specific procedures used in the 
production of and ensure full traceability / accountability of all components, materials and 
equipment used, and the operators for each batch of sodium fluoride F 18 injection are provided in 
attachment ______, page  _____. 
 
B.  REPROCESSING OF PET DRUG PRODUCT 
  39 Draft  Not for Implementation 
    Check below as appropriate and provide the indicated information: 
 
(cid:31)  A PET drug product batch or lot will not be reprocessed. 
 
(cid:31)  A PET drug product batch or lot may be reprocessed under the specific conditions 
(circumstances) described in attachment _____, page _____.  
 
The validated procedures used in reprocessing are described in attachment ______, page _____. 
 
C.  PACKAGING AND LABELING 
 
The components used in the packaging of the drug product vial and the method of labeling are 
described in master production and control records on page ______ (attachment _____).  
 
The specifications for the packaging components and the acceptance procedures for each lot are 
provided in attachment ______, page ______. 
 
 
7.  CONTAINER / CLOSURE 
 
  We use a presterilized, presealed, pyrogen-free container/closure, consisting of USP Type I glass, 
gray butyl rubber stopper, and aluminum crimp seal, from a commercial supplier: _____Yes _____ No. 
 
  If no, full information on the container/closure along with its sterilization procedures and sterility 
assurance is provided in attachment ______, page ______. 
 
  If yes, the _____ ml container/closure, consisting of USP Type I glass, gray butyl stopper, and 
aluminum crimp seal, is obtained from the following manufacturer. The specifications and the 
procedures used for accepting a lot of the container/closure are provided in attachment ____, page 
_____. 
 
 
Container/Closure catalog #   ___________________________________ 
Name and address of supplier   ___________________________________ 
___________________________________ 
___________________________________ 
    Drug master file number     ___________________________________ 
 
A letter of authorization from the DMF holder, authorizing FDA to refer to the DMF in connection with 
our  application, is provided in attachment _____, page ______. 
 
 
8.  CONTROLS FOR THE FINISHED DOSAGE FORM 
 
A.  SAMPLING PROCEDURES 
 
Each batch of sodium fluoride F 18 injection will be produced for distribution: 
  In a single multidose vial _____. 
  In multiple vials (single or multiple dose) _______. 
 
(i)  If each batch is produced in a single vial, a description of how the representative sample is 
obtained (e.g., the amount of volume that is withdrawn from the finished drug product container 
and how it is distributed among individual tests) is provided in attachment _______, page ______.   
 
  (ii)  If each batch is produced in multiple vials, a description of sampling techniques that ensure that 
  40 Draft  Not for Implementation 
the test sample is representative of the entire batch is provided in attachment _____, page 
______. 
 
B.  REGULATORY SPECIFICATIONS  
 
Each batch of the sodium fluoride F 18 injection will meet the following specifications during its entire 
shelf life when tested according to the standard test procedures described in the SOPs submitted in 
this application. 
 
[Note: The following tests are related to a commonly used production method. In the event that the 
production method does not use a component listed below or uses an alternate method of production 
or produces additional impurities, appropriate tests, acceptance criteria, procedures, and a testing 
schedule that is more appropriate for such production method should be proposed.] 
 
       
TEST  ACCEPTANCE    PROCEDURES  TESTING 
CRITERIA  SCHEDULE 
       
Appearance  Colorless and free from  Visual observation under  Test completed 
particulate matter   lighted conditions  prior to release of 
  drug product 
SOP# _____________ 
     
 
The measured half-life is  Measurement of a  Test completed 
Radionuclidic 
between 105.0  115.0  sample in a dose  prior to release of 
identity 
minutes  calibrator over a10  drug product 
  minute period 
 
 
SOP# _____________ 
       
Radiochemical  The retention time (R) of  State specific  Test completed 
t
identity  drug product test solution  chromatography  prior to release of 
corresponds (e.g., < +10%)  procedure  drug product 
to the R of sodium fluoride   
t
reference standard  SOP#______________ 
       
Radionuclidic purity  State limit and provide  State suitable method of  State schedule 
  justification in an  analysis of  decayed  and provide 
attachment   sample  justification 
Attachment___________    Attachment____ 
Page________________  SOP# _____________  Page_________ 
       
Radiochemical  NLT1 95% fluoride F 18  State specific  Test completed 
purity  chromatography  prior to release of 
  procedure  drug product 
 
SOP#______________ 
       
Assay  ____mCi to ____ mCi / mL  See USP   Test completed 
(Radioactivity  @ EOS ( This should be    prior to release of 
concentration)  same as stated strength of  SOP# _____________  drug product 
drug product)   
       
