Inspections, Compliance, Enforcement, and Criminal Investigations

Innovative Compounding Pharmacy 6/20/16

  

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

Public Health Service
Food and Drug Administration
 San Francisco District
1431 Harbor Bay Parkway
Alameda, CA 94502-7070
Telephone (510) 337-6700 

 

UNITED PARCEL SERVICE
DELIVERY SIGNATURE REQUESTED
 
Ref No. 484658
WARNING LETTER
June 20, 2016
 
Masoud Rashidi, PharmD, Pharmacy Manager
Innovative Compounding Pharmacy, Inc.
820 Wales Drive, Suite 3
Folsom, CA 95630-5546
 
 
Dear Dr. Rashidi:
 
From April 13, 2015, to April 17, 2015, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Innovative Compounding Pharmacy, Inc., located at 820 Wales Drive, Suite 3, Folsom, CA. This inspection was conducted as a result of a complaint received regarding an adverse event reportedly experienced by a patient who received a domperidone product that was prepared by your firm. 
 
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.  The investigators also noted that your firm produces domperidone drug 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 investigators observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk. For example, our investigators observed an unidentified item on the ceiling of your firm’s ISO 5 laminar hood and operators with facial and neck exposure while working in the aseptic processing areas. In addition, your firm does not use sterile wipes, lint-free mop heads, or a sporicidal agent as part of the disinfection program to clean the ISO 5 hood and ISO 7 cleanroom where sterile drug products are prepared. Also, your facility does not regularly monitor pressure differentials between the ISO 7 cleanroom and the anteroom during operations. Furthermore, your firm failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection in the ISO 5 area in which sterile products are being produced. 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 April 17, 2015. FDA acknowledges receipt of your firm’s response to the Form FDA 483, dated May 1, 2015.
 
Based on this inspection, it appears that you are producing 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 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 quality for the exemptions under section 503A. 
 
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, and that you produce drug products containing domperidone.  Compounded drug products containing domperidone are not eligible for the exemptions provided by subsection (a) of 503A of the FDCA, because domperidone is not the subject of an applicable USP or NF monograph, is not a component of an FDA-approved human drug, and does not appear on a list of bulk drug substances that may be used for compounding developed by the Secretary.[1] 
 
Accordingly, the drugs you compound without valid prescriptions for individually-identified patients and any drug products you compound using domperidone are not entitled to the exemptions in section 503A.
 
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
 
The drug products that you manufacture and distribute without valid prescriptions for individually-identified patients and the domperidone products you manufacture are misbranded drugs in violation of section 502(f)(1) of the FDCA.
 
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. Furthermore, because you manufacture and distribute a portion of your drugs without valid prescriptions for individually-identified patients and manufacture drugs containing the bulk drug substance domperidone, 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. 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. 
 
Misbranded Drug Products
 
You compound products containing the bulk drug substance domperidone and 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, and they are not exempt from the requirements of section 502(f)(1) of the FDCA [see, e.g., 21 CFR § 201.115].  
 
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 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. For example, our investigators observed an unidentified item on the ceiling of your firm’s ISO 5 laminar hood, and operators with facial and neck exposure while working in the aseptic processing areas. In addition, your firm does not use sterile wipes, lint-free mop heads, or a sporicidal agent as part of the disinfection program to clean the ISO 5 hood and ISO 7 cleanroom where sterile drug products are prepared. Also, your facility does not regularly monitor pressure differentials between the ISO 7 cleanroom and the anteroom during operations. Furthermore, your firm failed to demonstrate through appropriate studies that your hoods are able to provide adequate protection in the ISO 5 area in which sterile products are being produced. Therefore, your products may be produced in an environment that poses a significant contamination risk. 
 
The FDA investigators also observed 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)). 
  1. Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room to produce aseptic conditions (21 CFR 211.42(c)(10)(v)). 
  1. Aseptic processing areas are deficient regarding the system for monitoring environmental conditions (21 CFR 211.42(c)(10)(iv)). 
  1. Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions (21 CFR 211.42(c)(10)(vi)). 
  1. Your firm failed to adequately design the facility with adequate separation or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(b)).  
  1. Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(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)).  
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
 
We have reviewed your firm’s planned corrective actions, as documented in your May 1, 2015 response to the Form FDA 483 of inspectional observations issued at the close of the inspection.  The corrective actions described in your response appear to be inadequate to correct the observed insanitary conditions and GMP violations at your facility. For example, your response did not address the use of non-sterile wipes and non-lint free mop heads used in the ISO 7 anteroom and ISO 5 laminar hood. In addition, your response failed to address the cause of the unidentified object found on the ceiling panel of your ISO 5 hood, and you did not describe the interim actions to be performed while the ceiling panel is replaced, or the steps to be taken after the installation. Your firm did not state whether the cleanroom certification and routine particle monitoring will be performed under dynamic conditions. Also, your response did not indicate that you have certified the pressure gauges used to perform the filter integrity bubble point tests for sterile drug products. The implementation and adequacy of your firm’s planned corrective actions will be verified during FDA’s next inspection.
 
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.
 
In your response, you also referenced your purported compliance with the United States Pharmacopeia (USP)-National Formulary (NF) General Chapter <797> Pharmaceutical Compounding--Sterile Preparations. As noted above your firm has manufactured and distributed drugs without valid prescriptions for individually-identified patients and drug products containing the bulk drug substance domperidone, and the manufacture of such drugs is subject to FDA’s finished drug product CGMP regulations, 21 CFR parts 210 and 211. 
 
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, 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 chosen to hire a contract testing laboratory to perform some of the required testing of your finished drug products.  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 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 the FDCA, 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 that your firm complies with all requirements of federal law, including 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 the reference number listed above and 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 you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the corrective action.  Your written notification should be addressed to:
 
Lawton W. Lum, Director of Compliance
FDA San Francisco District Office
U.S. Food and Drug Administration
1431 Harbor Bay Parkway
Alameda, CA 94502-7070
 
If you have questions regarding any issues in this letter, please contact Mr. Campbell via email at Russella.Campbell@fda.hhs.gov or by phone at 510-337-6861.
 
 
Sincerely,
/S/ 
Kathleen M. Lewis, J.D.
District Director
San Francisco District
 
 
 
cc:       
Virginia Herold, Executive Officer
California State Board of Pharmacy
1625 N Market Street
Sacramento, CA 95834


[1] Domperidone was nominated for inclusion on the list of bulk drug substances that can be used in compounding that must be developed through regulation pursuant to section 503A(b)(i)(A)(i)(III) of the FD&C Act (503A bulk drug substances list). On June 9, 2016, FDA issued a final guidance titled, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act. This guidance describes FDA’s regulatory policy for licensed pharmacists and licensed physicians that compound human drug products using bulk drug substances while the list is being developed. Specifically, the guidance states that until a substance has been considered and is identified in a final rule as being included or in the preamble of the final rule as not included on the 503A bulk drug substances list, FDA does not intend to take action against a licensed pharmacist or licensed physician for compounding a drug product from a bulk drug substance that is not the subject of an applicable USP or NF monograph or a component of an FDA-approved drug, provided that certain conditions are met, including that the substance appears on a list of substances that may be eligible for inclusion on the 503A bulk drug substances list, was nominated with sufficient supporting information for FDA to evaluate it, and has not been identified by FDA as a substance that appears to present safety concerns. Domperidone is not eligible for this policy because it appears on a list of substances that have been identified by FDA as presenting safety concerns. 
 
[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.

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