FDA Oversight of PET Drug Products -- Questions and Answers

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

Guidance
FDA Oversight of PET Drug Products
Questions and Answers
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2012
Procedural

Guidance
FDA Oversight of PET Drug Products
Questions and Answers
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2012
Procedural

TABLE OF CONTENTS
I. 	INTRODUCTION..............................................................................................................................................1
II. 	BACKGROUND ................................................................................................................................................1
III. 	QUESTIONS AND ANSWERS ...................................................................................................................2
A. 	G ENERAL Q UESTIONS ......................................................................................................................................2
1. 	Application Submission ..............................................................................................................................2
2. 	INDs............................................................................................................................................................7
3. 	ANDAs ......................................................................................................................................................10
B. 	CHEMISTRY, MANUFACTURING, AND CONTROLS ..........................................................................................17
1. 	General.....................................................................................................................................................17
2. 	Stability Testing ........................................................................................................................................22
3. 	Sterility Testing.........................................................................................................................................23
C. 	CURRENT G OOD MANUFACTURING P RACTICES .............................................................................................23
D. 	I NSPECTIONS ..................................................................................................................................................28
E. 	REGISTRATION AND LISTING..........................................................................................................................30
F. 	U SER F EES .....................................................................................................................................................30
APPENDIX A – PET NDA AND ANDA REGULATORY SCENARIOS............................................................33
APPENDIX B – CHANGES IN EQUIPMENT OR FACILITIES .......................................................................36

Contains Nonbinding Recommendations
Guidance1
FDA Oversight of PET Drug Products
Questions and Answers
This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I. 	INTRODUCTION
This guidance is intended to help producers of positron emission tomography (PET) drugs meet
the requirements for FDA’s drug approval process. This guidance provides questions and
answers that address nearly all aspects of the drug regulatory process, including application
submission, review, compliance with current good manufacturing practices, inspections,
registration and listing, and user fees.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
In 1997, Congress passed the Food and Drug Administration Modernization Act (Public Law
105-115) (the Modernization Act). Section 121 of the Modernization Act directed FDA to
establish appropriate approval procedures and Current Good Manufacturing Practices (CGMPs)
for PET drugs. The procedures were finalized and an implementation timeline was instituted on
December 10, 2009, when FDA published regulations that described the minimum CGMP
standards that each PET drug manufacturer is to follow during the production of a PET drug (see
21 CFR part 212) and the guidance PET Drugs – Current Good Manufacturing Practice
(CGMP).2 Under the requirements of section 121 of the Modernization Act, within 2 years
following that publication date, a new drug application (NDA) or abbreviated new drug
1 This guidance has been prepared by the PET Drugs Working Group in the Center for Drug Evaluation and
Research (CDER) at FDA.
2 The regulation, CGMP guidance, and supportive information, including historical documents, are available at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm085783.htm. The guidances
referenced in this document are available on the FDA Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update
guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs
guidance Web page.
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application (ANDA) must be submitted for any PET drug marketed for clinical use in the United
States.
Recognizing that many PET drug producers are unfamiliar with the drug regulatory process,
particularly the drug application and review process, FDA issued the guidance PET Drug
Applications – Content and Format for NDAs and ANDAs, and held a public meeting in March
2011 to assist applicants in preparing NDAs and ANDAs for the three most commonly used PET
drugs. Numerous questions have been raised since that public meeting on all aspects of PET
regulation. This guidance is being issued to respond to the questions that have been submitted to
date, and it will be revised periodically to respond to additional questions that have been
submitted and are expected to be submitted in the future.
In addition to this guidance, FDA has issued two other guidances, Media Fills for Validation of
Aseptic Preparations for PET Drugs and Investigational New Drug Applications for Positron
Emission Typography (PET) Drugs.
III. 	QUESTIONS AND ANSWERS
A. 	General Questions
1. 	Application Submission
Q1: 	Will FDA grant an extension for filing applications?
FDA does not intend to disrupt existing clinical use of PET drugs as long as appropriate
submissions are made and producers of PET drugs are moving to comply with regulatory
requirements. In December 2011, FDA announced that until June 12, 2012, FDA does not
intend to take enforcement action against a PET facility currently producing PET drugs for
clinical use for a failure to submit an NDA by December 12, 2011, provided that the facility
complies with all other FDA requirements, including current good manufacturing practices
(CGMPs). FDA will not exercise enforcement discretion after June 12, 2012. Therefore, if a
facility wishes to continue to produce PET drugs for clinical use after June 12, 2012, they must
have submitted an NDA or ANDA by that date, or be producing the drugs under an
investigational new drug application (IND). PET facilities who are unable to submit an NDA or
ANDA by June 12, 2012, or operate under an IND must find a new supplier who has submitted
an NDA or ANDA. 	All PET producers must be operating under an approved NDA or ANDA,
or effective IND, by December 12, 2015.
See Appendix A for FDA’s current views of how PET drug production can continue under
various application submission scenarios.
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Q2: 	If we do not file an ANDA by December 12, 2011, is it true we have to wait 3 full
years before we can submit those applications?
No. You may submit the application at any time, but you will be at risk of enforcement
action if you continue to produce PET drugs for clinical use after June 12, 2012, without
having submitted an NDA, ANDA, or in some cases, an IND. Applicants can continue
producing PET drugs for clinical use while the NDA, ANDA, or IND is under review
(see Appendix A).
Q3: 	Is FDA going to require inspections before PET drug producers can begin making
PET radiopharmaceuticals?
For PET drugs in clinical use before June 12, 2012, sponsors can continue to produce and
use a PET drug if an application for the drug has been submitted by June 12, 2012, and is
under review at FDA. The facility does not, however, need to be inspected before
production of PET drugs can continue. For example, if you already produce
Fludeoxyglucose F18 injection (FDG) for clinical use and have submitted an ANDA for
FDG for review, you may continue producing this product and the inspection will be
conducted at some time during the review.
No PET drugs for clinical use may be produced after June 12, 2012, unless an NDA or
ANDA has been submitted or the drug is being used under an expanded access program.
FDA does not intend to exercise enforcement discretion with regard to new PET
production facilities that have not been listed in a submitted application. For example, if
you have not previously been making FDG, Ammonia N13, or Sodium Fluoride F18 and
you wish to bring a new facility on line after June 12, 2012, to make one or more of these
drugs, you must first submit an ANDA, and it must be approved before you may market
the drug (see Appendices A and B).
Q4: 	If a manufacturer submits an NDA or ANDA for FDG before June 12, 2012, and the
manufacturer wants to (or needs to, due to equipment failure or other cause)
upgrade its FDG production method (which might require purchase of another
module that uses a different process), can the facility purchase the module, validate
the process, and amend the application before the initial inspection of the facility?
If, due to unforeseen circumstances, a change in manufacturing equipment or
manufacturing method becomes necessary after an application is submitted but before it
is approved, the applicant will need to submit an amendment to the application (see
Appendix B). The amendment must contain supporting data and describe all the changes
in manufacturing and controls required because of the change (see 21 CFR 314.70). The
applicant may also need to submit an assessment of whether the change will affect the
identity, strength, purity, or quality of the product described in the original application.
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Certain changes (e.g., change in strength, change in composition of the product in
relation to the reference listed drug (RLD)) may not be permitted in an ANDA without
prior FDA approval of the change (see 21 CFR 314.93).
When an NDA or an ANDA is submitted, the applicant is required in FDA Form 356(h)
to provide a complete listing of all the manufacturing, packaging, and control sites for
drug substance and drug product and provide information on readiness of each site for
inspection (see 21 CFR 314.50(d)(1)). If at the time of inspection the facility is not
ready, the application may not be approved. The inspector will be aware of the
application and any amendments to it at the time of the inspection.
After an application is approved, 21 CFR part 212 permits an applicant to change
equipment provided that it is qualified before use. Under FDA regulations at 21 CFR
314.70, certain changes after approval must be requested in a prior approval supplement
(PAS). If a PAS is required and an inspection requested, FDA would seek to perform the
inspection as soon as possible.
In preparation for the inspection, an amendment to the application that describes the
changes and provides supporting data will need to be submitted. Whenever an
amendment is submitted, a field copy (with certification) must also be submitted to
inform the inspector of changes (see 21 CFR 314.70(a)(5); see also Appendix B).
Q5: 	Can we submit an ANDA on CD? If so, do we need to submit a paper copy as back
up?
Information on electronic submission on physical media is available at
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirem
ents/ElectronicSubmissions/UCM163567.pdf.
It is not necessary to submit a paper copy of the entire submission as a back up.
However, if you are submitting on physical media (e.g., a CD or DVD), you should
submit a paper FDA Form 356h with original signatures. FDA requires this hard copy
document in the unlikely event that the physical media are damaged or corrupted and
rendered unreadable. Without the paper document, FDA would not be able to contact the
sponsor if the physical media are unreadable.
Q6: 	Will hybrid applications be accepted?
Yes. CDER’s Electronic Submissions Group (ESub Group) will grant waivers for hybrid
applications for PET producers. The ESub group will provide instructions to sponsors
and advise which forms and templates to use. The ESub group can be contacted at
ESub@fda.hhs.gov.
