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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Village Fertility Pharmacy, Inc. 2/28/14

  

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

Public Health Service
Food and Drug Administration
 New England District Office
One Montvale Avenue, 4th floor
Stoneham, MA 02180
Phone 781.587.7500
Fax 781.587.7556 
 
 
  
 
WARNING LETTER
CMS# 398380
 
 
VIA UPS OVERNIGHT
 
February 28, 2014
 
Mr. Stuart P. Levine
Village Fertility Pharmacy, Inc.
335 Bear Hill Road
Waltham, MA 02451
 
 
Dear Mr. Levine:
 
Between February 21, 2013, and March 13, 2013, U.S. Food and Drug Administration (FDA) investigators conducted an inspection of your facility, Village Fertility Pharmacy, Inc., [1] located at 335 Bear Hill Road, Waltham, MA.  During the inspection, the investigators noted that your firm produces injectable drug products in various concentrations in aqueous and oil bases, including Hydroxyprogesterone Caproate, Progesterone, and Leuprolide Acetate.  The investigators observed insanitary conditions for producing sterile drug products, which put patients at risk. For example, your firm used (b)(4) that were not for pharmaceutical use to sterilize injectable drug products, and the gloves worn by personnel who perform aseptic processing are not monitored for contamination. 
 
In addition, investigators visually inspected vials of Progesterone in Ethyl Oleate Injectable and Progesterone in Sesame Oil Injectable and observed that they contained dark visible and white/translucent particulates, respectively.  These observations and others were noted on a FDA Form 483 issued on March 13, 2013.  Furthermore, FDA laboratory analysis detected the presence of foreign and particulate matter in vials of your compounded Hydroxyprogesterone Caproate Injectable, Progesterone in Ethyl Oleate Injectable, and Progesterone in Sesame Oil Injectable, which were collected during the inspection. 
 
A.  Violations of the FDCA
 
Adulteration Charges
 
Under section 501(a)(2)(A) of the FDCA [21 U.S.C. § 351(a)(2)(A)], a drug is adulterated if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth or rendered injurious to health. Numerous subvisible microorganisms and other contaminants are ubiquitous in an ordinary environment. A firm producing sterile drugs must take certain steps in order to ensure removal of contaminants through various controls that focus on safeguarding drug sterility by assuring the quality of the processing environment (e.g., surfaces, personnel, air) and the materials that go into a drug product. Otherwise, drugs that are intended or expected to be sterile may become contaminated during preparation and, when administered to a patient, may result in infections and/or pyrogenic responses that pose a life-threatening health risk to a patient. Failure to take these steps when producing drugs that are intended or expected to be sterile causes the drugs to be prepared, packed, or held under insanitary conditions.
 
FDA investigators noted that drug products intended or expected to be sterile that were produced by your firm were prepared, packed, or held without taking necessary steps to ensure removal of contaminants present in the ordinary environment. Therefore, all of your 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 [21 U.S.C. § 351(a)(2)(A)]. Examples of the insanitary conditions observed at your firm include:
 
1) You filled your oil-based products using non-sterile equipment (use of squeeze bottles) into container-closure systems that were not depyrogenated (a process needed to remove or reduce pyrogens. Pyrogens can result in a serious and sometimes deadly immune response including fever, hypotension, and/or shock in a patient.). 
 
2) The (b)(4) intended to sterilize drug products were not suitable for pharmaceutical production and not properly tested for (b)(4). The (b)(4) used by your firm clearly stated that it was not for (b)(4). Furthermore, your firm did not perform (b)(4) on the (b)(4) to show that they were (b)(4) (that is, to ensure that the (b)(4) would prevent the drug products from becoming contaminated). 
 
3) Your firm does not perform fingertip sampling and gowning assessments as part of either an initial competency evaluation or a routine monitoring program to assess the aseptic practices of compounding personnel. 
 
4) Your firm does not perform environmental monitoring (viable airborne particle testing or nonviable particulate monitoring) under routine operational conditions to evaluate the suitability of the “ISO 5” environment for the production of sterile drug products. 
 
Each of these production processes described in items 1 to 4 above do not ensure removal of contaminants and, when producing drugs that are intended or expected to be sterile, result in drug products that may have become contaminated with filth or rendered injurious to health.
 
