PET Drug Applications - Content and Format for NDAs and ANDAs: Attachment I: Sample formats for chemistry, manufacturing, and controls (CMC) sections_2011

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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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 Agency’s 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.

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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

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Ammonia N 13 Injection
1. 	DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION
Component 	Composition/mL 	Composition/
sub-batch vial
Drug Substance
Ammonia N 13
____ to ____ mCi @ EOS1
(____ to ____ MBq @EOS)
____ to ____ mCi @ EOS1
(____ to ____ MBq @EOS)
Inactive ingredient(s)2
1. 	____________________
(e.g., Sodium chloride
injection, USP)
____________________
(e.g., 1 mL) 	_________________ mL
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
[Specifications to control identity,
purity, relevant quality should be
proposed]
TEST 	ACCEPTANCE
CRITERION
Attachment ______, page ______.
TEST
PROCEDURE
4. 	Identity test performed to release
each lot for production use
TEST 	PROCEDURE 	ACCEPTANCE
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
the inactive
ingredient
Name and address
of the manufacturer
Specifications,
representative COA and
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
1 	Attachment _____, page ____.
2 Attachment _____, page ____.
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3
Attachment _____, page ____.
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
supplier
Specifications, representative
COA, and acceptance
procedures for each lot are
included
1 Ammonium chloride 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
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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 	Component’s 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 _____μA + ____μA 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 ____________ μl 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
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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 preparation 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
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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
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schedules that are more appropriate for such production method should be proposed.]
TEST 	ACCEPTANCE
CRITERIA
TEST PROCEDURE
&
SOP NUMBER
TESTING
SCHEDULE
Appearance 	Colorless and free from
particulate matter
Visual observation under
lighted conditions
SOP# ______________
Each sub-batch of
a batch is tested
Radionuclidic
identity
The measured half-life is
between 9.5 – 10.5
minutes.
Measurement of
radioactivity for decay of
a sample over a 10
minute period
SOP# ______________
Quality control sub-
batch; testing for
first sub-batch is
completed prior to
preparation of
clinical sub-batches
Radiochemical
identity
The retention time (Rt) of
major peak in test solution
corresponds (e.g., + 5%)
with the retention time
peak obtained for the
reference standard
solution.
HPLC
SOP#_______________
Quality control sub-
batch; testing for
first sub-batch is
completed prior to
preparation of
clinical sub-batches
Radionuclidic purity 	State limit and provide
justification in an
attachment.
Attachment__________
Page_______________
Gamma spectroscopy of
decayed sample
SOP# _______________
State schedule and
provide justification
Attachment______
Page___________
Radiochemical
purity
NLT1 95.0 %
Ammonia N 13
HPLC
SOP#_______________
Quality control sub-
batches; testing for
first sub-batch for
first sub-portion
completed prior to
preparation of
clinical sub-batches
Assay
(radioactivity
concentration)
____mCi to ____ mCi / mL
@ EOS for each sub-
batch (vial)
Refer to USP
SOP# _______________
Each sub-batch
Specific activity NLT1 10 Ci / mmol 	HPLC
SOP# _______________
State schedule /
provide justification
PH 	4.5 – 7.5 (USP) pH paper with pH
reference standards
SOP# _______________
Quality control sub-
batch or each sub-
batch (depending
of production
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method); testing for
sub-batch is
completed prior to
final release
Membrane filter
integrity
Specify limit for the filter
being used.
Bubble point
measurement
SOP# _______________
State schedule for
each sub-batch.
Bacterial endotoxin
(LAL)
NMT2 175 EU/V, in which
V is the maximum
recommended total dose
in mL, at the expiration
time. For intrathecal
administration, please
contact the review
division.
Refer to USP
SOP# _______________
Quality control sub-
batch; testing for
first sub-batch
completed prior to
release
Sterility Testing 	Sterile 	Refer to USP
SOP# _______________
Quality control sub-
batch; test initiated
within 24 hours of
preparation.
Osmolality 	Isotonic (specify range) 	SOP# _______________ 	Validate / calculate
Chemical purity
(provide tests for
appropriate
chemical impurities
based on the
specific method of
preparation)
State limits for each 	State method and provide
SOP.
SOP# _______________
Quality control sub-
batch; testing for
first sub-batch is
completed prior to
preparation of
clinical sub-batch
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.]
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Test 	Test Procedure
Number
Attachment 	Page 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 product’s 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
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obtained from commercial sources and used in the product’s 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 manufacturer’s 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
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(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.