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Q7: 	Is there a way to determine whether a PET producer has submitted an NDA or
ANDA for approval or has received approval of an application?
There is no public list of submitted NDAs or ANDAs. FDA cannot publicly disclose
the existence of an NDA or ANDA before it is approved unless the applicant has publicly
disclosed the existence of the application (see 21 CFR 314.430(b)). Once a product is
approved, it is listed in FDA’s Approved Drug Products with Therapeutic Equivalence
Evaluations (the Orange Book). If you intend to purchase PET drugs for commercial use
from a producer of those drugs, you should seek assurance from the vendor that they have
submitted an application to FDA.
Q8: 	The guidance PET Drugs – Content and Format for NDAs and ANDAs, provides
reference to and advice to format an application in the common technical document
(CTD) format. The attachments to the guidance, which provide sample formats, are
not formatted according to the CTD. What is the correct format for the CTD?
The sample formats have been kept in the old Office of Generic Drug (OGD) format to
avoid confusion for the three commonly used drugs (FDG, Ammonia N13, and Sodium
Fluoride F18). You may organize the application in the CTD format and keep the
chemistry, manufacturing, and controls (CMC) sections (module 3 of the CTD format) as
formatted in the CMC attachment. Alternatively, you can organize the application,
including CMC, entirely in CTD format. The following FDA guidances provide further
information about the CTD format:
 	Submitting Marketing Applications According to the ICH-CTD Format –
General Considerations3
 	International Conference on Harmonization (ICH) guidance, M4:
Organization of the CTD
 	ICH guidance on M4Q: The CTD — Quality
Q9: 	If the drug substance and the drug product are the same, do applicants have to
repeat the information in the two sections of the CTD?
No. You do not have to repeat information if the drug product and substance are the
same. You can hyperlink to the section where the information is provided.
Q10: 	What are the differences between Module 3 for the NDA and ANDA?
3 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.
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The modules are the same.
Q11: 	Would FDA consider an application for FDG for a concentration greater than 300
millicuries (mCi)/milliliter (mL) and perhaps as high as 500 mCi/mL?
FDA has not placed any limit on the strength for the multidose vial. As long as the data
support manufacturability and stability of the product at the proposed strength, FDA will
consider the application. Be advised that if the proposed strength is not in the mCi/mL
range approved for the RLD, a suitability petition or a 505(b)(2)4 NDA must be
submitted (see 21 CFR 314.93). For further information on acceptable ranges, see the
guidance PET Drug Applications – Content and Format for NDAs and ANDAs.
Q12: 	Has FDA considered establishing a few different queues for PET applications?
No, FDA has developed internal tracking procedures specifically for PET products, but
we do not believe that a different queue is necessary.
Q13: 	If we use two different synthesizers to make the same product, do we need to submit
two NDAs or ANDAs?
You can have two different synthesizers in the same NDA or ANDA as long as the
finished product at the end is the same, meaning that the product meets the same set of
specifications and the formulation is the same. If the finished product formulation from
the two synthesizers is different, two separate applications may need to be submitted.
Please contact the Office of Generic Drugs (for an ANDA) or the Office of New Drugs’
Division of Medical Imaging Products (for an NDA) to discuss your options. However,
in certain cases, a formulation that differs in terms of exception excipients (e.g., a buffer,
an antioxidant or a stabilizer) may be submitted within the same ANDA; otherwise,
sameness to the RLD must be shown.
Q14: 	How much does FDA want to see in an application about the parameters and the
controls on the cyclotron itself?
Information about the operating parameters for cyclotron operation (e.g., the make of
cyclotron used, bombardment times, information on the target, and the target windows),
should be submitted. This information may be submitted by a reference to a Type-II
Drug Master File (DMF) if the isotope is obtained from outside sources. 	When buying
isotopes from a vendor, appropriate specifications should be established and the vendor
should be qualified.
4 See 21 U.S.C. 355(b)(2) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act).
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Q15: 	Will FDA treat foreign producers who seek to export PET drug products into the
United States differently than domestic producers?
No, FDA will not treat foreign PET drug product producers differently than domestic
producers.
In addition to other applicable requirements, all foreign drug establishments whose
products are imported or offered for import into the United States are required to register
their establishment with FDA and list all of their drug products in commercial
distribution in the United States. More information on the registration and listing process
is available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistration
andListing/ucm2007058.htm.
2. 	INDs
Q16: 	Who can sponsor an IND?
INDs can be sponsored by an individual (e.g., a physician), an institution, or a company.
Q17: 	It is not practical, even for a large clinical center, to submit an ANDA for PET
drugs with limited use (e.g., Ammonia N13). Will FDA allow the IND or Radioactive
Drug Research Committee (RDRC) pathway?
No. FDA has created a simple regulatory pathway to obtain an approved ANDA for
FDG, Ammonia N13, and Sodium Fluoride F18 and does not intend to exempt any PET
Center from the requirement to submit an NDA or ANDA to obtain FDA marketing
approval to support the clinical use of any of these three products after June 12, 2012.
For further information on the pathway, see the guidance PET Drug Applications –
Content and Format for NDAs and ANDAs.
Q18: 	Will drugs for which there is a United States Pharmacopoeia (USP) monograph be
exempt from submitting an IND?
No. The fact that a drug has a USP monograph does not eliminate the need for an IND,
although the drug might be eligible for an expanded access IND if the criteria are met
(see the guidance Investigational New Drug Applications for Positron Emission
Tomography (PET) Drugs).
Q19: 	What is the definition of clinical use in the context of PET drugs?
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Clinical use refers to administration of the drug to patients as a component of their
clinical care with no intent to study the safety or effectiveness of the drug in any
systematic way.
Q20: 	Can research be conducted under an IND for FDG, Ammonia N13, Sodium
Fluoride F18, or Rubidium Chloride Rb82?
Yes. Research and/or investigational studies using these drugs should be conducted
under an IND if they are being studied for purposes of commercial clinical use (see the
guidance Investigational New Drug Applications for Positron Emission Tomography
(PET) Drugs). Human research using a PET drug may be conducted under the RDRC if
it is basic science research and not research that is intended for immediate therapeutic,
diagnostic, or similar purposes, or research to determine the safety and effectiveness of
the radioactive drug or biological product for such purposes (see the guidance The
Radioactive Drug Research Committee: Human Research Without an Investigational
New Drug Application).
Q21: 	In submitting the physician-sponsored IND, one of the biggest hurdles is trying to
get the necessary preclinical pharmacological and toxicology data to support the
submission. Would FDA consider reducing the requirement?
If you have adequate evidence of the PET drug’s safe clinical use, you may submit that
clinical information to FDA for review and we will determine whether the drug is safe for
use within the proposed IND clinical study or studies. The existing clinical information
may limit or negate the need for preclinical data. Clinical information from the use of the
PET drug’s non-radiolabeled ligand may also prove sufficient to limit or negate the need
for preclinical data.
For PET drugs that have not been in clinical use, the extent of necessary preclinical data
depends on whether the PET drug ligand is a naturally occurring endogenous substance
in humans or not. In general, limited or no preclinical data are necessary to support the
use of a PET drug that consists of a ligand that is naturally occurring within humans, if
the only major ex vivo modification is the radiolabeling of the ligand. The extent of
preclinical data necessary to support a clinical study or studies under an exploratory IND
is more limited than the preclinical data necessary for a traditional IND (see the guidance
Exploratory IND Studies).
Q22: 	Many trials for therapeutic drugs are currently being conducted abroad. If a PET
drug is used to determine eligibility for the clinical trial abroad, what would FDA
need to know about the PET drug when approval is sought under an NDA for the
therapeutic drug?
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The answer to this question depends on several factors. If the use of the PET drug to
determine eligibility is an approved indication in the United States, we would need CMC
data to show that the PET drug used in the trial is comparable to the drug that is approved
for use in the United States. For example, if a PET drug were to be approved in the
United States to identify early Parkinson’s or Alzheimer’s disease, the foreign trial’s PET
drug would need to be bioequivalent to the approved drug in the United States.
If the use of the PET drug to determine eligibility is not an approved indication in the
United States (e.g., no PET drugs are currently approved to determine whether a patient
has early Parkinson’s disease or Alzheimer’s disease), the safety and efficacy of the PET
drug for that use would have to be established and the data submitted within an NDA.
Q23: 	If a PET drug producer creates a centralized IND (e.g., an IND for multicenter
participation and protocol compliance, image acquisition standardization, image
output harmonization) to use FDG in biomarker trials and that producer has an
ANDA, can the applicant cross-reference the CMC data in the ANDA or must the
applicant submit the CMC documentation with the IND?
Cross-referencing to the approved ANDA is acceptable provided that the drug used in the
biomarker trials is the drug produced under the ANDA.
Q24: 	What is FDA’s current position regarding the continued use of PET drugs
(Fludeoxyglucose F18 Injection, Sodium Fluoride F18 Injection, and Ammonia N13
Injection) in ongoing clinical trials for new uses of these products or to support
clinical trials of therapeutic drugs?
