# Presentation: 690277

## FDA Approach to PET CGMP

- Brian Pendleton, J.D.
- May 21, 2002

## Summary

- Chronology
- Preliminary draft proposed rule overview
- Differences between 212 & 210/211
- Draft guidance overview
- Response to issues of PET community
- Other changes to preliminary draft regs
- Next steps

## Chronology for PET CGMP

- 1997:  FDAMA section 121
- February 1999:  public meeting on draft outline for PET CGMPs
- September 1999:  public meeting on preliminary draft regulations
- March 22, 2000:  public meeting
- April 1, 2002:  preliminary draft proposed rule (PDPR) and draft guidance

## CGMP Overview

- PDPR includes proposed regulations (draft) and preamble (explanation)
- Draft guidance provides details and recommendations on compliance

## Important Principles

- Designed to accommodate not-for-profit, academically oriented institutions as well as larger commercial producers
- Incorporates principles from USP General Chapter <823> on compounding of radiopharmaceuticals for PET

## Important Differences Between PET CGMP and Parts 210 & 211

- Fewer required personnel with fewer organizational restrictions
- Allowance for multiple operations (or storage) in same area
- Streamlined requirements for aseptic processing

## PET CGMP vs. 210/211 (cont.)

- Streamlined QC requirements for components
- Specialized QC requirements for PET drugs produced in multiple sub-batches
- Self-verification of significant steps in PET drug production

## PET CGMP vs. 210/211 (cont.)

- Same-person oversight of production, batch record review, and product release
- Simplified labeling requirements

## Draft Guidance

- Provides guidance on acceptable approaches to complying with proposed regulations
- Different recommendations on how to comply based on size, scope, and complexity of operations

## Guidance Overview (cont.)

- Recommendations on resources, controls, documentation, other aspects of CGMP
- Examples of methods and procedures that different types of PET centers can use to meet proposed regulations

## Response to Issues Raised by PET Community

- Several key issues regarding 1999 preliminary draft regulations (and one related to March 2000 *Federal Register* notice)
- FDA response posted on PET web site along with preliminary draft proposed rule and draft guidance

## Designation of PET Centers as “Manufacturers” or “Industry”

- Concern: most PET centers do not regard themselves as “manufacturers” due to location within institutions & production of drugs for in-house administration to patients
- PDPR and draft guidance refer to “PET drug producers” and “PET drug production”

## Not-for-Profit Institutions vs. Commercial Manufacturers

- FDAMA 121(c)(1)(B): “take due account of any relevant differences” between not-for-profit institutions and commercial manufacturers
- CGMP is related primarily to size, scope, and complexity of operations, rather than not-for-profit or for-profit status

## NFP vs. Commercial (cont.)

- Not-for-profit status does not appear to have significant bearing on quality of drugs administered to patients or on facilities & procedures needed to ensure quality
- Proposed regulations designed to be flexible enough for all types of PET centers
- Guidance offers different recommendations depending on size and scope of operations

## PET Drug Production vs. Practice of Pharmacy

- Addressed in draft guidance (pp. 4-5)
- FDA-regulated production ends at final release of finished product
- After receipt at facility for administration to patients, becomes practice of pharmacy and medicine subject to State & local law
- Distribution (to receiving facility) subject to CGMP but usually not focus of inspection

## Identity Testing

- Concern:  ID testing of all components
- Draft proposed rule:  ID testing only on each lot that yields an active pharmaceutical ingredient and each lot of inactive ingredient (testing of reagents and solvents not mandatory)
- If product marketed as finished drug intended for IV administration is used as inactive ingredient, ID test not required

## Identity Testing (cont.)

- Concern:  proposed conditions on using supplier COA in lieu of identity testing
- Draft proposed rule:  when use COA from reliable supplier, no need to perform ID test on each component lot or conduct visual ID of each lot of containers and closures

## Reserve Samples 

- Concern:  opposed to requirement to keep reserve sample from each batch for 30 days (sometimes patient may require entire batch)
- Draft proposed rule deletes reserve sample requirement

## Final Release Despite Equipment Failure

- Concern:  that release not be barred due to inability to complete a particular test
- Draft proposed rule:  seeks comment on whether to allow such release and, if so, what conditions are appropriate

## Process Validation

- Concern:  retrospective, repeated end-product testing should be sufficient for well-established PET drugs
- Draft proposed rule:  if PET center has history of producing particular drug, retrospective validation is adequate if no change in process and no process-related failures

## Other Changes to Preliminary Draft Regulations

- Replaced “theoretical yield” with “action limits on radiochemical yield” (in master production & control record)
- Clarified that for drug produced in sub-batches, only need to show that initial sub-batch that’s representative of entire batch conforms to specifications

## Other Changes (cont.)

- Deleted requirement to notify prescribing doctor of sterility test failure
- Deleted requirement specifying contents of drug product label

## Other Changes (cont.)

- Deleted requirement to confirm that prescriptions are reviewed to ensure they have been properly filled
- Reduced record retention requirement from 3 years to 1 year

## Next Steps

- Consider comments on PDPR from PET community
- Make appropriate revisions to draft regulations and issue proposed rule
- Review comments, revise as appropriate, and issue final rule

## Next Steps (cont.)

- Draft guidance:
- revise to reflect any changes to draft regulations and consider comments received
- issue new draft when proposed rule is published
- consider comments received
- issue final guidance