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.   GENERAL  QUESTIONS ......................................................................................................................................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 GOOD MANUFACTURING PRACTICES .............................................................................................23
  
D.   INSPECTIONS ..................................................................................................................................................28
  
E.   REGISTRATION AND  LISTING..........................................................................................................................30
  
F.   USER FEES .....................................................................................................................................................30
  
APPENDIX A   PET NDA AND ANDA REGULATORY  SCENARIOS............................................................33
  
APPENDIX B  CHANGES IN EQUIPMENT OR FACILITIES .......................................................................36
  
 
 
 
  Contains Nonbinding Recommendations 
 
1
 
Guidance
 
 
FDA Oversight of PET Drug Products
  
 
Questions and Answers  

 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
I.   INTRODUCTION 
 
This guidance is intended to help producers of positron emission tomography (PET) drugs meet 
the requirements for FDAs 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.       
 
1 
 Contains Nonbinding Recommendations 
 
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 FDAs current views of how PET drug production can continue under 
various application submission scenarios. 
     
 
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  Contains Nonbinding Recommendations 
 
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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  Contains Nonbinding Recommendations 
 
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. CDERs 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. 
 
4 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
 
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 FDAs 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 FDAs current thinking  on this topic. 
 
5 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
 
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). 
 
6 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
 
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? 
 
 
7 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
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 drugs 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 drugs 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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  Contains Nonbinding Recommendations 
 
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 Parkinsons or Alzheimers disease, the foreign trials 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 Parkinsons disease or Alzheimers 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 FDAs 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? 
 
  FDAs 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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  Contains Nonbinding Recommendations 
 
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 drugs 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 
 
1 0
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
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 products 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 submissioneither 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 FDAs 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 FDAs 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 facilitys 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 FDAs 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 FDAs current thinking  on this topic. 
 
2 5
 
 
 
 
 
 
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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 facilitys 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 CDERs 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 Facilitys Status  You Submitted an NDA or   You Did Not Submit an NDA or ANDA for the  You Submitted an IND for the  Particular Drug  
ANDA for the Particular  Particular Drug Before 6/12/2012  Before or After 6/12/2012 
Drug Before 6/12/2012 
Your facility was  FDA intends to exercise  If you continue to  produce FDG, NaF,  or  You may not continue to  produce FDG, NaF, or Ammonia for  
producing   enforcement discretion  Ammonia for clinical use after 6/12/2012, you   clinical use under an IND.  You must have submitted an  NDA or 
Fludeoxyglucose F18  and you can continue   may be subject to enforcement action  until you  ANDA  or you may be subject to enforcement action. 
injection (FDG),  making the PET drug  for  submit an NDA  or  ANDA.      
Ammonia N13   clinical use while the     
injection (Ammonia),  NDA  or ANDA review is  Once your application is submitted and  has been  You must submit an IND if  you are developing FDG, NaF, or 
or Sodium Fluoride  pending. ***   filed, you may  resume production while  review is   Ammonia for a new use for which you intend to submit an 
F18 injection  (NaF),    pending. ***    NDA, and the other criteria for when an IND is required are 
for clinical use*   If the Office of New    met.   
before 6/12/2012   Drugs (OND) issues a   If OND issues a Refuse to File letter or OGD 
(note that each drug is  Refuse to  File letter or   issues a Refuse to Receive letter based upon 
to be considered   OGD issues a  Refuse to  inadequacy of the submitted documents, you must 
independently).   Receive letter based upon  halt production.   
  inadequacy of the 
submitted documents, 
you must halt  production.   
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.*      met. You may  begin production of the drug  for this  
If OND  issues a Refuse    investigational use****  under a traditional IND 30  days after 
to File letter or OGD  FDA receives the IND unless the investigation is put on clinical 
issues a Refuse to  hold.   
Receive letter based upon 
inadequacy of the 
submitted documents, 
you must halt  production.   
 
Continued on next page 
 
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 Contains Nonbinding Recommendations 
 
Appendix A (continued)  
Your Facilitys Status  You Submitted an NDA or ANDA*  You Did Not Submit an NDA or ANDA for the  You Submitted an IND for the  Particular Drug  
for the Particular Drug Before  Particular Drug Before 6/12/2012  Before or After 6/12/2012 
6/12/2012 
Your facility was  If you submitted an  NDA for that  If the PET drug  would be difficult to commercialize  FDA intends to exercise enforcement discretion 
producing PET drugs  particular  drug, ** you may   because of the unique  circumstances of its  and you may continue  production  of the drug  for  
other than FDG, NaF, or   continue production while the  production (e.g., the isotope properties, very  short   clinical use while your expanded access IND is 
Ammonia for clinical  NDA is under review. ***    half-life) and  nature of use (e.g., use is limited to a  under review unless the IND is put on clinical 
use* before  6/12/2012     small niche population), you  may produce the PET  hold. 
(e.g., Fluorodopa F18  If the Office of New Drugs issues  drug for clinical use under an expanded access IND    
injection, Choline C-11   a Refuse to File letter based  upon   if the criteria are met.   See guidance   
injection).  inadequacy of the submitted   Investigational New Drug Applications for Positron  
documents, you must halt   Emission  Typography (PET) Drugs. 
production.     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. 
Your facility was not  You may not  begin production  You  may not begin production for clinical use until  You may begin production of the drug  for clinical  
producing PET drugs  for clinical use until you  have an   you have an approved NDA,  ** unless you  have an   use under an expanded access or traditional IND 
other than FDG, NaF, or   approved  NDA** unless you  expanded access IND in effect.  30 days after IND submission unless the IND is  
Ammonia for clinical  have an expanded access IND in    put on  clinical hold. 
use before 6/12/2012,   effect.  If the PET drug  would be very difficult to  
but you would like to   commercialize because of the unique  circumstances 
start production  of a  of its production (e.g., the isotope properties, very  
new PET drug  for  short half-life) and nature of  use (e.g.,  use is limited  
clinical use.*  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. 
 