Specific activity  No carrier added   None, prepared by no  No testing 
  carrier method of  performed 
synthesis 
       
  41 Draft  Not for Implementation 
pH  State limit and provide  pH paper with pH  Test completed 
justification   reference standards  prior to release of 
(Note: the currently    drug product 
approved drug product ahs  SOP# _____________ 
pH limits of 6.0  8.0) 
Attachment __________ 
Page________________ 
       
Membrane filter  Specify limit for the filter  Bubble point  Test completed 
integrity  being used  measurement  prior to release of 
    drug product 
SOP# _____________ 
Bacterial  NMT2 175 EU/V, in which V     
State test procedure  Test completed 
endotoxins  is the maximum 
SOP# _____________  prior to final 
(LAL)  recommended total dose in 
release of drug 
mL, at the expiration time.  
product 
For intrathecal 
administration, please 
contact the review division. 
       
Sterility testing  Sterile  State test procedure  Test initiated 
SOP# ____________  within 24 hours of 
preparation 
       
Osmolality  Isotonic (specify range)  SOP# _____________  Validate / 
Calculate 
1.  NLT = No Less Than 
 [Note: If a stabilizer is added, test for the assay of stabilizer should be included in the specifications. If 
residual solvents may be present they should be tested as part of the finished product testing] 
 
 
9.  DESCRIPTION OF ANALYTICAL TEST PROCEDURES 
 
Each standard test procedure is included in the application as identified below: 
 
[Note: Each procedure should include the following: (1) the analytical supplies and their quality used; 
(2) all the equipment and the settings used during the performance of the procedure; (3) the 
preparation of test, standard, and analytical solutions; (4) detailed description of the test procedure; (5) 
exact calculations performed in quantitative procedures; (6) the recording of the results; and (7) the 
system suitability test(s) performed (including performance schedule, system suitability standards 
used, and the acceptance criteria that ensure proper performance of the equipment). Each procedure 
should be reliable and capable of providing valid data. Where applicable, the procedure should be 
specific and stability indicating. For chromatographic, spectroscopic (e.g., gamma) and microbiologic 
procedures, validation data that show suitability of the test procedure for the intended purpose should 
be included in the attachment where the test procedure is included.] 
 
       
Test  Test Procedure  Attachment  Page Number 
Number 
       
Appearance       
       
Radionuclidic identity       
       
Radiochemical identity and       
  42 Draft  Not for Implementation 
purity  
       
Radinuclidic purity       
       
Assay (Radioactivity       
concentration) 
       
pH       
       
Membrane filter integrity test       
       
Bacterial endotoxins (LAL)       
       
Sterility test       
       
Osmolality       
 
 
[Note: Above list of test procedures should correspond to the tests proposed as part of the 
specifications, and the list may be amended as necessary] 
 
 
10. MICROBIOLOGICAL VALIDATION 
 
This part describes the information you should submit in Section 10 (microbiological validation) of your 
NDA/ANDA for PET drug products.  At the end of this section, there is a table of contents that you can use 
to list the information submitted in your NDA/ANDA. Only the indicated information should be should be 
submitted in this part of the CMC section of your NDA/ANDA and the descriptive guidance provided to 
assist you need not be included. 
 
The microbiological validation section of the CMC section of your NDA/ANDA should be used to describe 
the procedures that ensure sterility of injectable PET radiopharmaceuticals.  Information common to other 
sections should be provided directly, and not by reference, to other sections because the microbiological 
validation attachment is reviewed separately from the chemistry section by microbiology reviewers.  The 
introduction to this section should describe the products container and closure system (size, shape, and 
composition), and the time and maximum volume of product solution that may be administered to a 
patient.  Additionally, each of the following issues should be addressed in the microbiology section: 
 
  Production Site.  The production site (name and complete address) should be identified and 
accompanied by a description of the production area. The description should include the presence of 
environmental controls (e.g., laminar air flow hoods, biosafety cabinets, isolators) that protect product 
components from microbiological sources of contamination.  
 