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[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
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Radiochemical
impurities
YES 	NO
Chemical purity 	YES 	NO
Membrane filter
integrity test
YES 	NO
Bacterial endotoxin
(LAL) YES 	NO
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.
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Fludeoxyglucose F 18 Injection
CMC Sections
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Fludeoxyglucose F 18 Injection
1. 	DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION
Component 	Composition/mL 	Composition/batch
Drug Substance
2-Deoxy-2[18
F]fluoro-D-
glucose
_____ to _____ mCi @EOS1
( ____ to _____ MBq @ EOS)
____ to _____ mCi @EOS1
( ____ to ____ MBq @ EOS)
Inactive ingredient(s)2
1.
____________________
(e.g., Sodium chloride
injection, USP)
2. 	___________________
_
____________________
(e.g., 1 mL)
_____________________
_________________ mL
___________________
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-β-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-
β-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
purified on site?
_______ Yes _______ No. If yes, method of
purification is provided in attachment _______,
page_____.
4. 	Specifications
(Specifications that control the
identity, purity and quality of
each lot should be included)
TEST 	ACCEPTANCE 	TEST
CRITERION 	PROCEDURE
Appearance 	_______
Specific identity 	_______
(e.g., IR, NMR)
Purity 	_______
(e.g., chromatography)
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Melting point 	_______
Optical rotation 	________
Attachment ________, Page ________
5. 	Representative certificate of
analysis (COA) from supplier
Copy of representative certificate of analysis is
provided in attachment _______, page_______.
6. 	Identity test performed to confirm
structure to release each lot for
production
TEST 	PROCEDURE 	ACCEPTANCE
CRITERION
_____ 	_______ 	___________________
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 	[ 18
O] Water
2. 	Name and address of the target
material manufacturer
3. 	Specifications
[Specifications that control
identity, purity, and quality of
each lot should be included]
TEST 	ACCEPTANCE 	TEST
CRITERION 	PROCEDURE
Identity 	_______________________
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
each lot for production
TEST 	PROCEDURE
_____ 	___________
Detailed test procedure
ACCEPTANCE CRITERION
______________________
is included in attachment
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________, page_____.
5. 	Certificate of analysis (COA) 	Copy of representative certificate of analysis is
provided in attachment ______, page_______.
6. Is the target material recycled? ______ Yes ______ No.
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
(Check the box that applies to
your situation)
1. The fluoride reagent is prepared using a
____MeV particle accelerator utilizing
18O(p, n)18F reaction on H218O.
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______.
4. Specifications
(Provide appropriate
specifications that control the
quality of each lot this material)
TEST 	ACCEPTANCE 	TEST
CRITERION 	PROCEDURE
_______ 	________ 	_________
_______ 	________ 	_________
Attachment _______, page _______.
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5. 	Provide acceptance
procedure(s) used to release
each lot of the reagent for use in
production
Attachment ______, 	page_______.
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
sponsor’s proposed specifications.]
C. 	INACTIVE INGREDIENTS
The following inactive ingredient(s) are used in the fludeoxyglucose F 18 injection.
Name 	Function of
the inactive
ingredient
Name and address of the
manufacturer
Specifications,
representative COA and
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
supplier
Quality grade (e.g., ACS, USP,
etc.) or specifications,
representative COA and
acceptance procedures for
each lot are included
1
Attachment _____, page ____.
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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
supplier
Specifications,
representative COA and
acceptance procedures for
each lot are included
1 	2-Fluoro-2-deoxy-D-glucose 	Attachment __, page____
2 2-Chloro-2-deoxy-D-glucose Attachment___, page____
3
Kryptofix, 222 (4,7,13,16,21,
24-hexaoxa 1,10diazabicyclo
[8.8.8] hexacosane)
Attachment___, page____
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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 	Component’s function 	Amount used
[Example: 1,3,4,6-Tetra-O-
acetyl-2-O-trifluoro
methanesulfonyl-β-D-
mannopyranose]
_______ mg + __mg
[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 supplier’s DMF or provided in your NDA/ANDA:
(i) 	Particle Accelerator (e.g., cyclotron) Used
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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 _____μA + ____μA 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____________ μl 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
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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.