*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 
 
34 
 Contains Nonbinding Recommendations 
 
 
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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 Contains Nonbinding Recommendations 
 
APPENDIX B  CHANGES IN EQUIPMENT OR FACILITIES  
(APPLIES ONLY TO FDG, AMMONIA, AND NaF) 
Your Status  The Equipment and Procedures  The Equipment Is Different, But Does  The Equipment and Procedures Are Different, Resulting 
Are Identical  Not Result  in Any Formulation or  in a Formulation or Strength Change 
Strength Change 
You submitted an  You do not need  to  amend the   You must amend the application to   You cannot change formulation or strength in an  ANDA, 
NDA or  ANDA   application.  You can make this  describe the new equipment and   although you  may change exception excipients (buffers, 
before 6/12/2012,  change under your quality systems.  procedures and provide supporting data  preservatives, or antioxidants).  Any other change in  
and you  want to add  The change validation data  will be  for the change.   formulation from  the reference listed drug  (RLD) requires 
or replace  subject to audit during the PAI    an NDA or a separate ANDA that references another 
production  inspection.   See the ICH guidance for  If you submit an appropriate amendment   designated RLD.  **  Any change in  strength from the RLD 
equipment described  industry Q10 Pharmaceutical Quality  to  the pending application  to add the  requires an NDA or  a suitability petition and a new ANDA.  
in the application at  System.  equipment, you may begin production   
the facility described   for clinical use while the NDA or   If the exception excipients change, you must amend the 
in the application  ANDA review  is pending. *  application to  describe the new equipment and procedures  
before  the NDA or    and the change to the exception excipients, and provide  
ANDA is approved.    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  You must amend the application to   You must amend the application to   You cannot change formulation or strength in an  ANDA, 
NDA or  ANDA   describe the new facility and  provide  describe the new facility and  provide  except you may change exception excipients (buffers, 
before 6/12/2012,  new CMC data for the drug  produced   new CMC data for the drug  produced at   preservative, or antioxidants).  Any  other change in  
and you  want to add  at the new facility.  See the ICH  the new facility.  formulation from  the reference listed drug  (RLD) requires 
additional  guidance for industry  Q10     an NDA.  Any change in  strength  from the RLD requires an 
production facilities  Pharmaceutical Quality System.   If you submit an appropriate amendment   NDA  or a suitability petition and a new ANDA. **   
to your application     to  the pending application  to add the   
before the  If you submit an appropriate  equipment or  production facility, you  
application is  amendment to  the pending   may begin production for clinical use  
approved.  application to add the equipment or   while the NDA review is pending. *  
production  facility, FDA intends to  
exercise enforcement discretion and 
you may begin production for clinical 
use while the NDA or  ANDA  review  
is pending. * 
 
Continued on next page  
36  Contains Nonbinding Recommendations 
 
Appendix B (continued) 
Your Status  The Equipment and Procedures  The Equipment Is Different, But  The Equipment and Procedures Are Different, Resulting 
Are Identical  Does Not Result in Any Formulation  in a Formulation or Strength Change    
or Strength Change 
Your facility is  No supplement is required.  You can  You must submit a supplement to the  You must submit a supplement to the application under 21  
producing a PET drug   make this change  under your quality  application under 21 CFR 314.70 that   CFR 314.70 that describes the new equipment and provides  
under an approved   systems.  The change validation data  describes the new equipment and   data supporting the change. 
NDA  or ANDA, and   will be subject to audit during  the  provides data supporting the change.      
you want to add or   surveillance inspection.  We  suggest    You may not  begin production for clinical  use using the new 
replace production  that you provide this information in   You may  not begin production for  equipment until the NDA  or  ANDA supplement is approved 
equipment described in   your annual report.    clinical use using the new equipment  or accepted as  a CBE supplement under 21 CFR 314.70.* 
the application at the  until the NDA or  ANDA supplement 
facility described in the  is approved or accepted as a changes  
application.   being effected  (CBE) supplement  
under 21  CFR 314.70. 
 
Your facility is  You must submit a supplement to the  You must submit a supplement to the  You must submit a supplement to the application under 21  
producing a PET drug   application to describe the additional  application under 21 CFR 314.70 to   CFR 314.70 to describe the new production  facility and  
under an approved   production  facility and provide new  describe the additional  production  provide new CMC data for the drug  produced at the new 
NDA  or ANDA, and   CMC data for the drug  produced at   facility and  provide new CMC data for  facility. 
you want to add an   the new facility.  the drug produced at the new facility.   
additional production      You may not  begin  production at the new facility until the 
facility.  You may not  begin production at the   You may not  begin production at the   supplement is approved or accepted as a CBE supplement  
new facility until the supplement is  new facility until the supplement is  under 21  CFR 314.70. 
approved or accepted as a CBE  approved or accepted as a CBE 
supplement under 21 CFR 314.70.    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