Inspections, Compliance, Enforcement, and Criminal Investigations

John W Hollis Inc 9/4/14

  

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 
New Orleans District
404 BNA Drive
Building 200 – Suite 500
Nashville, TN 37217
 
Telephone: (615) 366-7801
FAX:   (615) 366-7802 

 

September 4, 2014
WARNING LETTER NO. 2014-NOL-20
 
UNITED PARCEL SERVICE
Delivery Signature Requested
 
John W. Hollis, President and Owner
John W. Hollis Inc., dba John Hollis Pharmacy
110 20th Avenue North
Nashville, Tennessee 37203
 
Dear Mr. Hollis:
 
Between February 4 and March 21, 2014, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, John Hollis Pharmacy, located at 110 20th Avenue North, Nashville, Tennessee.  During the inspection, the investigators noted that you were not receiving valid prescriptions for individually-identified patients for a portion of the drug products you were producing. In addition, the investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk.  For example, our inspection found your facility was not physically designed and environmentally controlled to minimize airborne contamination, and the ISO 5 hood was located in an unclassified area. This area had no HEPA filters, no air pressure differentials, and the “sterile product compounding room” and the “ante room” were separated by plastic strips that provided no actual “room” separation. Your firm did not adequately monitor and control the microbial and particulate quality of the environment and personnel. Additionally, the flow and handling of materials that were placed in the ISO 5 hood posed an unacceptable contamination hazard. Operators loaded the materials on a tray in the ante-room with bare unsanitized hands and then they carried the tray to an unclassified room.  The outer surfaces of these materials were not disinfected prior to entry into the ISO 5 hood.  Furthermore, there was no hand washing prior to donning gloves or gowning, and the operators touched non-sterile surfaces and proceeded with aseptic manipulations without sanitizing their gloves.  A Form FDA 483 was issued to your firm on March 21, 2014.
 
Based on this inspection, it appears you are producing drugs that violate the Federal Food, Drug, and Cosmetic Act (FDCA).  
 
A. Compounded Drugs under the FDCA
 
Section 503A of the FDCA [21 United States Code (USC) 353a], describes the conditions under which certain compounded human drug products are entitled to exemption from three Sections of the FDCA: compliance with current good manufacturing practices (CGMP), Section 501(a)(2)(B) [21 USC 351(a)(2)(B)]; labeling with adequate directions for use, Section 502(f)(1) [21 USC 352(f)(1)]; and FDA approval prior to marketing, Section 505 [21 USC 355(a)]. Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under Section 503A of the FDCA.  
 
During our inspection, investigators observed that your firm does not receive valid prescriptions for individually-identified patients for a portion of the drug products you produce. Accordingly, the drugs you compound without valid prescriptions for individually-identified patients are not entitled to the exemptions in Section 503A of the FDCA.[1]
 
In addition, we remind you there are a number of other conditions that must be satisfied to qualify for the exemptions in Section 503A of the FDCA.[2]
 
B. Violations of the FDCA
 
Because the drug products that you manufactured and distributed without valid prescriptions for individually-identified patients are not the subject of approved applications, they are unapproved new drugs and misbranded drugs in violation of Sections 505(a) and 502(f)(1) of the FDCA, respectively. In addition, your sterile drug products are prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or whereby they may have been rendered injurious to health. As such, all sterile drug products you manufacture are adulterated within the meaning of Section 501(a)(2)(A) of the FDCA. Furthermore, because you manufactured and distributed drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs is also subject to FDA’s CGMP regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. FDA investigators observed significant CGMP violations at your facility, causing such drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the FDCA. 
 
Unapproved New Drug Products
 
You do not have any FDA approved applications on file for the drug products for which you have not obtained valid prescriptions for individually-identified patients.[3] Under Sections 505(a) and 301(d) of the FDCA [21 USC 331(d)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under Section 505 of the FDCA is in effect for the drug. Your marketing of these products, or other applicable products, without an approved application violates these provisions of the FDCA.
 
Misbranded Drug Products
 
Additionally, because the drug products for which you have not obtained valid prescriptions for individually-identified patients are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use these products safely for their intended uses.  Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under Section 502(f)(1) of the FDCA, and they are not exempt from the requirements of Section 502(f)(1) of the FDCA (see, e.g., 21 CFR 201.115).  The introduction or delivery for introduction into interstate commerce of these products therefore violates Section 301(a) of the FDCA [21 USC 331(a)]. It is also a prohibited act under Section 301(k) of the FDCA to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being misbranded.
 
