Inspections, Compliance, Enforcement, and Criminal Investigations

Martin Avenue Pharmacy, Inc. 3/18/15

  

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

Public Health Service
Food and Drug Administration
 Chicago District
550 West Jackson Blvd., 15th Floor
Chicago, Illinois 60661
Telephone: 312-353-5863 

 

March 18, 2015
WARNING LETTER
CHI-3-15
 
VIA UPS NEXT DAY
 
Thomas G. Marks, President
Martin Avenue Pharmacy
1247Rickert Drive
Naperville, IL 60540-1008
 
Dear Mr. Marks:
 
From June 30 to July 21, 2014, a U.S. Food and Drug Administration (FDA) investigator conducted an inspection of your facility, Martin Avenue Pharmacy, located at 1247 Rickert Drive, Naperville, Illinois. During the inspection, the investigator noted that you were not receiving valid prescriptions for individually-identified patients for a portion of the drug products you were producing.  The investigator also noted that your firm produces domperidone products.  Domperidone is not the subject of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, nor is it a component of an FDA-approved human drug product, and it does not appear on a list developed by the Secretary under section 503A(b)(1)(A)(i)(III) of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353a(b)(1)(A)(i)(III)].  In addition, the investigator observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, your firm used non-sterile (b)(4) for cleaning and material disinfection prior to introduction into the ISO 5 area, did not use a sporicidal agent to clean the ISO 5 and cleanroom areas, and conducted inadequate environmental monitoring. Furthermore, an operator was observed producing sterile drug product with poor aseptic technique by touching the interior of containers with non-sterile gloves and placing open vials in a reusable foam holder that can harbor microbial contamination. Our investigator also noted that your firm failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 area in which sterile products are processed. Therefore, your products may be produced in an environment that poses a significant contamination risk. FDA issued a Form FDA 483 to your firm on July 21, 2014. We acknowledge receipt of your firm’s response to the Form FDA 483, dated August 7, 2014. We also acknowledge your action on August 21, 2014, to recall all compounded sterile products within expiry and to cease production of compounded sterile preparations until further notice.   
 
Based on this inspection, it appears you have produced drugs that violate the 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 are entitled to exemption from three sections of the FDCA: compliance with current good manufacturing practices (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 for the exemptions under section 503A of the FDCA.  
 
During the FDA inspection, the investigator 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.  
 
The drug products you compound with domperidone, which is not the subject of an applicable USP or NF monograph, not a component of an FDA-approved human drug, and does not appear on a list developed by the secretary under section 503A(b)(1)(A)(i)(III) of the FDCA, are also not entitled to the exemptions in section 503A of the FDCA.[1]
 
In addition, we remind you that 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 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, respectively. Furthermore, the domperidone products you produce are also unapproved new drugs and misbranded drugs in violation of sections 505(a) and 502(f)(1) of the FDCA, 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 whereby they may have been 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 manufactured and distributed a portion of your drugs without valid prescriptions for individually-identified patients, the manufacture of those drugs is subject to FDA’s CGMP regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. The FDA investigator observed significant CGMP violations at your facility, causing your 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 or the domperidone products you produce.[3]  Under sections 505(a) and 301(d) of the FDCA [21 U.S.C. § 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 domperidone drug products and 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 U.S.C, § 331(a)]. It is also 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
 
Additionally, the FDA investigator 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, your firm used non-sterile (b)(4) for cleaning and material disinfection prior to introduction into the ISO 5 area, did not use a sporicidal agent to clean the ISO 5 and cleanroom areas, and conducted inadequate environmental monitoring. Furthermore, an operator was observed producing sterile drug product with poor aseptic technique by touching the interior of containers with non-sterile gloves and placing open vials in (b)(4) that can harbor microbial contamination. Our investigator also noted that your firm failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection of the ISO 5 area in which sterile products are processed. Therefore, your products may be produced in an environment that poses a significant contamination risk. 
 
The FDA investigator 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 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)].
 
2.    Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas [21 CFR 211.42(c)(10)(iv)].
 
3.    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)].
 
4.    You 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 contamination that would alter the safety, identity, strength, quality or purity of the drug product [21 CFR 211.67(a)].
 
5.    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)].
 
6.    Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups during the course of certain procedures [21 CFR 211.42(c)].
 
7.    Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination [21 CFR 211.28(a)].
 
8.    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)].
 
9.    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)].
 
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 and results in the drug being adulterated.
 
C. Corrective Actions
 
We acknowledge your action, starting on August 21, 2014, to recall all compounded sterile products within expiry and to cease production of compounded sterile preparations until further notice.  
We have reviewed your firm’s planned corrective actions, as documented in your August 7, 2014, response to the Form FDA-483 Inspectional Observations issued at the close of the inspection, and they do not meet the minimum requirements of 21 CFR 210 and 211 and are inadequate to correct the observed insanitary conditions at your facility. 
 
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 should correct all insanitary conditions at your firm before you resume operations. As discussed above, your firm has manufactured and distributed drug products without valid prescriptions for individually-identified patients, and the manufacture of such drug products is subject to FDA’s drug CGMP regulations, 21 CFR 210 and 211. Before resuming operations, you should fully implement corrections that meet the minimum requirements of 21 CFR Part 211 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. 
    
You should also correct the violations of FDCA sections 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.
 
If you decide to resume sterile operations, 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 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, 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. In addition to taking appropriate corrective actions, you should notify this office prior to resuming production of any sterile drugs in the future. 
 
Your response should be sent to: Carrie Ann Plucinski, Compliance Officer, Food and Drug Administration, 550 W. Jackson Blvd., 15th floor, Chicago, IL 60661. Refer to the Unique Identification Number (CMS Case # 447940) when replying. If you have any questions about the content of this letter, please contact Ms. Plucinski at 312-596-4224.
 
Sincerely,
/S/
Steven B. Barber
Acting District Director
 
 
cc:        Dr. Yashwant Amin
            Director of Drug Compliance
            Illinois Department of Financial and Professional Regulation
            9511 Harrison Street
            Des Plaines, IL 60017

[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 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 because they are not generally recognized as safe and effective for their labeled uses.

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