Inspections, Compliance, Enforcement, and Criminal Investigations

Physician Preferred Medical, LLC 1/20/16

  

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

Public Health Service
Food and Drug Administration
 Dallas District Office
4040 North Central Expressway
Suite 300
Dallas, Texas 75204-3128 

 

January 20, 2016
 
2016-DAL-WL-08
 
WARNING LETTER
 
Kenneth Ryan Orton, Owner
Physician Preferred Medical, LLC
dba PPM Pharmacy
3300 NW 56th Street, Suite 101
Oklahoma City, Oklahoma 73112
 
 
Dear Mr. Orton:
 
From February 3, 2015, to February 19, 2015, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Physician Preferred Medical, LLC, dba PPM Pharmacy, located at 3300 NW 56th Street, Suite 101, Oklahoma City, Oklahoma 73112. 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, the investigators observed that unfilteredHVAC air flows directly into the cleanroom. In addition, your firm uses non-sterile wipes and non-sterile disinfecting agents to clean the production areas and does not monitor pressure differentials throughout the day, especially during periods of production. Therefore, your products maybe produced in an environment that possesses a significant contamination risk.
 
FDA issued a FDA 483 to your firm on February 19, 2015. FDA acknowledges receipt of your firm’s response to the FDA 483, dated March 10, 2015.
 
Based on this inspection, it appears that 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 U.S.C. § 353a] describes the conditions under which certain compounded human drug products qualify for exemptions from three sections of the FDCA: compliance with current good manufacturing practice (CGMP), section 501(a)(2)(B) of the FDCA [21 U.S.C. § 351(a)(2)(B)]; labeling with adequate directions for use, section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)]; and FDA approval prior to marketing, section 505 of the FDCA [21 U.S.C. § 355]. Receipt of valid prescriptions for individually-identified patients is one of the conditions necessary to qualify for the exemptions under section 503A of the FDCA.
 
During the FDA inspection, the 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.[1] 
 
B. Violations of the FDCA
 
Because the drug products that you manufacture and distribute 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 [21 U.S.C. §§ 355(a) and 352(f)(1)], respectively.
 
In addition, drug products that are intended or expected to be sterile were prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth, or rendered injurious to health, causing them to be adulterated within the meaning of section 501(a)(2)(A) of the FDCA [21 U.S.C. § 351(a)(2)(A)]. Furthermore, because you manufacture and distribute your drugs without valid prescriptions for individually-identified patients, the manufacture of such 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 [21 U.S.C. § 351(a)(2)(B)]. 
 
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.[2] Under sections 301(d) and 505(a) of the FDCA [21 U.S.C. §§ 331(d) and 355(a)], 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 [21 U.S.C. § 355] 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
 
You compound drug products for which you have not obtained valid prescriptions for individually-identified patients that are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written 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 [21 U.S.C. § 352(f)(1)], 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 is a prohibited act under section 301(a) of the FDCA [21 U.S.C. § 331(a)]. 
It is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] 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 and results in the drug being misbranded.
 
Adulterated Drug Products
 
FDA investigators noted the drug products in your facility that were 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 [21 U.S.C. § 351(a)(2)(A)]. For example, the investigators observed that unfiltered HVAC air flows directly into the cleanroom. In addition, your firm uses non-sterile wipes and non-sterile disinfecting agents to clean the production areas and does not monitor pressure differentials throughout the day, especially during periods of production.     
 
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 [21 U.S.C. § 351(a)(2)(B)]. The violations include, for example:
  1. 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)).
  1. Your firm failed to have adequate exhaust systems or other systems adequate to control contaminants during production (21 CFR 211.46(c)).
  1. Your firm failed to clean and, where indicated by the nature of the drug, sterilize and process container closures to remove pyrogenic properties to assure they are suitable for their intended use (21 CFR 211.94(c)).
  1. 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)).
  1. Your firm does 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)).
  1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).  
  1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], 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 [21 U.S.C. § 331(k)] 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 and results in the drug being adulterated.
 
C. Corrective Actions
 
We have reviewed your firm’s planned corrective actions, as documented in your March 10, 2015, response to the FDA 483 that was issued at the close of the inspection. Although your proposed corrective actions appear to address the insanitary conditions noted in your facility, your response is deficient as it does not include sufficient information to fully evaluate the adequacy of the proposed corrective actions. For example, while you state you have (b)(4), you have not provided supporting documentation to allow FDA to evaluate the changes. You also stated that your (b)(4) was validated; however, you have not provided a completed validation report.
 
FDA strongly recommends that 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.
 
We note that during the inspection, you informed investigators that you planned to (b)(4).  However, as discussed above, the drug products your firm manufactures and distributes without a valid prescription for an individually-identified patient do not qualify for the exemptions under section 503A of the FDCA.  Should you continue to manufacture and distribute drug products without valid prescriptions for individually-identified patients, the manufacture of such drugs will be subject to FDA’s drug CGMP regulations (21 CFR Parts 210 and 211), among other requirements described above, and, before doing so, you should fully implement corrections that meet the minimum requirements of 21 CFR Part 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.
 
In addition to the issues discussed above, you should note that CGMP regulations require 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, as amended by the Food and Drug Administration Safety and Innovation Act (Pub.L. 112-144, Title VII, section 711).  We note that you have (b)(4) of your finished drug products.  If you (b)(4) 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 your compounded drug products are neither adulterated nor misbranded.  See 21 CFR 210.1(b), 21 CFR 200.10(b).
 
In addition, you should also correct the violations of sections 501(a)(2)(A), 502(f)(1), and 505 of the FDCA, noted above. Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether the drugs are compounded and distributed after receipt of a prescription for an identified individual patient.
 
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 that 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 fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken 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 that 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 completed. 
 
Your firm’s response to this letter should be sent to: Dallas District Office, ATTN: John W. Diehl, 4040 North Central Expressway, Suite 300, Dallas, Texas 75204. If you have any questions about the contents of this letter, please contact: John W. Diehl, Compliance Officer, at 214-253-5288.
 
Sincerely,
/S/                                                           
Reynaldo R. Rodriguez, Jr.
Dallas District Director 
 
CC:
 
John A. Foust, Pharm.D.
Executive Director
Oklahoma State Board of Pharmacy
2920 N Lincoln Blvd, Suite A
Oklahoma City, Oklahoma 73105
 


[1] The Compounding Quality Act (CQA) contains a number of other provisions, including 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]The specific products made by your firm are drugs within the meaning of section 201(g) of the Act, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases and/or because they are intended to affect the structure or any function of the body. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses. 

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