The Coalition for PET Drug Approval has compiled questions and answers that were posed during the FDA Public Meeting on March 2, 2011.
We continue to develop answers to the questions posed by Coalition representatives during the FDA meeting. Please check back regularly to see additions to the Q & A. Questions are sorted by area of most relevance.
Acceptability of Filing an ANDA:
Q: 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 the FDA inspection (after submission of the ANDA)?
Dr. Kasliwas of the FDA stated that validation data, the analytical validation data and other validation data has to be submitted in the application, and it’s part of the review process. During inspection, the inspector may look at the source data.
Q: The guidance provides reference to and advice to format an application in the CTD format. The attachments to the guidance which provides sample format are not formatted according to CTD format. As a result, the discussions and suggestions regarding the formatting of the application are inconsistent and confusing. What is the correct format for the application?
Dr. Shimmer of the FDA stated that the Electronic Technical Document (eCTD) format is the preferred format. Recognizing that most are going to be submitting…a few ANDAs, it may not make sense to invest monetarily to submit via…the eCTD format. So there are other options, and these other options are these hybrid electronic submissions, which amount to scanned electronic copied organized in the CTD format.
They can be submitted via the Gateway or they can be submitted on physical media. So by physical media, I mean CDs or DVDs…you are required to use hyperlinks.
Q:The guidance provides that paper applications are acceptable. Discussion is provided regarding an electronic submission. The way the information is presented does not make a clear differentiation between submitting an application “electronically” on media, such as a pdf file on CD-ROM, versus an electronic submission of an e-CTD (which is an xml formatted file) through an established FDA electronic portal. Please advise as to how to submit a CD-ROM copy with a paper submission. It is our understanding that this has become an expectation of the FDA which is not mentioned.
Dr. Shimmer stated that FDA will take them, will review them… but applicants must submit multiple copies…and also submit a red chemistry or review copy and a maroon copy to the field. If you submit in paper, you have to submit a copy to your local field to facilitate the inspection. Even if you make a paper submission, labeling is still required to be submitted electronically.
Compliance and Inspections:
Q: Can the initial FDA inspection for an academic setting be scheduled in advance since academic sites don’t have a corporate QA office that can jump on a plane and guide the consumer safety officer through the facility and associated paperwork (and instead have patients each day to serve)?
Mr. Hasselbalch of the FDA noted a tradition of pre-scheduling or scheduling preapproval inspections. So it’s not unknown to FDA to call in advance and make arrangements for the time we’ll arrive. FDA is encouraging that now.
FDA will continue to do so and perhaps consider specifying, in particular, academic sites more lead time so they can be better prepared and have the appropriate people on site for that inspection.
You need to be prepared, that part, 212.110, says that records should be readily available for review and coying by FDA employees….we understand these are small facilities and you may need help, but you also should be organized such that you should have enough resources, given the appropriate schedule, to be able to handle an inspection.
Q: The FD&C Act specifies that inspections will be made upon drug producers once every two years. However, in the Q&A for the proposed 21 CFR Part 212, the statement is made that the FDA will continue to perform surveillance inspections of a number of PET facilities each year. Please clarify the inspection profile.
Does this mean that each PET facility, producing commercial materials, will be inspected within the two years beginning December 12, 2011?
Mr. Hasselbalch indicated that these are fairly standard objectives. FDA thinks they apply just as well to PET production facilities as they do to other types of facilities….FDA does these inspections to verify readiness for production and GMP compliance…and understands that PET drugs are now generally in commercial production…this year there are a lot more inspections due to submission of ANDA and NDA applications.
Q: Will PET facilities submitting ANDA/NDA and registering in accordance with section 510 of the FD&C Act be inspected prior to the approval of their ANDA/NDA? If so, under what timeframe and against what checklist/inspection criteria?
There is currently no PET Production Inspection Guidance available. The FDA is in process of writing this Guidance, but it will hopefully be available later this year.
Q:Inspections have raised the issue on the requirement of mandatory standard for cyclotron maintenance including target rebuilds. Can the FDA comment on the relevance of the request (given the nature of performance of the cyclotron and final product testing)?
This question was not directly discussed during the public meeting. Dr. Kasliwal did mention that the information regarding the cyclotron that the FDA will want to see as part of the process are parameters such as beam current, bombardment times and information on the type of target body material and target windows.