FDA’s position is as follows:
 	If the PET drug used in the clinical trial is being made at a facility for which
manufacturing data have been submitted in an NDA or ANDA for the PET
drug, then FDA does not intend to object to use of the PET drug without an
IND until December 12, 2015, if this and the other requirements in 21 CFR
312.2 are met (see 21 CFR 312.2(b)).
 	However, if significant manufacturing deficiencies are found during the NDA
or ANDA review, or during inspection of the facility the PET drug is sourced
from, FDA may notify the sponsor that the PET drug should no longer be used
in clinical trials.
After December 12, 2015, investigational use of a PET drug must be covered by an IND
unless it is exempt from all of the IND requirements.
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Q25: 	For a PET drug that has not been approved, what documentation must be provided
to support an IND that is already in effect for a therapeutic drug that relies on the
PET drug to monitor disease progression or otherwise evaluate the efficacy of the
therapeutic drug?
Before December 12, 2015, no CMC documentation for the PET drug needs to be
submitted to the IND for the therapeutic drug as long as the PET drug is manufactured at
a facility for which supportive manufacturing information has been submitted in an NDA
or ANDA. After December 12, 2015, for PET drugs manufactured at facilities that are
not named in an approved NDA or ANDA, CMC documentation for the PET drug will
need to be submitted to the IND for the therapeutic drug.
Q26 	How will an investigator know whether an NDA or ANDA has been submitted and
what records should be submitted to document that the PET drug was sourced from
a facility named in an NDA or ANDA?
Documentation should be maintained at the trial site where the investigation is being
conducted that indicates the number of the NDA or ANDA that contains the CMC data
for the facility from which the drug is sourced. Over the next several months, clinical
investigators should make sure this documentation is in place for the PET drugs used in
their investigations.
Q27: 	If an approved PET drug is used to determine eligibility for patient entry into an
investigational therapeutic trial, will we have to submit an IND for the PET drug
and an IND for the therapeutic drug?
No. If the PET drug’s use in the investigational trial is not for an approved indication,
the sponsor could describe the investigational use of the PET drug in the original IND for
the therapeutic drug trial. Two INDs would not be necessary in this situation. 	The
therapeutic drug IND would need to either provide documentation that the PET drug is
sourced from a facility with an approved NDA or ANDA, or provide sufficient CMC data
to support its use in the trial.
3. 	ANDAs
Q28: 	Do I need to use the same manufacturing process as the reference listed drug
(RLD)?
No. Within the context of ANDAs, FDA regulations define a drug that is “the same as” a
listed drug to mean a generic drug that has the “identical . . . active ingredient(s), dosage
form, strength, route of administration, and conditions of use” as its RLD (See 21 CFR
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314.92(a)(1)). 	Differences in the manufacturing processes do not affect whether a
product may be submitted and approved under an ANDA.
Q29: 	Will we need to contact the NDA holder to obtain a sample of the RLD for the
comparison testing?
Obtaining the RLD for comparison testing is not necessary. FDA recognizes that for
PET products, it may not be possible to do a direct comparison with an RLD product
because of the short shelf life of these products.
Q30: 	A recently approved ANDA for FDG has different inactive ingredients than its
RLD, although the drug was found to be bioequivalent. Will this ANDA be
considered an RLD?
No, the ANDA would not be identified as an RLD in the Orange Book.
Q31: 	If an ANDA applicant is referencing an NDA, does the applicant have to perform all
of the quality control testing listed in that approved NDA? For example, if the
High-Performance Liquid Chromatography (HPLC) and osmolality testing are
listed in the RLD NDA, does the ANDA applicant have to include that testing?
No. Each application is reviewed on its own merits. The application must establish the
necessary quality standards, tests, and specifications, and demonstrate that the quality
standards will be met over the life of the product.
Q32: 	How would an ANDA applicant be able to demonstrate sameness to the RLD if the
composition per batch is not known by the applicant?
The batch size for a generic drug does not have to be the same as the RLD. Only the
parameters that are listed in the labeling of the RLD, including strength, which is
radioactivity per unit volume at calibration time (e.g., end of synthesis (EOS)), must
match (see Q43 for definition of EOS). If an RLD lists a range for volume as opposed to
the exact volume, the ANDA applicant may also list a range for volume. The strength of
each manufactured batch must reside in the approved range of strength for the PET drug.
Q33: 	When we submit our ANDA, do we need to submit all of the method validation data,
or will that be reviewed at the time of FDA inspection?
The method validation data must be submitted in the application and reviewed by the
review division for suitability and acceptability (see 21 CFR 314.50(d) and 212.60(c)).
The inspector may look at the source data during the inspection.
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Q34: 	If specific standard operating procedures (SOPs) are referenced within the ANDA
submission, must the actual SOPs be submitted or may they be made available for
review during the inspection? If the SOPs are submitted, can they be amended
during the review process?
You do not need to submit SOPs in an application. It is sufficient that the SOPs be made
available during the inspection.
Q35: 	When we are validating instruments, do we need to submit the data or just the
results and procedures?
Analytical validation data, not just the results and procedures, should be submitted in the
application.
Q36: 	What specific types of information would be necessary in a post-deadline
amendment to allow changes by manufacturers without disruption to supply?
See Appendix B.
Q37: 	We have ordered software to maintain our SOPs, but the software will not be
installed until after we submit the ANDA. Can we submit an amendment to the
ANDA with the software information once it is installed?
It is not necessary for applicants to submit their SOPs, or information on the software
used to maintain the SOPs, as a part of their ANDA submission. The qualification,
maintenance, and changes of software for SOPs will be evaluated during inspection.
Q38: 	Because some PET production facilities use different synthesizers, the phosphate
buffer and amount of ethanol in their ANDA product may differ from the RLD.
How can these producers use the same labeling as the NDA?
Any modifications you make to exception excipients when compared to the RLD must be
reflected in your labeling, and these are permissible changes to ANDA labeling. See the
guidance PET Drug Applications – Content and Format for NDAs and ANDAs for
permissible changes to the exception ingredients.
Q39: 	When FDA says that the resulting product should be the same, does it mean all
excipients should be identical, meaning exception and non-exception excipients?
Although drugs approved in ANDAs are generally the same as the RLD, there are
differences that are permitted. The inactive ingredients for generic drug products for
parenteral use are allowed to differ from those of the RLD only in preservative, buffer,
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and/or antioxidant. These excipient classes are often referred to as exception excipients.
The differences in exception excipients must not affect the safety or effectiveness of the
generic drug (see 21 CFR 314.94(a)(9)). Additional differences in non-exception
excipients are not permitted.
Q40: 	Is it possible to submit two formulations, where the only difference is the buffer, in
one ANDA?
The Office of Generic Drugs (OGD) has agreed to permit an exception to the policy
established in the CDER guidance Variations in Drug Products that May Be Included in
a Single ANDA. Recognizing the special nature of these products, the exception will
apply solely to applicants seeking approval of PET drug products and will allow an
applicant to submit more than one formulation in a single ANDA.
More specifically, OGD will permit an applicant to seek approval of two formulations
provided that the two formulations differ only with respect to “exception excipients”
(preservative, buffer, antioxidant) as listed at 21 CFR 314.94 (a)(9)(iii). For example,
OGD would permit an applicant to seek approval of two formulations, one using a citrate
buffer and one using a phosphate buffer in a single ANDA. Applicants must be aware
that all relevant CMC, Microbiology, and Labeling information will need to be compiled
in the ANDA to support the approval of each formulation.
Once the ANDA is approved, the applicant will also be responsible for maintaining and
submitting all postmarketing reports pursuant to 21 CFR 314.80 and 314.81. When
submitting any postmarketing reports, the applicants’ reports must be able to distinguish
between the different formulations.
Q41: 	Why are the effects of different inactive ingredients on viscosity and specific gravity
of the proposed PET drug product relevant for PET products?
When the issue of different inactive ingredients is raised during a review, it is usually
because inactive ingredients for parenteral generic drugs may differ from their RLDs only
with regard to antioxidants, buffers, or preservatives (see 21 CFR 314.94(a)(9)(iii)).
Although differences in inactive ingredients may not affect the properties of the drug
product such as viscosity and specific gravity, under FDA regulations the inactive
ingredients must be the same, except as noted in Q13 above (see 21 CFR
314.94(a)(9)(iii)).
Q42: 	How do differences in excipients affect bioequivalence?
If the proposed product is not qualitatively (Q1) and quantitatively (Q2) identical to the
RLD, the product’s bioequivalence must be demonstrated in accordance with 21 CFR
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320.24. FDA will permit a quantitative difference of ± 5 percent while still considering
the product to be quantitatively equivalent. For intravenously administered PET drug
products, FDA has determined that bioequivalence has been demonstrated in cases where
(1) differences in the inactive ingredients are sufficiently small that they will not
significantly affect the physical and chemical properties of the drug product, and (2) the
inactive ingredients have been previously used in the same or greater quantities in an
approved drug product for the same route of administration (see 21 CFR 320.24(b)(6)).
