Docket Management
Docket: 99N-4063 - Current Good Manufacturing Practice for Positron Emission Tomography Drug Products;Draft Rule
Comment Number: EC -2

Accepted - Volume 1

Comment Record
Commentor Dr. Timothy DeGrado Date/Time 2002-06-05 11:03:07
Organization Duke University Medical Center
Category Academic

Comments for FDA General
Questions
1. General Comments Dear Sirs/Madams, I appreciate the opportunity to comment on the drafted CGMPs for PET drug products. I attended the public meeting on May 21, 2002. My desire is to underscore several comments that were already presented at this meeting. 1) There is no rational reason to distinguish between small and large PET manufacturers. In both academic centers and in commercial installations, the manufacturing process and the quality control is commonly carried out by one trained chemist or chemistry technician. If there are more than one personnel in the PET chemistry lab, they will have different responsibilities that do not overlap, for example, one is making FDG, while the other is working on another radiotracer synthesis. Only one person is commonly employed to accomplish the synthesis of a given PET drug for a given synthesis run, regardless of size of operation or amount of PET drug manufactured. Thus, a larger program may employ more chemists, but each chemist will likely be assigned to different tasks, as will be more efficient than assigning multiple chemists to the same multiple tasks. Furthermore, the size of a PET chemistry operation should not be characterized by the number of doses produced or amount of PET drug produced. The amount of PET drug produced and number of doses produced is primarily determined by the length of bombardment of the PET cyclotron target, and this requires no more preparation time or staffing for one dose as it does for large numbers of doses. 2) Self-checking should be allowed for verification activities and documentation of in-process controls and QC of end-product, regardless of the size or scope of the PET chemistry operations. 3) The documentation requirements for material receiving and in-process controls are very labor intensive and have a negative economic impact on the operation of PET manufacturing practice without an impact on the safety of the patients receiving PET radiopharmaceuticals. Every batch of PET radiopharmaceuticals that is currently manufactured under USP guidelines is tested for pyrogenicity and sterility (sterility requires 2 weeks, so it cannot be done before release of the drug for use). Testing is also routinely done before injection for appropriate chemical purity, radiochemical purity, pH, bacterial filter integrity and other pertinent parameters. Since each and every injected PET drug is subjected to end-product testing, the requirements for material receiving and in-process control and documentation should be relaxed. Specifically, identity testing of active components is not necessary. Documentation of measurement of every aspect of the synthetic process, for example, temperature or pressure is not necessary. Documentation of quality control and maintenance of chemistry systems that control the functions of the process, such as temperature and pressure, also is not necessary. If there is a product and the product is systematically tested for chemical purity, radiochemical purity, etc., then there is not a need for the documentation of in-process parameters and quality control procedures for equipment that is currently CGMP for nonradioactive drugs. What remains critical is the establishment of the end-product quality control methods, the documentation of the quality control for the end-product QC equipment, and periodic review of the end-product QC documentation, QC methods, and equipment maintenance by a trained radiochemist. An abbreviated list of in-process controls should be established by a trained radiochemist appropriate to the synthesis procedure to ensure that operations were performed according to pre-established standard operating procedure (SOP). 4) Investigational PET radiopharmaceuticals should not be required to be manufactured under CGMPs, but should be manufactured under current USP guidelines which have the appropriate and necessary requirements to ensure safety to patients that receive these radiopharmaceuticals. The synthesis procedures for research radiopharmaceuticals are often being changed and optimized to increase radiochemical yield. It would be unduly restrictive to impose rigid SOPs on the manufacturing process of these radiopharmaceuticals. It would be impractical in light of the flexibility needed in the synthesis process to fix it at such an early stage in the development process and constantly have to receive approval of these changes from the FDA to continue operation under the IND. Again, the current practice of end-product QC of every batch of injected PET drug is the strongest guarantee of product safety. This is done for all batches of product.




EC -2