Inspections, Compliance, Enforcement, and Criminal Investigations

Montana Compounding Pharmacy 12/11/15

  

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

Public Health Service
Food and Drug Administration
 
Seattle District
Pacific Region
22215 26th Avenue SE, Suite 210
Bothell, WA 98021
 
Telephone:      425-302-0340
FAX:               425-302-0402 

 

December 11, 2015
 
OVERNIGHT DELIVERY
SIGNATURE REQUIRED


In reply refer to Warning Letter SEA 16-05

Roy G. Calcagno, R.Ph., Owner
Montana Compounding Pharmacy P.C.
dba Montana Compounding Pharmacy and Wellness Center
111 N. Higgins Avenue
Missoula, Montana 59802-4494
 
WARNING LETTER

Dear Mr. Calcagno:
 
From April 28, 2015, to May 8, 2015, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Montana Compounding Pharmacy P.C. dba Montana Compounding Pharmacy and Wellness Center, located at 111 N. Higgins Avenue, Missoula, Montana. 
 
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 investigators noted that your facility was not adequately designed for sterile drug production. The general pharmacy area adjacent to your cleanroom was noted to be carpeted, including a section of carpet immediately outside the cleanroom entrance. The investigators observed a portable fence and pet bed and your co-owner stated that, at times, her dogs are brought to the facility. In addition, our investigators noted that non-sterile, non-pharmaceutical grade components, including (b)(4) obtained from a top loaded bottled water dispenser and (b)(4), were used in the production of drug products intended to be sterile. Moreover, your firm has never performed environmental monitoring in your facility and did not use a sporicidal agent or sterile wipes as part of the disinfection program for the aseptic processing area. Our investigators also noted that you used non-sterile gloves during aseptic production. Furthermore, your firm failed to demonstrate through appropriate studies that your hood is able to provide adequate protection of the ISO 5 area in which sterile products are processed.
 
FDA investigators collected environmental samples of multiple locations in your facility, including the aseptic processing area, and collected additional samples including wipes used to disinfect the aseptic work surface, (b)(4) used in sterile production, and (b)(4) septum covers utilized as container closures on vials of finished product intended to be sterile. Testing results of the samples identified microbial contamination, including spore-forming bacteria and mold. 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 May 8, 2015. FDA acknowledges your letter dated May 14, 2015, and response to the Form FDA 483 dated May 27, 2015. Based on this inspection, it appears that you have produced 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 are entitled to 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 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 of the FDCA.
 
In addition, we remind you there are a number of other conditions which must be satisfied to qualify for the exemptions in section 503A of the FDCA.[1]
 
B. Violations of the FDCA
 
The drug products that you manufacture and distribute without valid prescriptions for individually-identified patients 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 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 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. FDA investigators 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. 
 
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, 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 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, FDA investigators noted that drug products 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, FDA investigators noted that:
 
1.    Your facility was not adequately designed for sterile drug production. The general pharmacy area adjacent to your cleanroom was noted to be carpeted, including a section of carpet immediately outside the cleanroom entrance. The investigators observed a portable fence and pet bed and your co-owner stated that, at times, her dogs are brought to the facility. FDA environmental sample results from your laminar flow hood identified microbial contamination, including spore-forming bacteria and mold.
 
2.    Your firm used non-sterile, non-pharmaceutical grade components, including (b)(4) obtained from a top loaded bottled water dispenser and (b)(4), in the production of drug products intended to be sterile. Your firm had no data to indicate that these components were suitable for use in sterile drug production. FDA sample results of the (b)(4) identified microbial growth, including gram-negative bacteria. Gram-negative bacteria can produce additional bioburden, including bacterial endotoxin, which would not be removed by your (b)(4) used during aseptic production. Therefore, significant amounts of bacterial endotoxin could transfer into the finished injectable drug product, which poses a serious health risk to patients.
 
3.    Your firm had never performed environmental monitoring of your facility, including the ISO 5, ISO 7, and ISO 8 areas. In addition, your firm did not have adequate controls in place to ensure that the lower quality air from the unclassified areas was not introduced into the cleanroom where aseptic production occurred. For example, an air vent led out of the ISO 7 cleanroom into the unclassified general pharmacy area without additional controls to prevent the introduction of microbes and particulates into this area. 
 
4.    Your firm did not use a sporicidal agent or sterile wipes as part of the disinfection program to disinfect the work surface where aseptic processing occurred. FDA environmental sample results identified spore-forming bacteria at several locations within your aseptic processing area. Moreover, FDA sample results identified microbial growth on the wipes you sprayed with sterile (b)(4) and used to disinfect the work surface where aseptic processing occurred.
 
5.    You wore non-sterile gloves during aseptic production. In addition, FDA environmental sample results identified microbial growth on your mask and sleeve covers, which were observed to be introduced into the aseptic processing area.
 
6.    Your firm failed to demonstrate through appropriate studies that your hood is 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 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 maintain the buildings used in the manufacture, processing, packing, or holding of a drug product in a clean and sanitary condition (21 CFR 211.56(a)).

2.    Your firm failed to test samples of each component for conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(2)) and your firm failed to subject each lot of a component with potential for microbiological contamination that is objectionable in view of its intended use to microbiological tests before use (21 CFR 211.84(d)(6)).

3.    Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
 
4.    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)).
 
5.    Your firm failed to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination (21 CFR 211.28(a)).

6.    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)).

7.    Your firm failed to establish time limits, when appropriate, for the completion of each phase of production to assure the quality of the drug product (21 CFR 211.111).

8.    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)).   
 
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 taken in May 2015, to voluntarily recall all sterile drug products, and your letters dated May 14, 2015, and May 27, 2015, in which you state your firm’s decision to discontinue compounding sterile drug products as of May 13, 2015. Your May 27, 2015, letter indicated that you have no plans to resume compounding sterile products in the future. 
 
If you decide to resume production of sterile drugs, FDA strongly recommends that your management 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. Furthermore, should you continue to distribute drug products without valid prescriptions for individually-identified patients, the manufacture of such drugs would 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, and purity.
 
In addition, you should correct the violations of section 502(f)(1) 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 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 fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken 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 that 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 written notification should be addressed to:
 
Jessica L. Kocian, Compliance Officer
FDA Seattle District Office
U.S. Food and Drug Administration
22215 26th Avenue SE, Suite 210
Bothell, WA 98021
 
If you have questions regarding any issues in this letter, please contact Ms. Kocian at 425-302-0444.
 
Sincerely,
/S/ 
Miriam R. Burbach
District Director

[1]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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