Adulterated Drug Products
 
Additionally, FDA investigators noted that your sterile drug products 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, our investigators observed that your facility was not physically designed and environmentally controlled to minimize airborne contamination, and the ISO 5 hood was located in an unclassified area. This area had no HEPA filters, no air pressure differentials, and the “sterile product compounding room” and the “ante room” were separated by plastic strips that provided no actual “room” separation. Your firm did not adequately monitor and control the microbial and particulate quality of the environment and personnel. Additionally, the flow and handling of materials that were placed in the ISO 5 hood posed an unacceptable contamination hazard. Operators loaded the materials on a tray in the ante-room with bare unsanitized hands, and then they carried the tray to an unclassified room.  The outer surfaces of these materials were not disinfected prior to entry into the ISO 5 hood.  Furthermore, there was no hand washing prior to donning gloves or gowning, and the operators touched non-sterile surfaces and proceeded with aseptic manipulations without sanitizing their gloves.  FDA investigators also noted CGMP violations at your facility, causing the drug products for which you have not obtained valid prescriptions for individually-identified patients to be adulterated under Section 501(a)(2)(B) of the FDCA.  The violations include, for example:
 
1.    Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas [21 CFR 211.42(c)(10)(iii)].
 
2.    Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)].
 
3.    Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates [21 CFR 211.166(a)].
 
4.    Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes [21 CFR 211.113(b)].
 
5.    Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas [21 CFR 211.42(c)(10)(iv)].
 
6.    Your firm did not have, for each batch of drug product purporting to be sterile and/or pyrogen-free, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product [21 CFR 211.167(a)].
 
7.    Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination [21 CFR 211.28(a)].
 
Under Section 301(a) of the FDCA, the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under Section 301(k) of the FDCA to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce of the components used to make the drug and results in the drug being adulterated.
 
C. Corrective Actions
 
In your April 10, 2014, response to the Form FDA 483, Inspectional Observations, issued at the close of the inspection, you indicated you would no longer compound drugs for office use and would only fill prescriptions for individual patients. In addition, you stated that you intend to comply with United States Pharmacopeia (USP)-National Formulary (NF) General Chapter <797> Pharmaceutical Compounding--Sterile Preparations. As discussed above, your firm has manufactured and distributed drugs without valid prescriptions for individually-identified patients, and therefore, any continued manufacturing of such drugs would subject them to FDA’s drug CGMP regulations (21 CFR 210 and 211) as well as the new drug approval requirements in Section 505 of the FDCA and the requirement to label drugs with adequate directions for use in Section 502(f)(1) of the FDCA.  In addition, we found insanitary conditions at your firm in violation of Section 501(a)(2)(A). 
 
We acknowledge your action starting on May 13, 2014, to recall all aseptically filled sterile products within expiry and your verbal statement on May 14, 2014, during a teleconference with FDA officials, that you have ceased aseptic sterile operations.
 
If you decide to resume production of sterile drugs, FDA strongly recommends your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. You must correct all insanitary conditions at your firm before you resume operations. In addition, you should fully implement corrections that meet the minimum requirements of 21 CFR 211 in order to provide assurance that the drug products produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity.
 
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 FDCA, as amended by the Food and Drug Administration Safety and Innovation Act (Pub. L. 112-144, Title VII, Section 711). We note you have chosen to hire a contract testing laboratory to perform some of the required testing of your finished drug products. FDA (b)(4). 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. See 21 CFR 210.1(b) and 21 CFR 200.10(b).
 
In addition, you should correct the violations of FDCA Sections 501(a)(2)(A), 502(f)(1) and 505(a) noted above.
 
D. Conclusion
 
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 your firm complies with all requirements of federal law and FDA regulations.
 
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 15 working days of receipt of this letter, please notify this office in writing if you have taken any specific steps to correct violations.  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 the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be implemented.
 
Your written response should be sent to the U.S. Food and Drug Administration, Attention: Rebecca A. Asente, Compliance Officer, to the address above. If you have any questions regarding this letter, please contact Compliance Officer Asente via (504) 832-1290 extension 1104.
 
Sincerely,
/S/
Ruth P. Dixon
Acting District Director
New Orleans District
 
  
cc:  Tennessee Board of Pharmacy
        Tennessee Department of Health
        Health Related Boards
        665 Mainstream Drive
        Nashville, Tennessee 37243


[1]The Compounding Quality Act (CQA) contains a number of other provisions, including new exemptions and requirements for compounders seeking to operate as outsourcing facilities. A discussion of the CQA and the agency’s plans to implement the new law may be found at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/default.htm.
[2] For example, Section 503A also addresses anticipatory compounding, which includes compounding (not distribution) before receipt of a valid prescription order for an individual patient. We are not addressing anticipatory compounding here.
[3] The specific products made by your firm are drugs within the meaning of Section 201(g) [21 U.S. C. § 321(g)] of the FDCA because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they are “new drugs” within the meaning of Section 201(p) of the FDCA because they are not generally recognized as safe and effective for their labeled uses.

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