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□ 	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
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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
CRITERIA
PROCEDURES 	TESTING
SCHEDULE
Appearance 	Colorless and free from
particulate matter
Visual observation under
lighted conditions
SOP# ______________
Test completed
prior to release of
drug product
Radionuclidic
identity
The measured half-life is
between 105.0 – 115.0
minutes
Measurement of
radioactivity decay of the
sample over a 10
minute period
SOP# ______________
Test completed
prior to release of
drug product
Radiochemical
identity
The Rf of 2-deoxy-
2[18F]fluoro-D-glucose
corresponds (e.g., < +10%)
to the Rf (about 0.4) of 2-
deoxy-2-fluoro-D-glucose
reference standard, when
both are chromatographed
together side by side on the
same TLC
TLC, activated silica gel
plate developed in 95:5 /
acetonitrile : water (TLC
scanned in a radio-
chromatographic
scanner and by
treatment with
appropriate reagent)
SOP#_______________
Test completed
prior to release of
drug product
Radionuclidic purity 	State limit and provide
justification in an
attachment.
Attachment__________
Page_______________
State suitable method of
analysis of decayed
sample
SOP#_______________
State schedule
and provide
justification
Attachment____
Page_________
Radiochemical
purity
NLT1 90.0%
2-deoxy-2[18F]fluoro-D-
glucose
TLC, activated silica gel
plate developed in 95:5/
acetonitrile : water (TLC
scanned in a radio-
chromatographic
scanner)
SOP#_______________
Test completed
prior to release of
drug product
Radiochemical
impurities
State the maximum limit for
fluoride F 18 (free) and
provide justification.
Attachment____________
Page_________________
Provide test procedure
SOP# ______________
Test completed
prior to release of
drug product
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Assay
(radioactivity
concentration)
____mCi to ____ mCi / mL
@ EOS ( This should be
same as the stated strength
of drug product)
Refer to USP
SOP#_____________
Test completed
prior to release of
drug product
Specific activity 	No carrier added
2-deoxy-2[18F]fluoro-D-
glucose
None - prepared by no
carrier added method of
synthesis
No testing
performed
pH 	Specify justified limits
Attachment_________
Page______________
pH paper with pH
reference standards
SOP# _____________
Test completed
prior to release of
drug product
Kryptofix 222
(if used in
synthesis)
The size and intensity of
the spot in test sample,
that corresponds to the
50μg/ml kryptofix 222
reference standard spot,
does not exceed that of the
standard solution
TLC, comparison of drug
product with 50 μg / mL
reference standard
solution
SOP# _____________
Test completed
prior to release of
drug product
Residual solvents4
1. Acetonitrile
2. Diethyl Ether
3. Ethanol
1. NMT2 0.04% (w/v)
2. NMT2 0.5% (w/v)
3. NMT2 0.5% (w/v)
Gas chromatography,
flame ionization
detection
SOP# _____________
Test completed
prior to release of
drug product
2-Chloro-2-deoxy-
D-glucose (if it is a
possibility in
synthesis)
NMT2 1.0 mg / V3 	HPLC
SOP# _____________
Validation and on
annual batch
thereafter
Membrane Filter
Integrity
Specify limit for the filter
being used
Bubble point
measurement
SOP# _____________
Test completed
prior to release of
drug product
Bacterial
endotoxins
(LAL)
NMT2 175 EU/V, in which V
is the maximum
recommended total dose in
mL, at the expiration time.
For intrathecal
administration, please
contact the review division.
State test procedure
SOP# _____________ Test completed
prior to final
release of drug
product
Sterility testing 	Sterile 	State test procedure
SOP# _____________
Test initiated
within 24 hours of
preparation
Osmolality 	Isotonic (specify range) 	SOP# _____________ 	Validate /
calculate
Glucose 	NMT ___ mg/V3 	No test performed Calculated based
on the amount of
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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
Number
Attachment 	Page 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
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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 product’s 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 product’s 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
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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 manufacturer’s 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 manufacturer’s 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
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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.]
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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
Release
Test performed at
the end of proposed
expiry
Appearance 	YES 	YES
Radionuclidic identity 	YES 	NO
Radiochemical identity and
purity
YES 	YES
Radiochemical impurities
(free 18F fluoride)
YES 	YES
Radionuclidic purity 	YES 	YES
Assay (radioconcentration) 	YES 	NO
pH YES 	YES
Test for kryptofix 222
(or other catalyst)
YES 	NO
Test for residual solvents YES 	NO
2-Chloro-2-deoxy-D-
glucose YES 	NO
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 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
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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.
