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RESPONSE LETTER

Avella of Deer Valley, Inc.


Company:
Avella of Deer Valley, Inc.

1606 W. Whispering Wind Dr.
Phoenix, AZ. 85085
main (623) 742-1700 fax (623) 742-1705

 

February 10, 2014


Blake Bevill, Director
Compliance Branch
U.S. Food and Drug Administration
19701 Fairchild Drive
Irvine, CA 92612


Re: Avella of Deer Valley, Inc. Response to Warning Letter #10-14


Dear Mr. Bevill,

From February 19-25, 2013, the FDA field office conducted an Inspection of our pharmacy ("Avella Pharmacy") located at 23620 N. 20th Drive, Suite 12, in Phoenix, Arizona ("Inspection"). At the conclusion of the Inspection, we received an FDA Form 483 listing seven (7) observations. We responded to the FDA Form 483 addressing all seven observations on March 7, 2013. We then subsequently received an FDA Warning Letter on January 21, 2014.

This letter responds to the FDA Warning Letter. We respectfully request that this response is included with Avella Pharmacy's Warning Letter any time FDA provides a copy of the Warning Letter to anyone outside the FDA.

The Warning letter identifies two main concerns with Avella Pharmacy's compounding practices: (i) the drugs Avella Pharmacy compounds for office use (i.e., without prescriptions for individually-identifiable patients) do not meet the section 503A exemption in the Food, Drug, and Cosmetic Act ("FDCA"); and (ii) Avella Pharmacy's aseptic processing operations do not meet identified standards. We address each of these issues in turn below.

Section 503A Exemption

The Warning letter states that drugs compounded "without valid prescriptions for individually-identifiable patients are not entitled to the exemptions in section 503A" of the FDCA, as amended by the recently enacted Compounding Quality Act. The Warning letter further states that FDA investigators observed that Avella Pharmacy "did not receive valid prescriptions for individually-identifiable patients for a portion of the drug products" it produced and "[b]ased on this factor alone, those drugs were not entitled to the statutory exemptions for compounded drugs described in section 503A of the FDCA, and did not qualify for the agency's exercise of enforcement discretion set forth" in Compliance Policy Guide 460.200. Therefore, according to the Warning Letter, Avella Pharmacy should be subjected to the FDA's Current Good Manufacturing Practice ("CGMP") because the drugs were "unapproved new drugs and misbranded drugs".

As we noted in our response to the FDA 483, Avella Pharmacy is a pharmacy licensed by the Arizona State Board of Pharmacy. Avella Pharmacy is not licensed as a manufacturer, and does not engage in drug manufacturing. Rather, Avella Pharmacy compounds medications pursuant to valid physician orders, and Avella Pharmacy's compounding practices comply fully with Arizona law.

Arizona pharmacy law permits office-use compounding. See Ariz. Admin. Code § R4-23-410(B)(3). The Compounding Quality Act does not supersede, or otherwise impact Arizona's ability to regulate and permit office-use compounding. To the contrary - when it passed the Compounding Quality Act Congress intended to reinforce section 503A of the FDCA while still permitting states to regulate office use of compounded drugs. This is clear from many statements on the Congressional Record, including the following statement from Senator Tom Coburn:

There has been a lot of concern that by reaffirming section 503(a) of the Food, Drug and Cosmetic Act, office-use of compounded drugs is not recognized as permissible compounding activity. Therefore, I want to make clear that this legislation does not change current state law or authority over the dispensing or distribution of medications by pharmacists, compounded or manufactured, for a prescriber's administration to or treatment of a patient within their practice. Currently, the compounding and dispensing of prescription drugs for in-office administration by a prescriber to their patient is governed by state Boards of Pharmacy and states have determined what is best for their state regarding office-use. In fact, more than 40 states that have passed laws over the last 15 years related to current practices of using compounded drugs in the office context. The issue of office-use, indeed all pharmacy practice regulation is best left to the States. So the omission of office-use from 503(a) should not signal to the FDA that it has the authority to encroach upon state authority to regulate office-use.1

