D. Corrective Actions
We have reviewed your firm’s response to the Form FDA 483 dated March 26, 2016, and your response dated March 30, 2016. We acknowledge your recall of all sterile drug products within expiry initiated on May 13, 2016 due to a lack of sterility assurance, in response to an FDA Requested Recall letter issued on May 3, 2016. We also acknowledge that under the Final Order issued by the Board on July 1, 2016, your firm “may not engage in sterile compounding or dispensing any sterile drug products…for a minimum of two years from the effective date of this Final Order” and “may only dispense drugs on patient specific prescriptions...”
Regarding the insanitary conditions observations in the Form FDA 483, we cannot fully evaluate the adequacy of several corrective actions described in your responses because you did not include sufficient information or supporting documentation. For example, your firm has not provided documentation to show that a pressure gauge has been installed to monitor the pressure between the ISO 8 anteroom and the unclassified warehouse, as you indicated would occur in your response dated 3/30/16. Additionally, your response dated 3/26/16 states that certification of ISO 5 environments was performed under dynamic conditions. However, your response did not include any documentation to support this statement, or a detailed description of how dynamic conditions are simulated during performance of smoke studies.
You did not address certain observations related to insanitary conditions. For example, your responses did not propose any corrective action to the deficiency in the design of your facility, specifically, return air vents located next to HEPA filters in the ceiling of the ISO 7 cleanroom, rather than near the floor level. Additionally, according to your responses, your firm has not taken any corrective action to ensure that media fills are performed under the most challenging or stressful conditions.
Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether drug products you compound meet the conditions of section 503A.
Should you resume compounding and distributing drug products that do not meet the conditions of section 503A (e.g., the receipt of a prescription for an identified individual patient before a compounded drug product leaves the compounding facility), the compounding and distribution of such drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the drug CGMP regulations. Before doing so, you must comply with the requirements of section 505 and 502(f)(1) and fully implement corrections that meet the minimum requirements of the CGMP regulations.4
In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you introduce into interstate commerce are neither adulterated nor misbranded. [See21 CFR 210.1(b), 21 CFR 200.10(b)]. FDA strongly recommends that if you decide to resume production of sterile drugs following a successful petition to the Board after two years from the effective date of the Final Order, your management first undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance materials, and systems. In particular, this review should assess your aseptic processing operations. A third-party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.
The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.
If you decide to resume sterile operations following a successful petition to the Board after two years from the effective date of the Final Order, you should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction.
Within fifteen (15) working days of receipt of this letter, please notify this office in writing if you have taken any specific steps to correct the violations cited in this letter, or you may inform us that you do not intend to resume production of sterile drugs. If you intend to resume production of sterile drugs in the future following a successful petition to the Board after two years from the effective date of the Final Order, please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above violated the FDCA, include your reasoning and any supporting information for our consideration. In addition to taking appropriate corrective actions, you should notify this office fifteen (15) working days prior to resuming production of any sterile drugs in the future.
Your written notification should refer to the Warning Letter referencing CMS #522090. Please submit your written response to:
John W. Diehl
Director, Compliance Branch
U.S. Food and Drug Administration
Office of Pharmaceutical Quality Operations, Division 2
4040 North Central Expressway, Suite 300
Dallas, Texas 75204
If you have questions regarding the content of this letter, please contact Mr. Diehl at 214- 253-5288, or Rebecca Asente, Compliance Officer, at 504-846-6104.
Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division 2
Steven L. Russell
Larry D. Stephens, Co-Owner
Medaus, Inc. dba Medaus Pharmacy
6801 Cahaba Valley Road, Suite 116
Birmingham, Alabama 35242-9609
Larry D. Stephens
Susan Alverson, Executive Secretary
111 Village Street
Birmingham, Alabama 35242