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Sodium Fluoride F 18 Injection
CMC Sections
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Sodium Fluoride F 18 Injection
1. 	DRUG PRODUCT COMPONENTS AND QUANTITATIVE COMPOSITION
Component 	Composition/mL 	Composition/batch
Drug Substance
Sodium Fluoride F 18
____ to _____ mCi @ EOS1
( ____ to _____ MBq @EOS)
_____ to ______ mCi @ EOS1
( ____ to _____ MBq @EOS)
Inactive Ingredient(s)2
1. 	____________________
(e.g., Sodium chloride
injection, USP)
____________________
(e.g., 1 mL)
_________________mL
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
[Specifications that control
identity, purity, and quality of
each lot should be included]
TEST 	ACCEPTANCE 	TEST
CRITERION 	PROCEDURE
Identity 	____________ 	___________
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
each lot for production
TEST 	PROCEDURE 	ACCEPTANCE CRITERION
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_____ 	_______ 	______________________
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
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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 H218O:_____Yes
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.
4. Specifications
(Provide specifications that
control the quality of each lot this
material)
TEST 	ACCEPTANCE 	TEST
CRITERION 	PROCEDURE
_______ 	________ 	_____
_______ 	________ 	_____
Attachment _______, page _______.
5. 	Provide acceptance
procedure(s) used to release
each lot of the reagent for use in
production
Attachment ______, 	page_______.
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 sponsor’s proposed specifications]
B. 	INACTIVE INGREDIENTS
The following inactive ingredient(s) are used in sodium fluoride F 18 injection.
Name 	Function of
the inactive
ingredient
Name and address of the
manufacturer
Specifications, representative
COA and 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.
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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
supplier
Quality grade (e.g., ACS, USP,
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
supplier
Specifications, representative
COA and acceptance
procedures for each lot are
included
1 	Sodium Fluoride
Attachment _____, page ____.
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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 	Component’s 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 _____μA + ____μA 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
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are performed under ____ psi pressure.
(iii) Specifications for Target Body
• 	Volume of the target body is ____________ μl 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
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Check below as appropriate and provide the indicated information:
 	A PET drug product batch or lot will not be reprocessed.
 	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
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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
CRITERIA
PROCEDURES 	TESTING
SCHEDULE
Appearance 	Colorless and free from
particulate matter
Visual observation under
lighted conditions
SOP# _____________
Test completed
prior to release of
drug product
Radionuclidic
identity
The measured half-life is
between 105.0 – 115.0
minutes
Measurement of a
sample in a dose
calibrator over a10
minute period
SOP# _____________
Test completed
prior to release of
drug product
Radiochemical
identity
The retention time (Rt) of
drug product test solution
corresponds (e.g., < +10%)
to the Rt of sodium fluoride
reference standard
State specific
chromatography
procedure
SOP#______________
Test completed
prior to release of
drug product
Radionuclidic purity 	State limit and provide
justification in an
attachment
Attachment___________
Page________________
State suitable method of
analysis of decayed
sample
SOP# _____________
State schedule
and provide
justification
Attachment____
Page_________
Radiochemical
purity
NLT1 95% fluoride F 18 	State specific
chromatography
procedure
SOP#______________
Test completed
prior to release of
drug product
Assay
(Radioactivity
concentration)
____mCi to ____ mCi / mL
@ EOS ( This should be
same as stated strength of
drug product)
See USP
SOP# _____________
Test completed
prior to release of
drug product
Specific activity 	No carrier added 	None, prepared by no
carrier method of
synthesis
No testing
performed
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pH 	State limit and provide
justification
(Note: the currently
approved drug product ahs
pH limits of 6.0 – 8.0)
Attachment __________
Page________________
pH paper with pH
reference standards
SOP# _____________
Test completed
prior to release of
drug product
Membrane filter
integrity
Specify limit for the filter
being used
Bubble point
measurement
SOP# _____________
Test completed
prior to release of
drug product
Bacterial
endotoxins
(LAL)
NMT2 175 EU/V, in which V
is the maximum
recommended total dose in
mL, at the expiration time.
For intrathecal
administration, please
contact the review division.
State test procedure
SOP# _____________
Test completed
prior to final
release of drug
product
Sterility testing 	Sterile 	State test procedure
SOP# ____________
Test initiated
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
Number
Attachment 	Page Number
Appearance
Radionuclidic identity
Radiochemical identity and
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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 product’s 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 product’s 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
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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 manufacturer’s 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 manufacturer’s 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.
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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
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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
release
Test performed at
the end of
proposed expiry
Appearance 	YES 	YES
Radionuclidic identity 	YES 	NO
Radiochemical identity and
purity
YES 	YES
Radionuclidic purity 	YES 	YES
Assay (Radioactivity
concentration)
YES 	NO
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.
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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