Further, Senator Boozman submitted the following to the Congressional Record, again emphasizing that office-use compounding is regulated by the states, not FDA:

Office-use compounding and repackaging is acceptable under Arkansas law. Nothing in this law changes that. The omission of office-use from section 503(a) of the Food, Drug and Cosmetic Act should not signal to the FDA that it has the authority to encroach upon state authority to regulate office-use. This is not the intent of the law, and I will closely monitor FDA implementation as this process moves forward. If the state of Minnesota wants to prohibit drug repackaging and compounding - that's its decision. But again, this is by no means a green light for the FDA to usurp the rights of states. I want to make that crystal clear.2

Congress was "crystal clear" that it did not intend to regulate office-use compounding with the Compounding Quality Act. The intent of the Act was that office-use compounding continue to be regulated by the states. Arizona law permits such office-use compounding. Accordingly, Avella Pharmacy respectfully submits that its office-use compounding activities are permissible under the law.

Notwithstanding the foregoing statements of Congressional intent on the scope and purpose of the Compounding Quality Act, we recognize that the FDA is enforcing an opposing interpretation of the law. It now interprets section 503A of the FDCA as prohibiting office-use compounding. Consequently, Avella Pharmacy is taking steps to comply with this interpretation. We are actively moving toward registration as an outsourcing facility under the Compounding Quality Act. All non-patient specific orders will be compounded at this outsourcing facility, which will be registered and operated in accordance with FDA requirements. Also, per FDA's recommendation in the Warning Letter, Avella Pharmacy has hired an FDA consultant, (b)(4) to help in the engineering and design of the outsourcing facility's cleanroom. We expect this outsourcing facility to be operational no later than 10/1/14.

Once we have transitioned to the outsourcing facility model, orders compounded at our pharmacy will comply with the FDA's interpretation of the section 503A exemption and all other exemptions. That is, all drug products will be compounded for an identified individual patient based on receipt of a prescription order or expected receipt of such prescription order based on Avella Pharmacy's history of receiving valid prescription orders for the compounded drug product, as well as complying with all other requirements of the exemption.

Sterile Drug Products

The Warning Letter also states that "sterile drug products are prepared, packed, or held under insanitary conditions" making the sterile products adulterated. Please note that the FDA Inspection of Avella Pharmacy did not find that our pharmacy was unsanitary or filthy. The FDA 483 did not indicate that the aseptic processing area was unclean. Nevertheless, Avella Pharmacy continuously reviews opportunities for improvement, and therefore has implemented new policies and procedures since responding to the FDA 483 as part of this continuous improvement. We have implemented several new SOPs, retiring the SOPs mentioned in our FDA 483 response. These are discussed in more detail below.

Further, by 3/10/14, all technicians will use full body sterile garbing that will cover all exposed skin. Avella Pharmacy has purchased and is currently using the (b)(4) machine. This machine is run (b)(4) after routine cleaning and enhances the cleanliness of the aseptic environment by (b)(4) which mechanically lyses and kills bacteria and spores on contact. We also implemented SOP 03SEQ-18, (b)(4), on 11/14/13. Avella Pharmacy is currently implementing a (b)(4) procedure with the goal of providing a visual method of identifying problem areas and tracking our progress in correcting those problems.

In addition, on 1/28/14 we hired a microbiology laboratory technician who started work at Avella Pharmacy on 2/10/14. This position reports to the Director of Laboratory Services in the Quality Department and will help to develop a comprehensive environmental and personnel monitoring program that meets CGMP requirements. (See Attachment 1 for an organizational chart.) Specifically this position will perform (b)(4). The microbiology laboratory technician will be the Quality Assurance representative in the laboratory and will work with the aseptic pharmacists in monitoring the garbing and technique of the aseptic compounding technicians. The technician will also monitor the laboratory processes to be sure they are complying with our standard operating procedures and federal and state pharmacy law. We have attached the job description for this technician. (See Attachment 2.)

