April 18, 2019 Edition
Sorry to be a week behind on this edition’s action edits which were posted to FOIA April 11. I love being busy, but with so much turmoil and uncertainty in our field I’ve never been busier!
Peoples Pharmacy, Inc. of Austin, TX was issued an FMD-145 Letter and an SBoP Referral Letter on 03/12/2019, both letters referring to the organization’s 483 from December 7 2017. Interestingly, both letters were signed not by Commander John Diehl, but by Rebecca Asente, whose new title is “Acting Director, Compliance Branch, Office of Pharmaceutical Quality Operations Division II.” That’s the first I’ve heard about that, so if anyone knows more, please fill me in.
WellRx LLC (DBA Home Rx LLC) of Wheaton, IL received an FMD-145 Letter and an SBoP Referral Letter on 04/03/2019, both in reference to the entity’s 483 from November 13 2017.
QuVa Pharma, Inc. (503B) of Temple, TX was issued its third 483 on 03/14/2019. Two CSOs were on site for what appears to have been 10 days, typed the entity as an “Outsourcing Facility,” and recorded 9 Observations, including:
- Written procedures are lacking which describe in sufficient detail the receipt, identification, approval, and rejection of components. (Specifics state that “You firm uses (b)(4) for adjusting the pH of sterile drug products. The (b)(4) is labeled, “NOT FOR DRUG, FOOD, OR HOUSEHOLD USE.”)
- There are no established written methods of cleaning or methods of processing to remove pyrogenic properties. (“Specifically, your firm has not validated the depyrogenation process for the (b)(4) used in compounding sterile drug products. Your firm has not demonstrated that the washing process you have implemented is adequate for endotoxin removal. Your firm had a confirmed endotoxin failure in January 2019 (Finished product let #10019623 of Heparin PF 0.25 U/mL (b)(4) of 0.5 NS-Bulk lot#(b)(4)”)
- Aseptic processing areas are deficient regarding the system for monitoring environmental conditions. (2 interesting specifics to read)
- The separate or defined areas and control systems necessary to prevent contamination or mix-ups are deficient. (Rust and residue on tote hinges used to move materials into filling areas, rust noted on wheels of trash cart in ISO 7 and the inside of the trash lid in the ISO 8 Ante Room)
- Production personnel were not practicing good sanitation and health habits. (Specifically, your firm does not have handwashing facilities near the gowning area for entry into compounding areas, including entry into ISO 7 Cleanrooms/ISO 5 (b)(4). In addition, your written procedures regarding gowning do not require hand washing.)
- Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that components, in-process materials, and drug products conform to appropriate standards of identity, strength, quality and purity. (“Specifically, your firm has not validated the incubation temperature and time for growth promotion of media and the environmental and personnel monitoring plates.”)
- Compounding drugs that are “Essentially Copies” of approved drugs. (Examples cited: Neostigmine methylsulfate 1 mg/ml, Glycopyrrolate 0.2 mg/ml, and Midazolam PF 1 mg/ml)
- Labeling that does not include information required by 503B(a)(10), including lack of “This is a compounded drug,” “Not for resale,” and if distributed without a valid prescription, “Office Use Only.”
- Containers that lack “www.fda.com/medwatch” and “1-800-FDA-1088.”
I was caught a bit off guard by such an extensive and fundamental set of Observations, because the last few QuVa 483s were fairly acceptable. The most recent 483 at their New Jersey establishment had only two Observations, one that dealt with cleaning and the other with Part 11. The most recent 483 at Sugar Land, TX had a single Observation that three technicians rested elbows inside the ISO 5 area. The previous 483 for this facility (Temple, TX) from April 2018 had just four Observations, and although they were somewhat more troubling (“The quality control unit lacks authority to fully investigate errors that have occurred.”), the flaws didn’t seem so fundamental as the nine above. It’s also unusual to see FDA assign two CSO resources to one inspection, so it will be interesting to follow going forward.