Examples of situations where FDA has determined that a bioequivalence study is not
necessary to demonstrate bioequivalence include:
 	Presence of or absence of a preservative, buffer, or an antioxidant in the
proposed PET drug product, where these ingredients and their amounts have
been previously approved in a drug product and their amounts do not
significantly affect physical or chemical properties (e.g., specific gravity,
viscosity, pH) in relation to the RLD (see 21 CFR 314.94(a)(9)(iii)).
 	Presence of or absence of a preservative, buffer, or an antioxidant in the
proposed PET drug product, where this change does not affect tonicity
(osmolality) of the solution in relation to the RLD or the applicant has
established that the change in tonicity will not affect safety or effectiveness of
the product (see 21 CFR 314.94(a)(9)(iii)).
To demonstrate bioequivalence under 21 CFR 320.24(b)(6), the application should
include a discussion to support that the proposed product differences from the RLD are
not likely to affect the safety or efficacy of the product.
Q43: 	Why is a suitability petition required for a change in the total volume or total
radioactivity per vial for a PET drug?
A 505(j) product is required to have the same strength as the RLD (see 21 CFR
314.92(a)(1)). For PET drugs, the radioactive concentration (e.g., mCi/mL) at the
calibration time is generally considered to be the strength. Therefore, if this differs, a
suitability petition (SP) is needed before submitting a 505(j) application. The strength is
compared based on stated strength at the time of calibration, which for a multidose vial of
a PET drug is generally at the end of synthesis (EOS). In this guidance, EOS means at
the end of manufacturing of the finished drug product. For unit-dose vials, the strength is
calibrated to a particular time from the EOS of a unit dose.
The total radioactivity or total volume in a vial is indicative of batch size, and if it does
not have an impact on the strength, a suitability petition is not needed. Because large
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amounts of radioactivity may have an impact on stability of the finished product,
appropriate stability studies are needed to support the stability of the product.
If you need to submit an SP, the petition must be approved before your ANDA is filed.
You may refer to approved suitability petitions as the basis for submission of your
ANDA. FDA has approved two suitability petitions for FDG (docket numbers FDA
1997-P-0054 and FDA 2010-P-0444). More information on SPs can be found in the
guidance PET Drug Applications – Content and Format for NDAs and ANDAs.
Q44: 	Recently there was an NDA approved for sodium fluoride, where the labeling states
that the total volume and total radioactivity per vial are variable. Do producers still
need to submit a suitability petition if the total content, the total amount of drug in
the vial or the total amount of active ingredient in the vial, is different?
No. See the response to question Q43 above.
Q45: 	If a producer wishes to apply for a concentration higher than 37.5 mCi/mL for
Ammonia N13, is it preferable to file a suitability petition or file a 505(b)(2) NDA?
Both routes are available. FDA recently approved SP 2011-P-0337 that asked us to
permit the submission of an ANDA containing a concentration of Ammonia N13 up to
260 mCi/mL. 	Because this suitability petition has been approved, it is easier for an
applicant to submit an ANDA that cites this suitability petition. If an applicant wishes to
pursue approval of a concentration greater than 260 mCi/mL, a new suitability petition
would need to be submitted. Once a suitability petition is approved, then any applicant
may use the approved petition as the basis for submitting its ANDA for the change
approved in the petition, until an ANDA based on the petition is approved. Once an
ANDA is approved for the change permitted in the petition, any applications submitted
after the approval date of the first ANDA must cite the approved ANDA as their basis of
submission (see 21 CFR 314.94(a)(3)). The suitability petition will no longer be a valid
basis for submitting an ANDA once there is a product approval.
For other changes that an applicant wishes to pursue via the SP process, it is likely easier
to employ the suitability petition pathway so long as the applicant has an adequate
submission timeline in place to allow for the 3- to 4-month period for petition approval.
If an applicant does not have sufficient time for the petition process, a 505(b)(2)
application may be quicker. Further, applicants should balance any perceived ease of
submission with the prospect of user fees (application, yearly product and establishment
fees) that would be assessed to 505(b)(2) applicants but are not assessed for ANDA
submissions.
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Q46: 	Once an ANDA is submitted, how should FDA be notified of changes in processes or
hardware that may be required because of a breakdown in equipment or for some
other reason?
See Appendix B.
Q47: 	In preparing our application, we have been advised that the manufacturer of the
sterile empty vial does not have a drug master file (DMF). What information should
we provide in our ANDA about the vial?
A DMF is not required for the submission of an ANDA. You may attempt to
obtain information for the vial from the vial manufacturer and include this in your ANDA
submission. The type of information submitted in the ANDA should include information
on type of container material (e.g., type of glass used and information on conformance
with USP chapter <661>), type of closure (e.g., type of rubber formulation used,
quantitative composition of the formulation, and information that the formulation meets
the USP chapter <661>, USP chapter <87>, and USP chapter <88>), and type of crimp
seal used. In addition, information you have to assure sterility, apyrogenicity, and
container closure integrity should be provided. For more information, please see the
guidance Container Closure Systems for Packaging Human Drugs and Biologics –
Chemistry, Manufacturing, and Controls Documentation.
Q48: 	What do we have to reference in the ANDA labeling regarding changes in pediatric
dosing?
ANDA labeling is required to be identical to the RLD labeling upon which the applicant
is basing their ANDA, with certain exceptions. Therefore, an ANDA applicant will only
be permitted to incorporate pediatric labeling when the RLD also contains identical
pediatric labeling. Applicants who wish to pursue approval of new or additional pediatric
indications must conduct the requisite studies to show that the product is safe and
effective for use in the pediatric population.
Generally, pediatric studies are conducted in the context of an NDA submission—either a
505(b)(1) or 505(b)(2) submission. However, an applicant may first secure approval of
an ANDA and then submit a 505(b)(2) supplement to the approved ANDA. Applicants
wishing to pursue approval of additional pediatric labeling should first discuss their
proposal with FDA before conducting any studies or submitting any information.
Q49: 	Considering that PET drugs are distributed outside the normal channels of
distribution for drugs, what is the responsibility of academic PET drug producers
for printing and distributing a package insert for PET drugs under an approved
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application? What is the responsibility for the commercial sector, considering the
batch vial does not enter the ordinary channels of distribution?
The package insert is generally supplied by the manufacturer (academic or commercial
PET producers) with the product. FDA does not have any requirements related to a
package insert for the unit dose dispensed from a released multidose vial and does not
regulate the practice of pharmacy. When the manufacturing and pharmacy units are at
the same site, the package insert may be retained at the site.
B. 	Chemistry, Manufacturing, and Controls
1. 	General
Q50: 	Does FDA have a document describing good review practice of chemistry?
No. We do not have a document describing the conduct of the chemistry review.
However, we do have a number of guidances on CMC that direct the technical review
process. We are not planning on issuing a specific document for PET review practices at
the present time.
Q51: 	System suitability requirements in USP chapter <621> suggest that the tailing factor
and resolution (or column efficiency, as appropriate) are to be determined on a daily
basis. What is FDA’s view on system suitability for manufacturing for PET drug
products?
The system suitability testing and acceptance criteria should be appropriate for the
intended use of the method. The function of the system suitability test is to ensure that
the analytical system, including the equipment, is working properly at the time of
analysis. The system suitability testing should be performed before the time of analysis
on any day of use. The system suitability testing and acceptance criteria are submitted as
part of the test method in the application. The review division determines its suitability
for the intended use. The inspector may look at the source data during the inspection and
verify that system suitability is being performed for each day of use.
For chromatographic systems used in testing, in general, a justification for not using the
tailing factor and resolution should be provided. FDA expects that the system suitability
at a minimum will consist of injection of three replicates of standard solution in the
validated range, where the acceptance criteria should consist of meeting a specified
relative standard deviation (RSD) and specified relative retention time. FDA would
accept appropriate periodic verification of column efficiency.
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Q52: 	Will FDA accept the use of materials meeting other Agencies’ compendial
requirements (e.g., European Pharmacopeia), assuming these materials would be
declared in the ANDA or NDA, and would be sourced and managed using the local
Quality Management System?
If a material (e.g., an excipient) has a USP monograph, generally, the material should
meet the USP monograph requirements. However, FDA will accept materials that meet
the requirements of other compendial monographs provided that comparability is
established and any differences are justified. If there is no USP monograph, then other
quality standards may be proposed in the application. If the requirements for other
compendia are more robust than USP requirements, FDA would consider the other
requirements, when proposed. Many times vendors provide materials that meet
requirements of multiple compendial monographs. The quality of these materials should
be suitable for the intended final dosage of the drug product.
Q53: 	Will FDA provide clarity on expectations around Quality by Design (QbD)
applicability to PET products?
The QbD approach is optional. We recommend that you refer to the following ICH
guidance documents:
 	Q8(R2) Pharmaceutical Development
 	Q9 Quality Risk Management
 	Q10 Pharmaceutical Quality System
If you want to develop a QbD approach to your drug, we recommend that you discuss the
details with the review division at the End of Phase-2 meeting or earlier.