We have provided detailed updates of our responses to the FDA 483 Inspection observations below.

1. Observation 1:

a. Observation 1(a): Technicians were observed with exposed skin around the eyes and neck within the cleanroom environment.

Additional Corrective Action: By 3/10/14, all technicians will use full body sterile garbing that will cover all exposed skin including the eye and neck region. Avella Pharmacy's Quality Assurance team is currently evaluating samples of garb offered by different manufacturers. Once garb is selected, the staff will be trained on proper donning methods. In addition, state of the art automatic doors have been installed to allow easy hands-free entry into the cleanroom to reduce the chance of contaminating the gloves upon entry. Since responding to the FDA 483, we have also implemented SOP 03S-03, Personnel Hand Hygiene and Gowning.

Timeframe: The hands-free doors were installed on 4/30/13. All aseptic compounding technicians were trained on proper donning methods for garbing covering all exposed skin on 9/19/2013, 10/31/13, and 2/7/14. The full body sterile garbing will be donned by all aseptic compounding technicians by 3/10/14. SOP 03S-03, Personnel Hand Hygiene and Gowning, was implemented on 6/13/13 and revised on 2/7/14.

b. Observation 1(b)(l)&(ll): Operator observed donning sterile gloves In the anteroom area (ISO 7) prior to entry into the cleanroom and subsequent ISO 5 environment. Operator observed cleaning Interior hood surface while wearing sterile gloves.

Additional Corrective Action: Since responding to the FDA 483, we have implemented SOP 03S-02, Cleaning of the Aseptic Laboratory. A "pre-cleaning" of each (b)(4) cabinet by a trained and designated person continues to be performed at the "beginning" of each day to minimize the amount of interior surface cleaning performed by the operator prior to start of aseptic operations. In addition, (b)(4) machine is used to (b)(4) the cleanrooms prior to the beginning of the shift. The (b)(4) difficult to reach areas of the laboratory and kills bacteria, fungus, and spores on contact. Each operator continues to use sterile (b)(4) for spraying of sterile gloved hands and air-drying. All sterile compounding laboratory compounding staff have been trained on the revised procedure and training was documented. In addition, Avella Pharmacy installed state of the art automatic doors to allow easy hands-free entry into the cleanroom, as mentioned above.

Timeframe: SOP 03S-02, Cleaning of the Aseptic Laboratory, was implemented on 6/13/13. The hands-free doors were installed on 4/30/13 and the (b)(4) of the aseptic laboratory began on 12/3/13.

2. Observation 2:

a. Observation 2(a)(l)&(b)(i): Lack of routine viable air particulate monitoring (ISO 5 and ISO 7).

Additional Corrective Action: As noted in the FDA 483 response, the approved environmental monitoring company provided Avella Pharmacy with revised versions of the environmental test reports to indicate testing was performed under "dynamic conditions". Copies were provided to the FDA inspectors during the Inspection. All environmental test reports now include this language. Since responding to the FDA 483, we have implemented SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory, and SOP 03SEQ-22, Duo SAS Super 360. A SAS viable air impacter has been purchased and monitoring of the air in the clean room will be increased to (b)(4) once the microbiology laboratory technician is trained. This will allow Avella Pharmacy to quickly recognize when there are negative trends in the cleanroom and increase response time to the trends to reverse them.

Timeline: SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory, and SOP 03SEQ-22, (b)(4), were implemented on 6/13/13 and 12/20/13, respectively. The (b)(4) was purchased on 12/9/13 and received by Avella Pharmacy on 1/8/14. The microbiology laboratory technician was hired 1/28/14 and began work on 2/10/14. The (b)(4) viable air monitoring will commence once the microbiology laboratory technician is trained by approximately 3/15/14.

b. Observation 2(a)(ii)&(b)(ii): Use of (b)(4) for environmental monitoring.