ACRX Specialty Pharmacy Inc of Las Vegas, NV was issued its first-ever 483 on 03/20/2019. A single Investigator was on site for 8 days, typed the establishment as a “Producer of Sterile and Non-Sterile Drug Products,” and recorded 9 Observations. The Observations were:
- Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established.
- Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.
- There is no written testing program designed to assess the stability characteristics of drug products.
- The distribution system is deficient in that each lot of drug product cannot be readily determined to facilitate its recall if necessary. Electronic records are used, but they do not meet requirements to ensure that they are trustworthy, reliable and generally equivalent to paper records. (*Note – I’ve tried to make a point of mentioning each time FDA has cited an organization for failure to comply with Part 11. The few times it’s been cited have been dominated by 503B ROFs, but this represents the rare citing of Part 11 against a 503A pharmacy.)
- Written procedures for cleaning and maintenance fail to include maintenance and cleaning schedules, description in sufficient detail of methods, equipment and materials used, description in sufficient detail ofthe methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance, instructions for protection of clean equipment from contamination prior to use and parameters relevant to the operation.
- Each batch of drug product purporting to be sterile and pyrogen-free is not laboratory tested to determine conformance to such requirements.
- Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the identity and strength of each active ingredient prior to release.
- Procedures describing the handling of all written and oral complaints regarding a drug product are not followed.
- Each batch of drug product required to be free of objectionable microorganisms is not tested through appropriate laboratory testing.
Front Door Pharmacy, LLC (DBA Pure Pharmacy) of Houston, TX was issued its first-ever 483 on 03/18/2019. A single Investigator was on site for 7 days, typed the entity as a “Producer of Sterile & Non-sterile Drug Products,” and recorded 11 Observations, including:
- Exposed skin in the Aseptic Processing Area;
- Inadequate Media Fills
- Inadequate changing/sanitization of gloves – “Personnel touched equipment or other surfaces outside the ISO 5 with gloved hands, then engaged in aseptic processing without changing or sanitizing gloves.”
- Inadequate disinfection of materials or supplies before entering Aseptic Processing Area
- Use of non-sterile disinfectants
- Inadequate validation of sporicidal agents used in cleanroom and ISO 5
- Facility design allows influx of poorer quality air into higher classified area (air returns adjacent to ceiling HEPAs, inadequate smoke studies)
- Laboratory test equipment used in the preparation and testing of collected samples are inadequate (incubator lacks controls for temperature and relative humidity)
- Inadequate segregation, cleaning of work surfaces, and cleaning of utensils to prevent cross-contamination (testosterone cream compounded in same environment as other non-sterile drugs without segregation, deactivation, and cleaning).
- ISO Class 5 areas not certified under dynamic conditions. (I keep hammering this again and again, but here is a quote from the specifics of this Observation – “Specifically, your firm’s clean room re-certification tests dated (b)(4) were documented as being performed under dynamic conditions. On 2/27/2019, the pharmacy contract clean room certifier was asked if he recertifies the clean room while pharmacy is performing media fills and/or compounding actual sterile drug products. He reported no, he simulates motion in the clean room compounding area and documents as being in a dynamic state. Pharmacist reported no media fills and/or drug compounding occurred during any of the clean room certifications.”)
- The ISO-classified areas have difficult to clean, particle-generating, or visibly dirty equipment or surfaces. “Specifically, during a walk-through on 2/25/2019, foreign particulate matter was observed in ISO 7 production area on top of (b)(4) which was not in service, adjacent to the ISO 5 Hood.”
Customceutical Compounding, LLC of Phoenix, AZ was issued its first-ever 483 on 03/08/2019. Two FDA Investigators were on site for an indeterminate number of days (maximum of 10), typed the entity as a “producer of sterile and non-sterile drugs,” and recorded 5 Observations. This entity produces intrathecal, possibly from non-sterile components. The Observations included:
- Inadequate procedures to prevent microbiological contamination (glove fingertips, media fills, smoke studies)
- Aspetic processing areas deficient
- Non-sterile clothing, exposed skin, tears in garb
- Inadequate cleaning and disinfection of room and equipment
- Inadequate containment and segregation to prevent contamination of non-sterile drug products (including soiled/damaged spoons, spatulas, mixing blades)
Buderer Drug Company of Avon, OH was issued its first-ever 483 on 02/14/2019. A single FDA CSO was on site for 4 days, typed the entity as a “Producer of Non-Sterile Drug Products,” and recorded a single Observation pertaining to non-pharmaceutical grade components used in formulation of non-sterile preparations.
