- Premier Pharmacy Labs, Inc.
8265 Commercial Way
Weeki Wachee, FL 34613
Food and Drug Administration
555 Winderley Place, Suite 200
Maitland, FL 32751
May 15, 2015
Re: Response to Premier Pharmacy Labs, Inc. Warning letter FLA-15-22
Dear Ms. Norris,
I am writing in response to the Warning Letter I received on April 28, 2015. The Warning Letter resulted from the FDA inspection of our facility conducted from April 10 to May 9, 2014. First, I wish to let you know that we take the Form 483 observations and the issuance of this Warning Letter very seriously and we are absolutely committed to complying with 503(b) compounding regulations. At the time of the audit, we were in the process of elevating our procedures and processes from what State Departments of Health had previously considered acceptable compounding practices to the newly legislated section 503B added to the Food Drug and Cosmetic Act just four months prior. We had utilized a third party consultant with experience in sterile processing and had taken a comprehensive assessment of our operation. The findings of our own gap assessment matched those findings later detailed in the Form 483, we were in the process of implementing quality improvements during the audit. We have invested significant time and resources in hiring quality personnel, training compounding staff, validating processes, calibrating equipment, and monitoring the facility and environment. We continually assess our quality system and continually improve our practices.
Thank you for this opportunity to respond to specific observations in the Warning letter. Regarding observations listed under Adulterated Drug Product listing:
1. We had been monitoring air pressure differentials from the ISO 7 areas and the ante room to the surrounding non-classified areas by reading calibrated magnehelic gauges daily. Please see Attachment 1 for a record of this monitoring. Daily reading has now been (b)(4) as well as at the start and finish of compounding a batch.
2. We are monitoring the fingertips of all sterile compounding technicians at the completion of each shift. Fingertips are (b)(4) both (b)(4) of each production run. (b)(4) to the (b)(4) and (b)(4) to (b)(4) any potential residual antimicrobials on the gloves. Growth promotion is performed on (b)(4) of media. TSA are incubated at (b)(4) and MEA are incubated at (b)(4). See Attachment 2 for Fingertip and Contact Plate Log. See Attachment 3 for EM SOP.
3. We are monitoring the surfaces of ISO 5 hoods with every shift. Hoods are sampled with (b)(4) and (b)(4) contact plates and treated as in response 2 outlined above. See Attachment 2 for contact plate log and Attachment 3 for EM SOP.
4. We are monitoring ISO 5 air hoods with (b)(4) and (b)(4) settling plates during compounding. Settling plates are (b)(4) during compounding in the hood, no compounding activity exceeds (b)(4). No plates are (b)(4) for longer than (b)(4). Plates are incubated as in Response #2. See Attachment 2 for log and Attachment 3 for SOP.
5. We have conducted smoke studies of our hoods and verified the flow is laminar. Video of the smoke studies are in Attachment 4 Smoke study (thumb drive).
6. We are actively sampling air in the ISO 5 hoods, ISO 7 Clean Room, and Gowning Area (b)(4) with a (b)(4) Air sampler. We are sampling (b)(4) of air at sites determined to be high risk, including all ISO 5 hoods, powder containment hoods, and areas of high activity. These air samples are taken in dynamic conditions, during periods of compounding activity. We are sampling with both (b)(4) and (b)(4) plates. Plates are incubated as outlined in Response 2. See Attachment 3 EM SOP for detail.
7. In addition to daily hood surface samples, we are taking surface samples of ISO 7 work surfaces on a (b)(4) basis. Surface samples include areas determined to be high risk, including frequently touched surfaces. These surfaces include equipment buttons, table tops, pass throughs and door knobs. See Attachment 3 EM SOP for detail.
8. Before an employee is allowed to enter the clean room, they must pass sterile gowning qualification. Qualification requires (b)(4) successful gowning events performed under supervision and sampled at conclusion of gowning with (b)(4) plates on finger tips, palm of hand, back of hand, elbow, inner sleeve, and chest zipper. Passing result requires no growth on all samples three times. Gowning requalification occurs (b)(4). See Attachment 5 for Gowning Protocol and Attachment 6 for a Gowning Validation Form.
9. Hoods are disinfected frequently with sterile (b)(4) IPA. At the end of every production day all hoods and surfaces are treated with a sporicidal disinfectant ((b)(4), or (b)(4)) according to use dilution and contact time. Please see Attachment 7 Cleaning Disinfection SOP
10. (b)(4) the clean rooms are treated to a (b)(4). This (b)(4) sterilization process has been validated by placing Biological Indicators in select locations. See Attachment SA and 8B for Disinfection Validations.
11. All (b)(4) and ovens have been mapped. Sterilization and depyrogenation of worse case loads have been confirmed by the use of Biological Indicators and (b)(4) spiked vials. See Attachment 9A and 9B for (b)(4) Validations. See Attachment l0A and l0B for Oven Validations.
12. Biological Indicators (Geobacil/us stearathermophilus) are placed in every oven and (b)(4) load. These are incubated at (b)(4) to confirm sterility of each batch. See Attachment 11A and 11B for (b)(4) Bl Logs.
13. We are dismayed to learn of the FDA's subpotent Multi-Trace 4 result from July 2013. Since June 2014 we have been following a CAPA SOP which requires investigations end in a true root cause and subsequent corrective and preventive actions are taken. See Attachment 12. In addition, we are retaining product in the event an investigation is required. See Attachment 13: "Quarantine Sheet"
14. Our Labels were updated in June 2014 and now include the statement "this is a compounded drug", adverse event reporting, active and inactive ingredients identified by established name and quantity or proportion of each ingredient. See Attachment 13 Quarantine Sheet for a checklist of information required on the label.
15. We have updated our product report to the FDA to include non-sterile drugs. See Attachment 14 for the updated lists (addendum on last page).
Regarding our corrective actions submitted May 29, 2014, we wish to take this opportunity to clarify some misunderstandings and detail additional improvements:
1. We sponsored a smoke study in May 2014. We regret the video did not accompany the 483 response. We have attached a copy of our most recent smoke study. We intend to repeat this study (b)(4). Please see attachment 4 (thumb drive).
2. As mentioned, we are monitoring clean room pressure differentials during compounding. We have recently increased the number of monitoring events. See Attachment 1.
3. Our SOP does include a map of sampling sites, please see Attachment 3.
4. We have decreased our action level to gloves and surfaces in ISO 5 hood to (b)(4). See Attachment 3.
5. Environmental monitoring trending analysis of the past several months show our compounding areas are in a state of control. We require that all excursions past Action Level are investigated to root cause, and product impact is assessed. See Attachment 15 for EM Monitoring results.
6. Environmental Monitoring site selection was based on risk analysis. Sites were based on high traffic, touch and product risk. These sites included the door knobs, tables and bins which are in the middle of the room. See Attachment 3 for Environmental Monitoring SOP and sample map.
7. We have retained the services of a consultant with expertise in sterile drug manufacturing. See Attachment 16 for his curriculum vitae.
8. We are in the process of validating endotoxin and sterility testing for finished products. Currently, no product is released for sterility unless previously validated by method suitability. We will have endotoxin validated by method suitability by May 20. We are working with our contract laboratories to validate potency testing.
Lastly, we would like to request that our responses be posted and available for public view along with the already posted 483 Observations and Warning Letter.
Vern Allen R. Ph.
Premier Pharmacy Labs Inc.