Additional Corrective Action: (b)(4) are now used (b)(4) in the ISO Class 5 environment. A (b)(4) has been purchased and monitoring of the air in the cleanroom will be increased to (b)(4) once the microbiology laboratory technician is trained. This will allow Avella Pharmacy to quickly recognize when there are negative trends in the cleanroom and shorten response time for corrective action.

Timeline: SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory, and SOP 03SEQ-22, (b)(4) were implemented on 6/13/13 and 12/20/13, respectively. The (b)(4) was purchased on 12/9/13 and received by Avella Pharmacy on 1/8/14. The microbiology laboratory technician was hired 1/28/14 and began 'work on 2/10/14. The (b)(4) viable air monitoring will commence once the microbiology laboratory technician is trained by approximately 3/15/14.

c. Observation 2(c)&(d): Lack of active non-viable particulate air monitoring (ISO 5 and ISO 7).

Additional Corrective Action: A (b)(4) has been purchased. The (b)(4) will be used to increase monitoring of the environment in the cleanroom to aid in recognizing undesirable particle trends in the aseptic environment. Nonviable particle monitoring will be increased in the ISO Class 5 and Class 7 environments from (b)(4) to (b)(4) once the microbiology laboratory technician is trained. Since responding to the FDA 483, we implemented SOP 03SEQ-05, (b)(4). As discussed above, we also implemented SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory.

Timeline: The (b)(4) was purchased on 12/9/13 and was received on 2/4/14. The microbiology laboratory technician was hired 1/28/14 and began work on 2/10/14 (b)(4) monitoring of nonviable particles in the aseptic laboratory shall be performed once the microbiology laboratory technician is trained on the use of the machine by approximately 3/15/14. SOP 03SEQ-05, (b)(4), was implemented on 12/20/13 and SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory was Implemented on 6/13/13.

d. Observation 2(e): Lack of active monitoring of differential pressures.

Additional Corrective Action: Pressures are now monitored all day and recorded (b)(4) under dynamic operating conditions. As noted above, we also implemented SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory.

Timeline: SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory was implemented on 6/13/13. Avella Pharmacy has been monitoring pressures all day and recording pressures (b)(4) under dynamic operating conditions since 3/28/13.

e. Observation 2(f): Insufficient frequency of personnel monitoring.

Additional Corrective Action: Routine sampling of every laboratory technician began on a (b)(4) basis in February 2014. Personnel monitoring, including fingertip and sleeve sampling, will increase in frequency once the microbiology laboratory technician is trained. Further, since responding to the FDA 483, we implemented SOP 03S-04, Monitoring of Aseptic Personnel.

Timeline: The SOP was implemented on 6/13/13 and revised on 2/7/14. The microbiology laboratory technician was hired 1/28/14 and began work on 2/10/14. The additional monitoring of personnel and environment will begin once the microbiology laboratory technician is trained by 3/15/14.

f. Observation 2(g)&(h): Insufficient frequency of environmental monitoring of the ISO 5 and ISO 7 environment, surfaces.

Additional Corrective Action: As discussed above, we implemented SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory. Further, the frequency of the monitoring of the surfaces of the ISO 5 and ISO 7 environment and surfaces will be increased to (b)(4) once the microbiology laboratory technician is trained.

Timeline: SOP 03S-05, Environmental Monitoring of the Aseptic Laboratory, was implemented on 6/13/13 and revised on 2/7/14. The microbiology laboratory technician was hired 1/28/14 and began work on 2/10/14. The additional monitoring of personnel and environment will begin once the microbiology laboratory technician is trained by 3/15/14.

The corrective actions to Inspection observations 3 through 7 were completed and addressed in our FDA 483 response. All appropriate staff have been trained on the updated SOPs discussed above. We expect to further update our SOPs after consultation with FDA consultant (b)(4).