Environmental Monitoring and Aseptic Processing:
Q: What is the FDA position on growth promotion testing for solid media? Currently, there have been differing responses from FDA inspectors, depending on the area of the country where the inspections are occurring. If we need to perform these tests, can we test 3 lots of material to validate our source of media from a specific manufacturer, and then perform the test on an annual basis? Or will the FDA require growth promotion testing on every lot of media?
Dr. Parella stated, for PET drugs, growth promotion testing is not a requirement for solid media for environmental monitoring. You don’t need to do growth promotion, but it is an incoming component. So you need to quality the vendor. You really need to have some identity to make sure that, in fact, it’s a reliable supplier and that the transportation doesn’t compromise the media. But as long as all of that is okay, then growth promotion is not required.
Q: Is growth promotion testing required on liquid media? How frequently is the testing required? Can 3 consecutive lots of media be tested to validate the manufacturer’s process and shipping; with single lot testing annually thereafter?
When media are purchased “ready-to-use” from a commercial vendor, the first three batches should be tested for growth promotion as part of the vendor qualification. Commercially prepared media used in the sterility test should be used within the label’s shelf life, stored according to the label’s recommendations, and one batch should be tested for growth promotion periodically (e.g. quarterly).
The periodic growth promotion testing could be performed in conjunction with an operator qualification as long as their timing is close. If this is the case, a positive control should be prepared by inoculating a separate vial from te same batch of media used for the media fill. This will also serve as a growth promotion test. The microbiology department within your hospital is an acceptable laboratory to perform this testing.
INDs for Investigational Use of PET Drugs:
Q: Will an IND need to be submitted by the December 12, 2011 deadline to support the use of an investigational PET drug in the situation where the investigational use has been ongoing without an IND?
FDA does not plan for sponsors to stop the ongoing PET drug investigational use in patients/subjects while the newly submitted IND is under 30 day FDA review. Instead, the investigational use of the PET drug can continue during the 30 day review. If FDA becomes aware of special concerns during or at the conclusion fo the review, FDA will contac the sponsors.
Q: Will FDA publish guidance on expanded access INDs?
FDA is developing guidance on expanded access INDs and anticipates this will be made available in Spetember 2011. FDA does expect thtat expanded access INDs will be an option for continued clinical use of certain PET drugs.
Q: System suitability requirements in USP 823 suggest that the tailing factor and resolution (or column efficiency, as appropriate) are to be determined on a daily basis. This frequency is too often; these should be included with other chromographic parameters that are to be determined on a more reasonable basis (e.g., six months). What is the FDA’s view on this for manufacturing under ?
Dr. Kasliwal and Dr. Duffy of the FDA stated that it is acceptable to have a different procedure than outlined in USP for determining system suitability, but that any differences must be justified based on specific circumstances and the FDA will evaluate the strength of the justification and make a ruling during the review of the NDA/ANDA applicaton. Dr. Perrella of the FDA stated that system suitability still needs to be performed on a daily basis.
Q:212.50(f) Would an NDA/ANDA submission be deemed adequate with the inclusion of the production and stability of a single batch if a full testing is always performed?
This question was not asked during the public meeting. Dr. Kasliwal mentioned in his presentation that the FDA expects to see stability data for three batches at the upper range of the proposed radioactive concentration as part of the application.
Q: Is identity testing on Mannose Triflate required (other than the ‘test’ in which Mannose Triflate can be used to produce FDG)?
Dr. Kasliwal mentioned in his presentation that a specific identity test is not required for mannose triflate because of the final product analysis, but there must be specifications for the mannose triflate that have to be met so that it can be released for the FDG production process.
Q:Expectations on handling invalid tests and sample size for repeat testing?
Dr. Perrella of the FDA stated that if a test is invalidated due to a technical issue and you can document the issue and the root cause, it is allowable to repeat the test. Both Dr. Duffy and Dr. Perrella of the FDA stated that the number of repeat tests needed depends on the nature of the test and the nature of the out-of-specification investigation.
Q: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?
This question was not directly discussed during the public meeting. In his presentation Dr. Kasliwal did mention that the diluting solution must be compatible with the drug product.