Q54: 	Is there a limit on the volume of PET drug product solution that can be filled in a
vial?
Under USP requirements (see General Chapter <1> Injections), if an injection drug
product is packaged as a multidose container, the volume in the container is limited to 30
mL. USP also requires that the multidose vials contain a substance or suitable mixture of
substances to prevent the growth of microorganisms. Larger volumes may be packaged
as pharmacy bulk packages, and do not need to contain a substance or substances to
prevent the growth of organisms. The pharmacy bulk packages are, however, required to
be handled as described in USP chapter <1> as part of the pharmacy operation.
If a PET drug product is produced as a single-dose container for use as a single patient
dose, its volume as a small-volume injection is limited to 100 mL or less (see USP
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General Chapter <1> Injections). Single-dose vial volumes larger than 100 mL are
considered to be large-volume intravenous solutions and treated as such.
Q55: 	A majority of the RLDs list the strength measured at the end of synthesis (EOS).
However, most of the drugs can be measured in a dose calibrator after the drug is
diluted. Do we have to match the timing of strength measurement exactly so that
the activity has to be EOS, or can we measure the activity at the calculation time?
The strength is measured at the EOS of the final formulation. The synthesis is not
completed until dilution to produce the finished formulation.
Q56: 	Under 21 CFR 212.50(f), would an NDA or ANDA submission be deemed adequate
with the inclusion of data from production and stability testing of a single batch if
full testing is always performed?
Release and stability data for a minimum of three consecutive batches should be
submitted for NDAs and ANDAs.
Q57: 	Please clarify the requirements regarding preparation of two or more units of FDG
injection from the same bulk product batch. What quality control sampling plan
will be acceptable? What are the restrictions on unit-dose preparation under the
ANDA or NDA, and what would be an acceptable quality control sampling plan?
We do not expect testing of samples from each vial when multiple vials are
manufactured. Where the test sample would come from depends, to an extent, on the
procedure (e.g., automated vs. manual) for filling the multidose vials. We would
recommend that you have a procedure in place to describe the subdivision of bulk vials.
For PET drugs, the test sample for chemical tests may be obtained from the bulk vial or
any of the other vials. 	The test sample for microbiological testing (sterility and bacteria
endotoxin tests) should come from the vial that represents the most likely place for
microbiological concerns (e.g., the first vial). Alternatively, if the fill procedure is such
that the most likely microbiological contamination vial cannot be clearly identified,
random selection should be used.
When unit doses are prepared as part of the pharmacy operation, the test sample to
release the batch must be obtained from the final multidose vial (see 21 CFR 212.70(c)).
When unit-dose vials are prepared as part of PET production, the vials should be
segregated from the beginning, middle, and end of the fill line and the vial or vials for
test sample should be drawn randomly from the segregated vials.
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In any case, the sampling procedure used should be described and justified in the
application.
Q58: 	Does FDA have any guidance on what level of reduced testing would be acceptable
once a product has undergone process verification?
According to 21 CFR 212.70(c), a PET producer needs to ensure that each batch (or for a
product produced in sub-batches, each sub-batch) of a PET drug conforms to
specifications. This may involve the following:
 	finished-product testing of each batch
 	in-process testing of an attribute that is equivalent to finished-product testing
of that attribute
 	continuous process monitoring of attributes with statistical process controls
 	some combination of these approaches
See the guidance PET Drugs – Current Good Manufacturing Practice (CGMP) and the
preamble to the final rule on CGMPs for PET drugs (74 FR 65409 (December 10, 2009)).
Using finished-product testing alone would require testing each batch of a PET drug
product for conformance to all specifications. In-process testing might involve use of an
online test to determine whether an attribute meets an appropriate acceptance criterion,
provided that the relevant attribute does not change during the production of the finished
product. Under this scenario, the in-process testing of an attribute could be an adequate
substitute for the finished-product testing for that attribute. Continuous process
monitoring with statistical process controls involves comprehensive testing of attributes
using online monitoring and corresponding adjustments to prevent an upward or
downward drift in batch-to-batch measurements of an attribute. Depending on the
particular PET drug product and specification, any of the suggested approaches might be
acceptable for determining compliance with specifications. When an approach is
proposed in the application, it should be justified by data. For approaches other than
testing each batch, you might need to provide the results of analyses of a statistically
relevant number of batches using alternative controls to justify these alternate
approaches. We recommend that the review division be consulted with specific
proposals before submission.
Q59: 	Are applicants required to check the osmolality for every batch of FDG prepared?
When the tonicity of a product is declared in its labeling, the manufacturing process
should be appropriately controlled to assure that the osmolality of every batch will
conform to labeled osmolality. Osmolality determined during development and
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validation might be sufficient to justify not performing testing of every batch. This data
should be submitted in the application.
Q60: 	When is it necessary to dilute final product to meet the concentration specification?
Is there a preference to use sterile water, normal saline, or half normal saline?
Normal saline is the most commonly used agent to maintain the isotonicity of the final
drug product. However, you may use any of the three named diluents. Justification
should be provided if an isotonic product cannot be formulated. In addition, for ANDA
products, the diluent used should be the same as the diluent used in the RLD for which
the ANDA is being submitted.
Q61: 	What are FDA’s expectations on handling invalid tests and sample size for repeat
testing?
Under 21 CFR part 212, it is acceptable to repeat a test that failed the first time if a
mistake or error was made in the first attempt to test (i.e., the test was truly invalid). It is
not acceptable to simply retest with a new sample because of a failing result; true out-of
specification results must be investigated to determine the cause of the failure to meet the
specifications, and corrections must be implemented as appropriate. If a repeat test is
appropriate, the sample size depends on what parameter is being tested and should be
chosen to ensure the test results are representative of the characteristics of the batch.
Q62: 	Does FDA have current information about drug master files (DMFs) that might
apply to PET?
PET producers should contact their suppliers to determine whether they have a DMF on
file with the FDA. FDA does not provide a list of DMFs that are available for reference.
For further information about DMFs, see FDA Manual of Policies and Procedures
(MAPPs) on DMF files, available at
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/
ucm079564.pdf. You can also direct any specific DMF questions to
dmfquestion@cder.fda.gov.
Applicants that plan to rely on one or more DMFs should provide a letter of authorization
from the DMF holder that gives the ANDA or NDA applicant the right to reference the
DMF and for FDA to refer to the DMF in its review of the application in the ANDA or
NDA.
Q63: 	Is notification to the FDA required for replacement of quality control equipment
(e.g., gas chromatography (GC), HPLC, or dose calibrator)
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Replacement of quality control equipment is managed under the facility’s quality system
and should be qualified for installation, operation, and performance; therefore,
notification is not necessary. However, any change in the analytical method should be
reported in accordance with 21 CFR 314.70.
Q64: 	Does a change in precursor require submission of a supplement?
Yes. The submission should be made under 21 CFR 314.70(b).
Q65: 	Does a change in container closure system require submission of a supplement?
Yes. The submission should be made under 21 CFR 314.70.
Q66: 	Does a change in the vendor of inactive ingredients or other auxiliary materials
require submission of a supplement?
No, these are reported in the annual report.
2. 	Stability Testing
Q67: 	The guidance PET Drug Applications – Content and Format for NDAs and ANDAs
(the PET drug applications guidance) states that quality control needs to be done for
three qualification batches at the highest concentration allowed. Upon how many
batches are we required to perform stability testing?
You should conduct stability testing of three batches. For more information, see
Attachment I of the PET drug applications guidance titled “Sample Formats – Chemistry,
Manufacturing, and Controls (CMC) Section.”5
Q68: 	Does stability testing need to be performed on each vial size, for example, 30 mL
and 50 mL, if the components are identical?
We recommend that you choose the highest vial size (i.e., the 50 mL size in the example).
In some cases, multiple presentations might need to be tested (e.g., if the headspace
oxygen-to-surface ratio differs significantly).
Q69: 	Are we required to perform forced degradation studies with these short shelf life
drugs?
5 Available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078740.pdf.
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For the commonly used PET drugs (e.g., FDG, Ammonia N13, Sodium Fluoride F18),
where the storage and other molecular stability characteristics under different conditions
have been well defined in the scientific literature, forced degradation studies are not
needed when an NDA or ANDA is submitted.
For new PET drugs, the molecular stability and storage conditions under certain stress
conditions (e.g., photo-stability, pH dependant stability) might need to be evaluated and
described in the application. The need for this testing should be discussed with the
review division during product development (e.g., at the End of Phase-2 meeting).
During inspection, the inspector may inspect the source data.
Q70: 	Assuming that product stability is demonstrated, is there any limit to expiry of the
product?
The stability data should support the proposed expiration dating period. These data are
submitted in the application for which the expiration dating period is approved. The
individual batch used may expire earlier than the approved expiration dating period. It is
expected that the product will be used before its specified expiry.
3. 	Sterility Testing
Q71: 	With respect to sterility testing, what are the requirements for the sample hold time
validation and expected storage conditions during hold time?
Sterility testing can begin 30 hours after manufacture without further justification.
