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.

Facility Question

Segregation of manufacturing and pharmacy activities: What are the FDAs filing and compliance expectations for how to delineate the separation of manufacturing and pharmacy activities?

In some sites, the drug product is synthesized and transferred into a dispensing cell in the radiopharmacy at which time the QC sample, sterility sample, and retention sample are extracted just prior to drawing the finished unit dose for administration. How would the FDA like to see the segregation of manufacturing activities from pharmacy practice activities?

Administrative Questions

1. Can the FDA open a docket so information could be accessible to the community?

2. Fees:

a. Application fees

b. Establishment fees

c. Product fees

3. Full prescribing information (package insert) must be developed against the RLD (reference listed drug) labeling. Considering that PET drugs are distributed outside the normal channels of distribution for drugs, it would be useful for the FDA to provide:

a. Guidance on the responsibility of academic PET drug producers for printing and distributing a package insert for PET drugs under an approved application.

b. Guidance for the commercial sector as the batch vial does not enter the ordinary channels of distribution, but rather the product is delivered to the prescribing physician in the form of a dispensed prescription from a pharmacy.

Environmental Monitoring and Aseptic Processing

1. Please specifically clarify the environmental air quality expectations/requirements for different areas within a PET manufacturing site.

2. In general, what are the minimal environmental air quality monitoring requirements?

Production Questions

1. Will the FDA accept the use of materials meeting other agency’s compendia requirements, (e.g., European pharmacopeia, and assuming these materials would be declared in an ANDA/NDA filing, and would be sourced and managed using the local quality management system (QMS))?

2. 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 chromatographic 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 212?

3. Given the scale of the typical PET manufacturing facility we are faced with a more rapid “equipment turnover” than a very large commercial manufacturing facility. If a facility submits an NDA/ANDA for FDG prior to 12/12/11 and the facility wants to (or needs to – due to equipment failure or other due cause) upgrade their FDG production method, which may require the purchase of another module that utilizes a different process:

a. Can the facility purchase the module, validate the process, and amend the ANDA prior to the initial inspection of the facility by the FDA since this FDA inspection may take several years to complete?

b. What is the process for notifying the FDA of this change as the inspector will be looking for the MX box during the ANDA approval inspection?

4. 212.50(f) – Would an NDA/ANDA submission be deemed adequate with the inclusion of the production and stability of a single batch if full testing is always performed?

5. Does the FDA have any guidance on what level of reduced testing would be acceptable once a product has undergone process verification?

6. Is identity testing on mannose triflate REQUIRED (other than the “test” in which mannose triflate can be used to produce FDG)?

7. Expectations on handling invalid tests and sample size for repeat testing?

Acceptability of Filing an ANDA

1. 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)?

2. Sample labeling is provided only for one RLD (reference listed drug) and one of the specific RLD strength. Guidance states that if labeling is different you must do a side-by-side. Will the FDA provide an example of all the RLD labeling? For clarity, a statement should be provided in the guidance that makes it clear that the reference to any of the RLD formations/labeling selected to use as a RLD for filing an ANDA should be provided.

Compliance and Inspections

1. 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)?

2. The Food, Drug, and Cosmetic Act (FD&C Act) specifies that inspections will be made upon drug producers once every two years. However, in the questions and answers for the proposed 21 CFR 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 expected inspection profile. Does this mean that each PET facility producing commercial materials will be inspected within the two years beginning December 12, 2011?

3. Forced degradation studies: Will we be required to perform forced degradation studies with short “shelf life” drugs.

4. 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 take three 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?

5. Inspections have raised the issue on the requirement of mandatory standards 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)?

General Question

Will the FDA provide greater clarity on expectations around Quality-by-Design applicability to PET products?

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