Option Care Enterprises, Inc. (DBA Option Care of Little Rock, AR) was issued its first-ever 483 on 3/12/2019. A single FDA Investigator was on site for 5 days, typed the entity as a “Producer of Sterile Drug Products” and recorded 3 Observations:
- Materials or supplies were not disinfected prior to entering the aseptic processing areas
- Your facility design allowed the influx of poor quality air into a higher classified area, specifically doors to two qualified air zones were open simultaneously.
- Media fill simulations were not adequate.
John’s Pharmacy Inc. of Sullivan, IL was issued its second 483 on 02/22/2019. Its first 483 was issued on 1/10/2017 and led to a Referral Letter to the Missouri SBoP. No FMD-145 Letter was posted, although I would have expected one. For the new 483, a single FDA Investigator was on site for just 3 days, typed the pharmacy as a “Producer of non-sterile drugs,” and recorded just 2 Observations. The Observations were:
- Non-pharmaceutical grade component (the water used to compound)
- Inadequate containment and segregation to prevent contamination (spatulas, mortars/pestles, beakers, balance, and capsule filling machines.
2019 Warning Letters
A Warning Letter was issued on JANUARY 20, 2019 to the BioScrip Corporate Office in regard to a 483 that had been issued to Infusion Partners of Canfield, OH on January 26, 2018. Note that it took almost a full calendar year for FDA to decide that a WL was indicated and to issue it, then three more months to post it. The full calendar year speaks to the number of sign-offs and disciplines that participate in the decision to sort circumstances as Voluntary Action Indicated (VAI) versus Official Action Indicated (OAI).
BioScrip is the parent company of Infusion Partners of Canfield and is merging with Option Care, as mentioned in a recent newsletter. Home infusion is my background and I’m always keenly interested in FDA’s approach to this sector. FDA has published some very hard-hitting 483s to home infusion providers (Lincare Inc (DBA United Medical Home Infusion) — 483 – 8/22/2017; Inventive Infusion Solutions, LP – 483 – 8/31/2018; I.V. Specialty LTD’s 483; Walgreens Infusion (San Antonio) – 483 – 8/6/2015) but they have rarely progressed to Warning Letters. The italics below are the specifics cited in the newly-posted WL and, taken together, they serve to help pharmacy leaders understand what might get us a Warning Letter:
“The FDA investigators noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example,
- The design of the ISO 5 area does not appear adequate. The front work areas in your ISO 5 hoods are not directly under the HEPA filters and your smoke study did not demonstrate that these areas are protected by laminar air flow. Your operators were observed to perform aseptic processing in these areas.
- The HEPA filter guards in the ISO 5 hoods had visible white and rust-colored residue. The HEPA filter guards in the ISO 7 cleanroom had flaking paint and rust-color discoloration.
- Our investigators observed poor aseptic practices, including an operator frequently moving their entire upper body into the ISO 5 hood during aseptic processing, an operator moving rapidly in the vicinity of the ISO 5 areas, an operator failing to change or disinfect gloves after exiting and re-entering the ISO 5 area, and operators failing to disinfect items when moving them from the unclassified area to the ISO 7 cleanroom via the (b)(4).
- The (b)(4) between the ISO 7 cleanroom and an unclassified room allowed the influx of unclassified air into your cleanroom. In addition, the (b)(4) had un-sealable doors, exposed particle board, rust-like discoloration, and visible dust.
- Your firm produced beta-lactam drugs without providing adequate containment and segregation to prevent cross-contamination. Multiple penicillin and cephalosporin drug products were produced in the same positive pressure ISO 5 laminar airflow hoods that are used to produce other injectable drugs, and you did not have adequate procedures to clean potential spills.”