Also, FDA laboratory analysis confirmed the presence of foreign and particulate matter in vials of several drug products produced by your firm and collected during the inspection – Hydroxyprogesterone Caproate Injectable, Progesterone in Ethyl Oleate Injectable, and Progesterone in Sesame Oil Injectable. Therefore, these drug products are adulterated within the meaning of section 501(b) of the Act [21 U.S.C. § 351(b)], in that the products did not meet USP compendia standards for quality and purity for Foreign and Particulate Matter set forth in the USP General Chapter <1> for Injections.
 
Furthermore, during the inspection, investigators reviewed reports of certain analytical testing performed by your contract laboratory. CPD-Leuprolide Acetate, lots number K2312-20 and K2312-13, which were produced by your firm and dispensed prior to testing by your contract laboratory, were found by your contact laboratory to be super-potent at 78.72 mcg/0.1ml (196.8% of the label claim) and 99.472mcg/0.1ml (198.9% of the label claim), respectively. Therefore, these drug products produced by your firm are adulterated within the meaning of section 501(c) of the Act [21 U.S.C. § 351(c)], in that each product’s strength differs from the strength stated on the label. 
 
Misbranded Drug Products
 
Additionally, the drug products compounded by your firm were misbranded within the meaning of Section 502(a) of the Act [21 U.S.C. § 352(a)] because their labeling was false or misleading. Hydroxyprogesterone Caproate Injectable, Progesterone in Ethyl Oleate Injectable, and Progesterone in Sesame Oil Injectable drug products are labeled for injection and must meet the compendial standards for injectable products. As discussed above, product samples indicate that Hydroxyprogesterone Caproate Injectable, Progesterone in Ethyl Oleate Injectable, and Progesterone in Sesame Oil Injectable drug products were contaminated with visible particulates. Therefore, the contaminated drug products bearing this labeling for injection are misbranded under Section 502(a) of the Act [21 U.S.C. § 352(a)] because the labeled directions for administration misleadingly implied the products were essentially free of visible particulates. 
 
Furthermore, the super-potent CPD-Leuprolide Acetate product discussed above is also misbranded under Section 502(a) of the Act [21 U.S.C. § 352(a)].
 
B.  Corrective Actions
 
We acknowledge your action on February 24, 2013, to recall all sterile products within expiry. We also understand that you were under a Cease and Desist and Quarantine Notice issued by the Commonwealth of Massachusetts Board of Registration in Pharmacy. On August 20, 2014, you entered into a Consent Agreement for Probation with the Commonwealth of Massachusetts.  We recognize that, pursuant to your Consent Agreement, you will not produce medium- or high-risk sterile drug products unless and until you receive approval from the Massachusetts Board of Registration in Pharmacy. In addition, we acknowledge that you indicated at the close of the inspection that you do not plan to produce sterile products from non-sterile Active Pharmaceutical Ingredients. 
 
FDA strongly recommends that you 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 and the root causes of your firm’s excessive assay specification failures. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation.
 
C.  Conclusion
 
Please note that 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 assure that your firm complies with all requirements of federal law and FDA regulations.
 
Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction. FDA may re-inspect to verify corrective actions have been completed.
 
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 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. 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 fifteen working days, state the reason for the delay and the time within which you will complete the correction.  
 
In addition to taking appropriate corrective actions, you should notify this office prior to resuming production of any medium- or high-risk sterile drugs in the future. Your notification should be addressed to:
 
Todd Maushart, Compliance Officer
FDA New England District 
U.S. Food and Drug Administration
One Montvale Avenue, 4th Floor
Stoneham, MA 02180
 
If you have questions regarding any issues in this letter, please contact our office at 781-587-7578.
 
 
Sincerely,
/S/ 
Miguel Hernandez
Acting District Director
New England District
Food and Drug Administration
                                               
cc: 
 
Madeleine Biondolillo, MD
Associate Commissioner, MA Department of Public Health
Director, Healthcare Safety and Quality
99 Chauncy Street
Boston, MA 02111


[1] Although sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FDCA or the Act) provide exemptions from certain provisions of the Act when certain conditions are met, the exemptions do not extend to the FDCA provisions that are discussed in this letter [21 U.S.C. §§ 353a, 353b]. As a result, this letter does not address whether your firm’s operations meet the conditions set forth in section 503A or section 503B of the Act.