  Processing Equipment and Components.  The methods for preparing equipment and components 
should be summarized in the submission.  When sterile vials, syringes, transfer sets, and filters are 
obtained from commercial sources and used in the products manufacture, a Certificate of Analysis 
from the suppliers may be substituted where appropriate.  Reusable equipment that contacts the PET 
drug solution during its manufacture should be prepared to eliminate endotoxins and sanitized (or 
sterilized) to control bioburden.  If components are sterilized at the PET facility, their sterilization 
processes and the components aseptic assembly should be verified experimentally and summarized 
in this section.  For sterilization done on-site, the performance of a sterilizer should be verified 
periodically and should be described, including a summary of the method and results from the last 
study.  Drug products for parenteral administration must be sterile.  PET solutions are usually filtered 
and aseptically transferred to a sterile, pyrogen-free container (for example, a multiple dose vial). 
Certain PET products may not use a vial for the finished dosage form, and these require special 
consideration.  Some PET facilities may use a long fluid line to deliver multiple batches of the product 
solution to a remote area for further processing.  These delivery lines should be described in the CMC 
  43 Draft  Not for Implementation 
section of your NDA/ANDA, including their preparation and the validation of the duration of use.  When 
special procedures and components are used, their impact on sterility assurance should be described. 
 
  Facility Environmental Controls.  A summary of the production process should address control 
systems in the work area used for preparing the finished dosage form.  The work area should be 
clean, and the synthesis unit should be in a location that permits materials to be transferred to the 
aseptic area without adulteration.  It is recommended that batch records indicate that sterile 
components, materials, and equipment are in protective wrapping or containers when transferred into 
the aseptic area.  Also, it is recommended that final containers, filter assembly, sterile fluid lines, vent 
filters, and needles are sterile, disposable, and for single use only.  
 
  The Aseptic Area.  Many facilities have an aseptic area for the transfer of the sterile solution into a 
sterile container for the finished product.  As appropriate, the application should include descriptions of 
the aseptic hood, isolator, or other suitable environmental system area used when preparing the 
finished product.  The air classification in the aseptic environment should be specified using standard 
nomenclature (e.g., ISO or US Fed. Std 209E). Microbiological testing of the aseptic environment 
should be done periodically, and the microbiological methods (sampling methods and frequency, 
culture media, incubation time and temperature) described.  These methods may include swabs or 
contact plates for surfaces, and settle plates or dynamic air samplers.  Airborne, non-viable particle 
counting should be summarized as part of the testing program, although these tests may be done less 
frequently than microbiological testing.  
 
  Aseptic Technique.  The qualification program for aseptic area operators should be summarized in the 
NDA/ANDA.  The aseptic techniques used to make a sterile product should be evaluated by process 
simulation studies. Simulations should be done 3 times to qualify a new operator.  Each operator 
should repeat one simulation annually, or anytime changes occur in the procedures.  Microbiological 
methods, acceptance criteria and results of these simulations (initial studies, or the last annual study) 
should be provided. 
 
  Filtration Process Qualification.  Sterilizing filtration is a critical procedure for removing 
microorganisms from solutions of injectable PET radiopharmaceuticals.  When the filters are made 
and sterilized by a commercial filter manufacturer, the filtration conditions of pressure and flow rate 
are generally provided by the filter manufacturer.  A certificate from the manufacturer is acceptable, 
but the filtration conditions such as pressure or volume should be identified in the batch record and not 
exceeded. Integrity testing by the drug manufacturer is not intended to confirm the filter porosity rating, 
as is the filter manufacturers testing.  However, in-process filter integrity tests to demonstrate that the 
membrane and housing have not lost the ability to retain microorganisms may be done according to 
the manufacturers recommended method or by an alternative filter integrity test method that 
demonstrates the filter membrane is not torn or detached from the housing.  The batch record should 
indicate that after filtering the PET radiopharmaceutical, the sterilizing membrane filter is tested for 
integrity before the product is released.  Filter integrity test methods and acceptance criteria should be 
described in the application. 
 
  Finished Product Microbiological Testing.  All products for parenteral administration, including PET 
radiopharmaceuticals, must be sterile and free of endotoxins (USP <1>, Injections).  Sterility and 
endotoxin tests should be initiated promptly after preparing the product.  Test methods should be 
described (or provided by a reference) in your NDA/ANDA.  Details of the methods should include 
sampling method, sample sizes, microbiological methods, acceptance criteria and actions following a 
failure.  The acceptance limit for endotoxins test results should also include the calculations that relate 
the patient dose to the endotoxins limit.  
 
You can use the following as a table of contents for the information you include in Section 10 on 
microbiological validation.  
 