Delays beyond this time need to be justified and shown to be valid (i.e., that
contamination, if present, would result in growth). Samples are to be stored appropriately
during the extended hold time; the hot cell might be appropriate for storage.
Q72: 	Would the air quality requirement still hold if the sterility inoculations were
performed in Hungate tubes, which is generally performed within the hot cell
environment, not a laminar flow environment?
We recommend that sterility tests be performed in a Class 100 environment so there is no
risk of environmental contamination. However, we do understand if the sterility testing
has to be performed in a hot cell because of the nature of the product.
C. 	Current Good Manufacturing Practices
Q73: 	Are there specific guidances for the qualification of vendors that would guide us in
selecting components and establishing standards for vendor compliance?
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No guidance on this topic is presently available.
Q74: 	FDA recently issued the guidance PET Drugs – Current Good Manufacturing
Practice (CGMP) (Small Entity Compliance Guide) that appears to be identical to the
guidance issued in December 2009. Is there a definition of small entity? Does the
August 2011 version differ from the version dated December 2009?
There are no substantive differences between the Small Entity Compliance Guide and the
guidance published in December 2009. The Small Entity Compliance Guide on Drug
CGMPs was prepared to comply with section 212 of the Small Business Regulatory
Enforcement Fairness Act (Public Law 104-121). The Act states the following:
For each rule or group of related rules for which an agency is required to prepare
a final regulatory flexibility analysis under section 605(b) of title 5, United States
Code, the agency shall publish 1 or more guides to assist small entities in
complying with the rule and shall entitle such publications “small entity
compliance guides .”
A definition for small entity can be found in section 211 of the Act.
Q75: 	Is identity testing on mannose triflate required? If required, does it need to be a
specific identity test?
Although an identity test on incoming components is required to be performed, a specific
identity test is not needed under certain conditions (see 21 CFR 212.40(c). When the
finished-product testing of a PET drug product includes testing to ensure that the correct
components have been used, the PET drug producer need only determine that each lot of
incoming components complies with written specifications by examining a certificate of
analysis provided by the supplier (21 CFR 212.40(c)(1)(i)). We believe that the use of
this type of finished-product testing makes specific identity testing of components
redundant and unnecessary. For example, when identity of the F18 radionuclide is
established as part of the finished-product testing and the method of production used is
well-documented and understood, it can be reasonably argued that the component that
yields this radionuclide is likely to be O 18 water. In this case, a specific identity test for
O 18 water is not necessary before the lot is used in production. Similarly, a specific
identity test before using a lot of mannose triflate might be redundant and unnecessary
when (1) a well-understood method of synthesis of FDG is used, (2) a test to confirm the
radiochemical identity is performed in the finished drug product, and (3) the mannose
triflate was obtained from a reliable supplier with whom a relationship has been
previously established and is accompanied by a certificate of analysis.
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Q76: 	What is FDA’s current thinking on conditional final release testing if there was a
problem or malfunction?
Under the CGMP regulations at 21 CFR 212.70, you may not release another batch of the
PET product until you have corrected the problem concerning the malfunction of
analytical equipment. A reserve sample is needed to complete the finished product
testing.
Q77: 	Which analytical techniques, if any, require validation?
New analytical procedures must be validated appropriately based on the intended use (see
21 CFR 212.60(c)). A compendial method, generally, does not need to be validated.
However, you will need to show that the method is suitable for your product, analytical
equipment, and system used. The following guidances may be useful in determining
which parameters to validate:
 	Text on Validation of Analytical Procedures (ICH Q2A)
 	Q2B Validation of Analytical Procedures: Methodology
 	Analytical Procedures and Methods Validation6
 	Validation of Chromatographic Methods
Q78: 	Although the radiosynthesis is processed in the hot cell, some operations are
performed in the laboratory, such as HPLC operation, buffer preparation, and
weighing raw materials on a scale. Is there any specified quality for the ceiling and
floor (e.g., should we use seamless, washable material)?
No. The ceiling, floor, and walls of the production and laboratory work area for PET
drugs must be clean and designed to minimize the level of particulate contamination in
the processing area of the final product (see 21 CFR 212.30). However, if you are
constructing a new PET facility, seamless ceilings and floors are recommended to help
ensure that they can be readily and thoroughly cleaned.
Q79: 	Can the PET drug solution obtained from a synthesizer in the final product vial
assembly be diluted to make the final formulation solution outside of the controlled
environment?
USP chapter <823> states that “solutions for parenteral administrations must be filter
sterilized and aseptically transferred to a sterile, nonpyrogenic” vial. Further, the chapter
also stipulates that aseptic manipulations must be performed within the aseptic hood. The
final product vial assembly (everything that is post sterile filter and including the sterile
6 This draft guidance, when finalized, will represent FDA’s current thinking on this topic.
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filter) should be assembled in an aseptic hood using aseptic techniques. All entries into
the sterile final product vial should be done using aseptic techniques. To mitigate the risk
of contamination, we recommend that the direct dilution of the product be performed in
the laminar flow hood. See also 21 CFR 212.30 and the guidance Media Fills for
Validation for Aseptic Preparations for PET Drugs.
Q80: 	Is it acceptable for the laminar flow hood to be in the same workspace as the
production?
Yes, it is acceptable to have the laminar flow hood in the same workspace. Controls
should be in place to prevent mix-ups and the potential for contamination. FDA expects
that the hood would be placed in a controlled and clean area.
Q81: 	At some sites, the drug product is synthesized and transferred into a dispensing cell
in the Radiopharmacy, at which time the Quality Control (QC) sample, sterility
sample, and retention sample are extracted just before drawing the finished unit
dose for administration. How would FDA like to see the segregation of
manufacturing activities from pharmacy practice activities?
Although there is no specific FDA requirement that manufacturing and pharmacy
activities should be in separate areas, pharmacy activities and relevant facility control
should comply with State Pharmacy regulation and USP chapter <797>.
If the proposed product is a multidose vial or a pharmacy bulk package, the operations
leading up to the production of these containers are considered to be manufacturing
operations. In this case, the QC sample must be obtained from the multidose vial with
appropriate sampling if multiple containers are manufactured in a batch. If the “HOW
SUPPLIED” section of the labeling indicates that the drug is supplied as a multidose
container or as a pharmacy bulk pack and the multidose vial or the pharmacy bulk pack is
released to the pharmacy, dispensing into unit doses (under the practice of pharmacy) is
considered a pharmacy operation.
Q82: 	Can the PET radiopharmaceutical manufacturing activities be conducted in the
same room as the PET dose dispensing?
Yes, the production of PET drug products and the dispensing by prescription of patient-
specific doses of PET drug in the practice of pharmacy may be done in the same work
area. The area of the facility for these two activities and the work flow should be
designed to prevent contamination and mix-ups.
Q83: 	Can the QC samples be drawn from the vial in the same hot cell where the PET
doses are dispensed?
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It is acceptable for the drawing of QC samples from a PET drug product batch vial in the
hot cell provided there are proper controls in place to prevent contamination and ingress
into the product vial. It is, however, preferable to withdraw the QC sample in the laminar
flow workstation to mitigate risk of microbial and particulate contamination. This is the
case when the dilution to the bulk sample vial is conducted in the laminar flow
workstation where the dose calibrator is located.
Q84: 	What is the proper procedure for dispensing the pharmacy dose?
The dispensing of the pharmacy dose should not be done inside the hot cell. Pharmacy
dispensing into individual prescription dose should be done under laminar flow,
complying with State Pharmacy regulation and USP chapter <797>.
Q85: 	Please clarify the environmental air quality expectations and/or requirements for
different areas within a PET manufacturing site. In general, what are the minimal
environmental air quality monitoring requirements?
The air quality in the production and laboratory areas should be controlled to minimize
the level of contamination (particulate and microbial) that may affect analyses or the
quality, purity, and strength of the PET drug.
The air quality in the hot cell should be clean and controlled to minimize the level of
particle and microbial contaminants that may affect the quality of the PET drug. We
recommend the use of High-Efficiency Particulate Air (HEPA) filtered air for this
environment when the product is being sampled or diluted to reduce the possibility of
microbial contamination.
Aseptic workstations (hoods) should meet Class 100 conditions using HEPA filtered
laminar flow air. We recommend that these workstations be located in the facility away
from foot traffic and other activity to reduce the chance of disruption to air flow and
contamination of the workstation.
Q86: 	Is it acceptable to use settling plates for environmental monitoring or will there be a
requirement to use an active air sampling system?
Yes, settling plates are acceptable. We recommend that microbial monitoring of the
aseptic workstation be conducted during sterility testing and critical aseptic
manipulations. The methods used may also include active air sampling.
Q87: 	Inspections have raised issues over the requirement of mandatory standards for
cyclotron maintenance, including target rebuilds. Can FDA comment on the
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relevance of the request given the nature of the performance of the cyclotron and
final product testing?
FDA has not imposed any mandatory standards for cyclotron maintenance or target
rebuild. Some attention may be devoted during an inspection to target window
maintenance because over a period of time, the target window foils may get etched by the
target beam that may cause leaching of unintended material (including radionuclides) into
the irradiated isotopic solution.