In addition to the corrective actions addressed in the FDA 483 response and discussed above in this response, we have made several other improvements to the current laboratory since responding to the FDA 483, as follows:

1. Sterile sleeves: Sterile sleeves were purchased for use in the aseptic laboratory. In September and October 2013, the aseptic laboratory staff were trained on the proper donning and use of sterile sleeves.

2. (b)(4) Contamination Control Floor Mats: In November 2013, Avella Pharmacy installed (b)(4) contamination control floor mats to reduce the bioburden in the cleanroom. (b)(4) contamination control floor mats eliminate foot and wheel borne particles, bacteria, and static prior the entry in the cleanroom.

3. Audits of testing labs: In October and November 2013, Linda Cappellini, RPh, Director of Laboratory Services, and Rex Swayne, Quality Assurance Manager, audited (b)(4), (b)(4), and (b)(4) to ensure that the laboratories Avella Pharmacy uses for sterility, potency, and endotoxin testing are following guidelines for the industry, including but not limited to USP 797.

4. (b)(4): In December 2013, Avella Pharmacy purchased and received the (b)(4) Staff was inserviced on the machine in the October 2013 annual compounder's meeting. Staff members Dustin Herring, Manager of Compounding Laboratory, (b)(6), and (b)(4), (b)(6), were trained on the use of the (b)(4) machine on 12/3/13. The staff started using the machine on 12/20/13, with the goal of reducing the microbial counts in the aseptic processing area. We implemented SOP 03SEQ-18, (b)(4), on 11/14/13.

5. Renovated ceiling in the cleanroom: The ceiling in the cleanroom was renovated on 12/14/13 to facilitate proper cleaning and to ensure all ceiling tiles were properly sealed.

6. New ducting: New ducting was installed on 12/15/13 to help modulate the cleanroom pressures more effectively.

Finally, as part of its commitment to obtain an outsourcing facility registration, Avella Pharmacy plans to construct a new cleanroom for the outsourcing facility. As we noted earlier in this letter, Avella Pharmacy has hired an FDA consultant, (b)(4), to help in the engineering and design of that cleanroom, per FDA's recommendation. The consultant will help identify and outline an action plan to comply with all CGMP requirements. Avella Pharmacy may also further revise its SOPs based on the consultant's recommendations. Avella Pharmacy has also created an Internal Sterile Compounding Committee to work with the consultant on the review of Avella Pharmacy's operations and to implement the consultant's recommendations. That Committee is made up of the following Avella Pharmacy employees:

• Linda Cappellini, RPh, Director of Laboratory Services (Committee Chair) (Note: This
  role is part of Quality Assurance- see the organizational chart in Attachment 1.)
• Rex Swayne, Quality Assurance Manager
• Dustin Herring, RPh, Manager of Compounding Laboratory, Deer Valley
• Chris Dinoffria, RPh, Pharmacist-in-Charge, Deer Valley
• Nathan Downhour, RPh, Executive Vice President Operations
• Jim Rehovsky, RPh, Vice-President, Ophthalmology

We hope that this letter demonstrates our long-standing and continued commitment to patient safety. Thank you for considering this response. If you should have any questions, please do not hesitate to contact me.

 

Sincerely,

/S/

John D. Musil, Pharm.D
Founder and Chairman

 


cc: Harland (Hal) Wand, Executive Director, Arizona State Board of Pharmacy
     Roger Morris, Quarles & Brady LLP
     Susan Trujillo, Quarles & Brady LLP

 

1 113 Cong. Rec. H.R. 3204 (daily ed. Nov. 18, 2013) (statement of Sen. Tom Coburn) (emphasis added).
2 113 Cong. Rec. H.R. 3204 (daily ed. Nov. 18, 2013) (statement of Sen. John Boozman) (emphasis added).