The Coalition for PET Drug Approval has compiled questions which they will be seeking answers to from the FDA. The answers will be posted for public review. At the present time these are the questions that have been compiled by the coalition.
1. Air, ceiling, floor, and wall materials: The radiosynthesis is processed in the hot cell; however, some operation is performed in the laboratory, such as HPLC operation, buffer preparation, weighing raw materials on a scale. Is there any specified quality for the ceiling and floor (for example, shall we use seamless, washable material)?
2. Segregation of manufacturing and pharmacy activities:
a. Can the PET radiopharmaceutical manufacturing activities be conducted in the same room as the PET dose dispensing?
b. Can the QC samples be drawn from the vial in the same hot cell where the PET doses are dispensed (pharmacy operation)?
ANDA/NDA Filing Questions
What does paper application mean for the ANDA?
a. Does this mean the entire document is submitted in paper, or is it required to save the sections as PDF files on a CD?
b. Is the PDF index required to be linked to the various sections in the document?
c. Are there any other links that need to be inserted?
a. What is the process for requesting “fee waivers”?
b. What fees have the potential to be waived?
c. Will academic sites preparing PET drugs for their internal patients (e.g., not distributing to others) be required to pay the fees?
2. The guidance provides reference to and advice to format an application in the CTD format. The attachments to this guidance which provides sample format are not formatted according to the CTD. As a result, the discussions and suggestions regarding the formatting of the application are inconsistent and confusing. What is the correct format for the CTD?
3. 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 on 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.
Environmental Monitoring and Aseptic Processing
1. Is there any specified air quality for the general (non-aseptic processing) areas of the laboratory?
2. Is there any specified air quality requirements for the hot cells?
3. Is it acceptable to use settling plates for environmental monitoring or will there be a requirement to use an active air sampling system?
4. Is growth promotion testing required for the contact plates (solid media) used in an ISO class 5 hood? How frequently?
5. 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?
1. Is it required to check the osmolality for every batch of FDG prepared?
2. Would the FDA consider an application for a concentration greater than 300 mCi/mL for FDG perhaps as high as 500 mCi/mL?
3. When is it necessary to dilute the final product to meet the concentration specification? Is there a preference to use sterile water, normal saline, or half normal saline?
4. In order for a site to apply for a concentration higher than 37.5 mCi/mL for N-13 is it better to file a petition or file a 505 (b) 2 NDA?
a. What is the current wait time for the petition?
b. In case the NDA approval is not received before the deadline, it is assumed the laboratory can continue producing PET drugs in a continuation mode until FDA approval is received. Is that correct?
5. Assuming that product stability is demonstrated during validation testing, is there any limit to expiration time of the product?
6. Is a type V DMF required for the chemical synthesis units? If a manufacturer does not file a type V DMF, how should the community proceed? What information do we need to file in the ANDA or NDA?
7. The new draft guidance states that the QC needs to be done for 3 qualification batches at the highest concentration allowed. Is it correct that a stability study is required for only 1 of these batches?
8. Which analytical techniques, if any, require validation?
Acceptability of Filing an ANDA
1. Pages 9 and 10 discuss the parameters considered in making a determination of a generic being identical and bioequivalent to a RLD. The requirement is to assess whether differences in inactive ingredients do or do not have an effect on viscosity and specific gravity of the proposed PET drug product. This seems totally irrelevant to PET drug products and without scientific merit. Please state the regulation where this requirement resides and clarify why the expectation to make this assessment exists.
2. The statement at the bottom of page 39 that discusses Q1 and Q2 ingredient differences is vague and could be very subjective. Can the FDA please clarify and give examples for inclusion in the guidance and for discussion at the meeting?
a. Please clarify if one must demonstrate by objective scientific evidence (data), or by presenting a sound scientific discussion, whether such differences will not affect the chemical or physical properties.
b. If the former, must a laboratory comparison between the RLD and the proposed drug be done?
3. If the proposed drug differs from the RLD in strength, route of administration, or dosage form, an ANDA may still be submitted, but the sponsor first must obtain FDA approval of a suitability petition. Among these attributes, only a change in strength is likely to be relevant for a PET drug. The guidance states that a change in mCi/mL at end of synthesis (EOS), total drug content, or amount of active ingredient are considered a change in strength which will require approval of a suitability petition before the ANDA may be filed. We ask the agency to discuss the merit for PET drugs, because the total content of the vial and the total amount of radioactivity are irrelevant to the safety and effectiveness of a PET drug, and rapidly changes naturally. Indeed, on January 26, 2011, the FDA approved an NDA submitted by NIH for sodium fluoride F 18, for which the labeling states that the total volume and total radioactivity per vial are variable. A change in activity concentration (mCi/mL) at EOS should be the only relevant consideration in determining whether a suitability petition needs to be submitted because of a change in strength from the RLD. Please clarify.
Compliance and Inspection
The commercial PET sector has experienced many routine PET establishment and pre-approval inspections. Their experience shows that most inspectors have not performed PET establishment inspections nor are they familiar with USP <823> prior to inspection. As a result, a disturbing trend has evolved where the industry has experienced the equivalent of “regulation by inspection” where inspectors rely on their previous experience with Part 211 to issue observations on inspections rather than rely on the specific provisions of USP Chapter 823 Part 212 and the unique nature of PET drugs, their manufacture, and the establishment. Precedent-setting 483 observations are being made which have no foundation in the USP general chapters, chapter 823, monographs, or the PET GMP Part 212, and associated guidance, or in traditional radiopharmaceutical industry practices at large. As the result of one inspector’s findings such observations could have industry-wide repercussions, which can be linked to a lack of understanding of the nature of PET and the tremendous disparity between the nature of a large industrial pharmaceutical establishment and the special nature of PET drugs and their manufacturing environment. The coalition will provide specific examples of “regulation by inspection” that the industry has experienced within the next week for discussion at the public meeting.
General Notations Regarding the Guidance Document
Formulation information is provided on pages 6-8 for 3 FDG RLDs, 2 NaF RLDs, and 1 ammonia RLD. Some of the information provided is not accurate or complete:
The 12/06 resided labeling for NDA 21-768 is not available on Drugs@FDA.
Fludeoxyglucose F 18 injection (NDA 21-768) and Fludeoxyglucose F 18 injection (NDA 21-870); labeling revision in 12/06 is inconsistent with the information provided.
Table lists as isotonic; labeling does not state isotonic.
Citrate content: labeling states the concentration of the active and inactive ingredients “in citrate buffer.”
NDA 21-870: 20-300 mCi/mL correct pH on the label is 4.5-7.5, not 5.5-7.5, as listed.
NDA 21-870: also original RLD strength is 20-200 mCi/mL, pH = 5.5-7.5. This information is not provided. The table on page 37, under generic drug fails to include the 20-300 mCi/mL strength. The table under RLD fails to list the 20-200 mCi/mL strength.
Page 40, table under RLD, 20-200 mCi/mL should be included.
Page 9, C-General recommendations, 3. Sodium Fluoride Injection: the statement that NDA 22-494 is listed as discontinued in the Orange Book is in error.
Page 26 discusses the field copy and includes a statement that it should contain the technical section, application form, and summary. The suggested format for an application as provided in the appendix of the draft guidance does not discuss a summary section. Please clarify if a summary should be included. In addition, the appendix refers to the “CMC” section; module 3 in a CTD format is called the “Quality” section. The inconsistencies in the appendix, as a guide for formatting the application and the discussion of the CTD format, create confusion about the expectations of the content of an application.