Inspectors may review the records on target window maintenance (including target
window rebuild) to identify any problems encountered, and corrective actions. Usually,
inspectors will only devote attention to this issue if a quality problem has been identified.
Q88: 	Are we required to submit a Field Alert Report to FDA on the failure of a
distributed batch to meet the specifications (e.g., sterility) established in the
application?
Yes (see 21 CFR 314.81). This also applies to PET drugs with an application pending
FDA approval.
Q89: 	If a PET producer submits a supplement to add a manufacturing facility or
facilities, how much media fill data should be submitted in the supplement?
If the new facility (or facilities) uses the same media fill methods and criteria that were
approved in the application, the supplement should refer to the approved application and
provide brief summaries of the media fill process descriptions and acceptance criteria for
all sites, along with a statement indicating that the media fills met their acceptance
criteria. The raw data should be available on site for examination during an FDA
inspection.
If the additional facility (or facilities) uses different manufacturing processes or media fill
procedures, the new media fill procedures and acceptance criteria would need to be
described in the supplement and reports for each facility’s aseptic process validation
should also be submitted.
D. 	Inspections
Q90: 	The FD&C Act specifies that drug producers will be inspected once every 2 years.
FDA previously stated that FDA will continue to perform surveillance inspections of
a number of PET facilities each year. Please clarify the expected inspection profile.
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We expect to perform a CGMP surveillance inspection of each PET facility once every 2
years on average, but may visit some sites more than once every 2 years when warranted,
such as when the site is named in an application for a new type of PET product or has
undergone substantial change.
Q91: 	Will PET facilities submitting applications and registering in accordance with
section 510 of the FD&C Act (21 U.S.C. 360) be inspected before approval of their
ANDA and/or NDA? If so, under what time frame and against what inspection
criteria?
As part of the drug approval process, a preapproval inspection (PAI) will be performed to
provide assurance that a PET drug production facility that is named in a drug application
is capable of producing the PET drug in accordance with CGMPs, and that the submitted
application data are reliable, accurate, and complete. FDA intends to prioritize
inspections to ensure facilities referenced in applications are inspected before the
application is ready for approval. Your facility should be ready for inspection when the
application is submitted.
The inspection criteria are described in Compliance Program 7356.002P
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UC
M277416.pdf).
Q92: 	Is a large-enough, dedicated cadre of trained inspectors available to ensure complete
review of manufacturing sites in timely fashion?
FDA has trained a cadre of inspectors, and we expect that inspections will be conducted
in a timely manner.
Q93: 	For applications with multiple manufacturing sites, will FDA use a risk-based
approach to select sites for inspection?
No. At the beginning of our PET facility inspection program, it would be difficult to
assess the risks at particular sites given that most facilities have never been inspected.
After we gain sufficient experience with PET facilities, we may consider changing to a
more risk-based approach.
Q94: 	During inspections, will FDA take into consideration that some SOPs might be
based on USP chapter <823> while others might be based on 21 CFR part 212, as
producers transition from compliance with the USP to the part 212 regulations?
Yes, FDA will take the transition into consideration during inspections.
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Q95: 	Can the initial FDA inspection for an academic setting be scheduled in advance
since academic sites do not have a corporate quality assurance office to guide the
investigator through the facility and associated paperwork?
Yes, it can be scheduled in advance. However, for-cause inspections are usually not
preannounced. 	It is important for a site to have records and information properly
organized to facilitate an efficient inspection (see 21 CFR 212.110).
Q96: 	For companies that have multiple production facilities, is there a way to address the
corrections at multiple sites as we are developing our responses to the Form 483
(i.e., the list of objectionable observations)?
If at the corporate level you are aware of sites having problems, you should initiate that
discussion with CDER’s Office of Manufacturing and Product Quality, Division of
Domestic Drug Quality. CDER will involve the districts where your manufacturing sites
are located in the review of your response and correction of the problems. Companies
with multiple sites should consider whether objectionable findings at any one site are also
applicable to other sites, and make necessary corrections at all affected sites whether or
not FDA has inspected and found similar problems.
E. 	Registration and Listing
Q97: 	How does drug registration relate to ANDAs, NDAs, and standard product labeling
(SPL)?
Manufacturers are required to register all facilities where they produce PET drugs and list
all PET drugs that are made at each facility (see 21 CFR part 207). Further information is
available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistrationandListi
ng/ucm078801.htm.
Q98: 	Is it appropriate to register as a manufacturing site ahead of submitting our ANDA?
Yes, you should register as soon as possible if you are already making PET drugs, and
you may register ahead of submitting your ANDA if you are not currently making PET
drugs. Please note that 21 CFR 207.21 requires registration within 5 days after first
manufacturing batches for distribution or submission of an NDA or ANDA.
F. 	User Fees
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Q99: 	Considering the March 10, 2000, PET Safety and Effectiveness Notice (65 FR
12999), what fees associated with an NDA for FDG, Ammonia N13, or Sodium
Fluoride F18 may be waived?
If you submit your NDA in accordance with the March 10, 2000, PET Safety and
Effectiveness Notice, your application fee will be waived. You will still be assessed the
product and establishment fees. However, you can request a waiver of the product and
establishment fees under the public health or barrier-to-innovation waiver. See responses
to questions posed on December 9, 2009, at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm193476.htm.
Q100: Will FDA waive application fees for other PET NDAs like it did for FDG, Ammonia
N13, and Sodium Fluoride F18?
FDA does not intend to provide a blanket waiver of application fees for NDAs for other
PET drugs. We will consider requests for waivers of fees on a case-by-base basis. We
recommend that you submit any request for a fee waiver sufficiently in advance of
submitting your application so that we have sufficient time to process it and provide a
response before you submit your application. There is no time limit for FDA to process a
waiver request, but we attempt to process requests for waivers of application fees within
90 days of receipt of the request.
Q101: When a product that is the same as an innovator product is approved and marketed
under an ANDA, the innovator product is no longer assessed annual product and
establishment fees. Does this only apply to the RLD when an ANDA for the same
strength is approved and marketed or do all NDAs for that product get an
exemption?
The ANDA product must be the same strength as the RLD for the RLD to get the benefit
of an exemption. See our responses to Q32 and Q43 for additional information on
determining the strength of PET products.
Q102: If an applicant identifies several different categories of waivers and exemptions for
which it might qualify, is it best to list all of them in the request or should only one
be chosen?
We encourage persons requesting a waiver to identify all the waivers and exemptions for
which they may qualify.
Q103: Do ANDA applicants need to obtain a waiver of fees before they submit their
application?
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No. PET drug ANDAs (both applicants and facilities) are exempt from generic drug user
fees. Applicants do not need to request any waivers or exemptions before submitting
their applications.
Q104: Would a nonprofit university that is affiliated with and distributes PET drugs to a
veterans hospital be exempt from fees under the State and Federal government
exemption?
If the State or Federal government-affiliated university distributes its product
commercially, meaning any distribution for financial reimbursement, goods, or services,
whether or not the amount of the charge covers the full costs associated with the product,
then the State or Federal government exemption would not apply (see the guidance User
Fee Waivers, Reductions, and Refunds for Drug and Biological Products). It would not
matter that the university distributed to the veterans hospital. The key point is whether
the product is distributed commercially. However, if the State or Federal government-
affiliated university gives the product away without any reimbursement, then the State or
Federal government exemption would apply. 	Please note that any recovery by a
university of all or parts of the costs of the manufacture or distribution of a product
makes the distribution commercial.
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APPENDIX A – PET NDA AND ANDA REGULATORY SCENARIOS
Your Facility’s Status 	You Submitted an NDA or
ANDA for the Particular
Drug Before 6/12/2012
You Did Not Submit an NDA or ANDA for the
Particular Drug Before 6/12/2012
You Submitted an IND for the Particular Drug
Before or After 6/12/2012
Your facility was
producing
Fludeoxyglucose F18
injection (FDG),
Ammonia N13
injection (Ammonia),
or Sodium Fluoride
F18 injection (NaF),
for clinical use*
before 6/12/2012
(note that each drug is
to be considered
independently).
FDA intends to exercise
enforcement discretion
and you can continue
making the PET drug for
clinical use while the
NDA or ANDA review is
pending. ***
If the Office of New
Drugs (OND) issues a
Refuse to File letter or
OGD issues a Refuse to
Receive letter based upon
inadequacy of the
submitted documents,
you must halt production.
If you continue to produce FDG, NaF, or
Ammonia for clinical use after 6/12/2012, you
may be subject to enforcement action until you
submit an NDA or ANDA.
Once your application is submitted and has been
filed, you may resume production while review is
pending. ***
If OND issues a Refuse to File letter or OGD
issues a Refuse to Receive letter based upon
inadequacy of the submitted documents, you must
halt production.
You may not continue to produce FDG, NaF, or Ammonia for
clinical use under an IND. You must have submitted an NDA or
ANDA or you may be subject to enforcement action.
You must submit an IND if you are developing FDG, NaF, or
Ammonia for a new use for which you intend to submit an
NDA, and the other criteria for when an IND is required are
met.