 
  44 Draft  Not for Implementation 
 
Test or Criterion  Document(s)  Page 
Number(s) 
Product Summary     
Container and Closure System     
Maximum Volume of Patient Dose     
Facility Description     
     
Sterile Equipment and Components     
Single Use  Certificate of Analysis   
Reusable  Sterilization Validation   
     
Environmental Controls     
     
Aseptic Area Environmental Monitoring     
     
Aseptic Process Simulation Methods and     
Results 
     
Sterile Filtration Process     
Microbial Retention Test or Certificate     
Pressure and Flow Rate Limits     
Filter Integrity Test Method     
Post-Use Integrity Test Limits     
     
Sterility Test Methods, Limits and Controls     
Actions if Test Fails     
     
Endotoxins Test Methods, Limits and Controls    
Determination of Endotoxins Limit     
Actions if Test Fails     
 
 
11. STABILITY AND BATCH DATA 
 
A.  EXPIRATION DATING PERIOD 
 
We propose an expiration-dating period of ________ hours from the EOS calibration time when 
sodium fluoride F 18 injection is stored at _____oC +/- ____oC (or controlled room temperature). 
 
   (Note: Refer to USP for controlled room temperature definition.) 
 
B.  STABILITY DATA/BATCH DATA 
 
If the submission is an NDA (under section 505 (b)(2) of the act), complete release and stability 
data on three batches of sodium fluoride F 18 injection prepared at the upper range of proposed 
radioconcentration and stored at _____oC +/- ____oC, are provided in attachment ______, page 
_____ . 
 
If the submission is an ANDA (under section 505(j) of the act), complete release data on three 
  45 Draft  Not for Implementation 
batches prepared at the upper range of proposed radioconcentration along with the stability data 
on one of the three batches of sodium fluoride F 18 injection prepared at the upper range of 
proposed radioconcentration and stored at _____oC +/- ____oC, are provided in attachment 
______, page _____. 
 
    Additionally for each batch,  
  The batch was stored in the same container/closure as it was produced: _____Yes. 
  The vial was stored in an inverted position: ______Yes. 
  All tests indicated in the specification section were performed at release: _____Yes. 
  The appearance, radiochemical purity, radionuclidic purity, and pH (and stabilizer 
concentration when present) were also evaluated at the end of proposed expiration dating 
period:_____Yes.     
 
[Note: If the application incorporates multiple production sites, please discuss with the reviewing 
division in advance of submitting the application concerning the stability and batch data that 
should be submitted. The phone number for the Division of Medical Imaging Products is (301) 
796-2050.] 
 
C.  POSTAPPROVAL COMMITMENTS 
 
We commit that; annually post-approval a minimum of one batch of sodium fluoride F 18 will be 
tested according to the protocol described below. The entire content of the batch vial will be stored 
inverted at _____ oC for ______ hours (from EOS), and tested according to the specifications and 
procedures described in this application for finished product testing. The results of such testing will 
be provided to the FDA in the annual report. 
 
     
Test  Test performed at   Test performed at 
       release  the end of 
proposed expiry 
     
Appearance  YES  YES 
     
Radionuclidic identity  YES  NO 
     
Radiochemical identity and  YES  YES 
purity 
     
Radionuclidic purity  YES  YES 
     
Assay (Radioactivity  YES  NO 
concentration) 
pH  YES  YES 
   
Membrane filter integrity test 
YES  NO 
   
Bacterial endotoxins (LAL) 
YES  NO 
 
     
Sterility test  YES  NO 
     
Osmolality  YES  NO 
        (Note: Include stabilizer at both time intervals, if present.) 
 
Additionally, we commit that any batch of sodium fluoride F 18 injection that fails to meet the 
acceptance criteria will not be released or if already distributed will be recalled from the market.  
 
  46 Draft  Not for Implementation 
We also commit that FDA will be notified of any changes to the approved application, beyond the 
variations already provided for in the application, and that any such change will be implemented 
according to the requirements under section 506A of the Food and Drug Modernization Act and / or 
21CFR 314.70 and 21 CFR 314.71 (for NDA) or under 21CFR 314.97 (for ANDA), as applicable. 
 
 
12. VIAL AND OUTER PACKAGING LABELS 
 
Draft copies of proposed vial and outer packaging labels are provided in attachment ______, page 
______.  
 
 
13. ENVIRONMENTAL ASSESSMENT 
 
In accordance with 21 CFR 25.31(b), the (insert name of sponsor) claims a categorical exclusion from 
the environmental assessment requirements of 21 CFR 25.20 for approval of sodium fluoride F 18 
injection on the basis that the estimated concentration of sodium fluoride F18 at the point of entry into 
the aquatic environment will be below 1 part per billion. Additionally, to (name of sponsor)s knowledge 
no extraordinary circumstances exist.  
  47