Your facility was not 	FDA intends to exercise 	You may not begin production of FDG, NaF, or 	You may not begin to produce FDG, NaF, or Ammonia for
producing FDG, NaF, 	enforcement discretion 	Ammonia for clinical use until you have an 	clinical use under an IND. You must have submitted an NDA or
or Ammonia for 	and you may begin 	approved NDA or ANDA. 	ANDA or you may be subject to enforcement action.
clinical use before 	production for clinical
6/12/2012, but you 	use while the review of 	If you begin production without an approved NDA 	You must submit an IND if you are developing FDG, NaF, or
would like to start 	your NDA or ANDA is 	or ANDA, you may be subject to enforcement 	Ammonia for a new use for which you intend to submit an
production for clinical 	pending. *** 	action. 	NDA, and the other criteria for when an IND is required are
use.*
If OND issues a Refuse
to File letter or OGD
issues a Refuse to
Receive letter based upon
inadequacy of the
submitted documents,
you must halt production.
met. You may begin production of the drug for this
investigational use**** under a traditional IND 30 days after
FDA receives the IND unless the investigation is put on clinical
hold.
Continued on next page
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Appendix A (continued)
Your Facility’s Status 	You Submitted an NDA or ANDA*
for the Particular Drug Before
6/12/2012
You Did Not Submit an NDA or ANDA for the
Particular Drug Before 6/12/2012
You Submitted an IND for the Particular Drug
Before or After 6/12/2012
Your facility was
producing PET drugs
other than FDG, NaF, or
Ammonia for clinical
use* before 6/12/2012
(e.g., Fluorodopa F18
injection, Choline C-11
injection).
If you submitted an NDA for that
particular drug, ** you may
continue production while the
NDA is under review. ***
If the Office of New Drugs issues
a Refuse to File letter based upon
inadequacy of the submitted
documents, you must halt
production.
If the PET drug would be difficult to commercialize
because of the unique circumstances of its
production (e.g., the isotope properties, very short
half-life) and nature of use (e.g., use is limited to a
small niche population), you may produce the PET
drug for clinical use under an expanded access IND
if the criteria are met. See guidance
Investigational New Drug Applications for Positron
Emission Typography (PET) Drugs.
If you continue to produce the drug for clinical use
without submitting an NDA or an expanded access
submission, you could be subject to enforcement
action until an NDA or IND is submitted.
Once an NDA** is submitted or the IND is allowed
to proceed, you could resume production while
review of the NDA is pending*** or as long as the
IND remains in effect.
FDA intends to exercise enforcement discretion
and you may continue production of the drug for
clinical use while your expanded access IND is
under review unless the IND is put on clinical
hold.
Your facility was not
producing PET drugs
other than FDG, NaF, or
Ammonia for clinical
use before 6/12/2012,
but you would like to
start production of a
new PET drug for
clinical use.*
You may not begin production
for clinical use until you have an
approved NDA** unless you
have an expanded access IND in
effect.
You may not begin production for clinical use until
you have an approved NDA, ** unless you have an
expanded access IND in effect.
If the PET drug would be very difficult to
commercialize because of the unique circumstances
of its production (e.g., the isotope properties, very
short half-life) and nature of use (e.g., use is limited
to a small niche population), you may produce the
PET drug for clinical use under an expanded access
IND if the criteria are met. See guidance
Investigational New Drug Applications for Positron
Emission Typography (PET) Drugs.
You may begin production of the drug for clinical
use under an expanded access or traditional IND
30 days after IND submission unless the IND is
put on clinical hold.
*Clinical use refers to administration of the PET drug to patients as a component of their clinical care with no intent to study the safety or effectiveness of the drug
in any systematic way.
**At this time, ANDAs may not be submitted for PET drugs other than FDG, Ammonia N13, and Sodium Fluoride F18.
Continued on next page
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Appendix A (continued)
***If problems are detected during an inspection, FDA may require you to stop production. You will be expected to have an approved application by December 12,
2015, or halt production.
****Investigational use, as distinguished from clinical use, is use in a study of the drug to establish the safety and/or efficacy of a new use of the drug to support an
application for approval of that use. Investigational use may also refer to use of certain PET drugs for clinical purposes under an expanded access IND.
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APPENDIX B – CHANGES IN EQUIPMENT OR FACILITIES
(APPLIES ONLY TO FDG, AMMONIA, AND NaF)
Your Status 	The Equipment and Procedures
Are Identical
The Equipment Is Different, But Does
Not Result in Any Formulation or
Strength Change
The Equipment and Procedures Are Different, Resulting
in a Formulation or Strength Change
You submitted an
NDA or ANDA
before 6/12/2012,
and you want to add
or replace
production
equipment described
in the application at
the facility described
in the application
before the NDA or
ANDA is approved.
You do not need to amend the
application. You can make this
change under your quality systems.
The change validation data will be
subject to audit during the PAI
inspection. See the ICH guidance for
industry Q10 Pharmaceutical Quality
System.
You must amend the application to
describe the new equipment and
procedures and provide supporting data
for the change.
If you submit an appropriate amendment
to the pending application to add the
equipment, you may begin production
for clinical use while the NDA or
ANDA review is pending. *
You cannot change formulation or strength in an ANDA,
although you may change exception excipients (buffers,
preservatives, or antioxidants). Any other change in
formulation from the reference listed drug (RLD) requires
an NDA or a separate ANDA that references another
designated RLD. ** Any change in strength from the RLD
requires an NDA or a suitability petition and a new ANDA.
If the exception excipients change, you must amend the
application to describe the new equipment and procedures
and the change to the exception excipients, and provide
supporting data for the change.
If you submit an appropriate amendment to the pending
application to add the equipment, you may begin production
for clinical use while the NDA or ANDA review is
pending.*
You submitted an
NDA or ANDA
before 6/12/2012,
and you want to add
additional
production facilities
to your application
before the
application is
approved.
You must amend the application to
describe the new facility and provide
new CMC data for the drug produced
at the new facility. See the ICH
guidance for industry Q10
Pharmaceutical Quality System.
If you submit an appropriate
amendment to the pending
application to add the equipment or
production facility, FDA intends to
exercise enforcement discretion and
you may begin production for clinical
use while the NDA or ANDA review
is pending. *
You must amend the application to
describe the new facility and provide
new CMC data for the drug produced at
the new facility.
If you submit an appropriate amendment
to the pending application to add the
equipment or production facility, you
may begin production for clinical use
while the NDA review is pending. *
You cannot change formulation or strength in an ANDA,
except you may change exception excipients (buffers,
preservative, or antioxidants). Any other change in
formulation from the reference listed drug (RLD) requires
an NDA. Any change in strength from the RLD requires an
NDA or a suitability petition and a new ANDA. **
Continued on next page
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Appendix B (continued)
Your Status 	The Equipment and Procedures
Are Identical
The Equipment Is Different, But
Does Not Result in Any Formulation
or Strength Change
The Equipment and Procedures Are Different, Resulting
in a Formulation or Strength Change
Your facility is
producing a PET drug
under an approved
NDA or ANDA, and
you want to add or
replace production
equipment described in
the application at the
facility described in the
application.
No supplement is required. You can
make this change under your quality
systems. The change validation data
will be subject to audit during the
surveillance inspection. We suggest
that you provide this information in
your annual report.
You must submit a supplement to the
application under 21 CFR 314.70 that
describes the new equipment and
provides data supporting the change.
You may not begin production for
clinical use using the new equipment
until the NDA or ANDA supplement
is approved or accepted as a changes
being effected (CBE) supplement
under 21 CFR 314.70.
You must submit a supplement to the application under 21
CFR 314.70 that describes the new equipment and provides
data supporting the change.
You may not begin production for clinical use using the new
equipment until the NDA or ANDA supplement is approved
or accepted as a CBE supplement under 21 CFR 314.70.*
Your facility is
producing a PET drug
under an approved
NDA or ANDA, and
you want to add an
additional production
facility.
You must submit a supplement to the
application to describe the additional
production facility and provide new
CMC data for the drug produced at
the new facility.
You may not begin production at the
new facility until the supplement is
approved or accepted as a CBE
supplement under 21 CFR 314.70.
You must submit a supplement to the
application under 21 CFR 314.70 to
describe the additional production
facility and provide new CMC data for
the drug produced at the new facility.
You may not begin production at the
new facility until the supplement is
approved or accepted as a CBE
supplement under 21 CFR 314.70.
You must submit a supplement to the application under 21
CFR 314.70 to describe the new production facility and
provide new CMC data for the drug produced at the new
facility.
You may not begin production at the new facility until the
supplement is approved or accepted as a CBE supplement
under 21 CFR 314.70.
*If problems are detected during an inspection, you might need to stop production. Production of a PET drug not under an approved NDA or ANDA while an
NDA or ANDA review is pending is only allowed through December 12, 2015.
**FDA may designate more than one PET drug product as an RLD if the formulations of the approved products are different with respect to non-exception
excipients (e.g., tonicity agent) and the differences in formulation would require an ANDA applicant to cite a different RLD.
37