Inspections, Compliance, Enforcement, and Criminal Investigations

Ranier's Compounding Laboratory 3/28/17

 

  

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PHILADELPHIA DISTRICT
U.S. CUSTOMHOUSE
2ND AND CHESTNUT STREETS
ROOM 900
PHILADELPHIA, PA 19106
TELEPHONE: 215-597-4390 

 

CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
WARNING LETTER
17-PHI-08
 
March 28, 2017
 
Francis H. Ranier, Owner
Ranier’s Compounding Laboratory
1107 Lowry Avenue, Suite A
Jeannette, PA 15644-3030
 
Dear Mr. Ranier:
 
From April 18, 2016, to April 22, 2016, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, Ranier’s Compounding Laboratory, located at 1107 Lowry Avenue, Suite A, Jeannette, Pennsylvania 15644-3030. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353a] for exemption from certain provisions of the FDCA. Specifically, the investigator noted that you failed to meet the conditions of section 503A of the FDCA, and, in addition, the investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.  
 
FDA issued a Form FDA 483 to your firm on April 22, 2016. FDA acknowledges receipt of your facility’s response, dated May 4, 2016. FDA also acknowledges the statement in your response letter indicating that your facility “will cease the practice of compounding ‘for office use.’” Based on this inspection, it appears that you produced drug products that violate the FDCA.
 
A.    Compounded Drug Products Under the FDCA
 
Section 503A of the FDCA describes the conditions under which human drug products compounded by a licensed pharmacist in a State licensed pharmacy or a Federal facility, or a licensed physician, qualify for exemptions from three sections of the FDCA: compliance with current good manufacturing practices (CGMP) (section 501(a)(2)(B)); labeling with adequate directions for use (section 502(f)(1)); and FDA approval prior to marketing (section 505) [21 U.S.C. §§ 351(a)(2)(B), 352(f)(1) and 355(a)].[1] Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A. 
 
B.    Failure to Meet the Conditions of Section 503A
 
During the inspection, the FDA investigator noted that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigator noted that your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced.
 
Therefore, you compounded drug products (collectively the “ineligible drug products”) that do not meet the conditions of section 503A and are not eligible for the exemptions in that section from the FDA approval requirement of section 505 of the FDCA, the requirement under section 502(f)(1) of the FDCA that labeling bear adequate directions for use, and the requirement of compliance with CGMP under section 501(a)(2)(B) of the FDCA.
 
Specific violations are described below.        
 
C.    Violations of the FDCA
 
Adulterated Drug Products
 
The FDA investigator 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, the investigator observed that:
  1. Aseptic operators placed their ungloved hands into the ISO 5 hood to don sterile gloves and failed to sanitize their gloved hands after touching non-sterile components prior to beginning aseptic operations. Moreover, the operators placed components within the ISO 5 hood that had the potential to block the movement of first air to critical in-process operations.
  1. Non-sterile wipes were used in the ISO 5 hood and your firm placed sterile water into a non-sterile spray bottle and used this to clean equipment used in the production of drug products intended to be sterile. In addition, a non-sterile towel was placed on the work surface of the ISO 5 hood and materials and components were placed on this towel during aseptic processing.
  1. Your firm did not disinfect components and materials during transfer from the ISO 6 compounding room to the ISO 5 hood.
  1. Your sterilizing filters may not be adequate for the volume of drug products processed as we noted that, on at least one occasion, your firm used multiple filters to produce one lot of a sterile drug product and these filters were not rated for the volume produced. Furthermore, your firm does not always test the integrity of these filters after use.
  1. White residue was observed on the face panel of the HEPA filter supplying air to the ISO 5 area.
  1. In-house sterilized glassware and stir bars used in the aseptic preparation of drug products were stored in an unclassified area without any information to support that the components remained sterile throughout the storage period.
Furthermore, the manufacture of the ineligible drug products is subject to FDA’s CGMP regulations, Title 21, Code of Federal Regulations (CFR), parts 210 and 211. The FDA investigator observed significant CGMP violations at your facility, causing the ineligible drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA. The violations included, 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 establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)). 
  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 establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
  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)). 
  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)).  
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 any human or animal 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.
 
Misbranded Drug Products
 
The ineligible drug products you compounded are intended for conditions 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, and they are not exempt from the requirements of section 502(f)(1) of the FDCA (see, e.g., 21 CFR 201.115). Accordingly, these ineligible drug products are misbranded under section 502(f)(1) of the FDCA. 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 misbranded.
 
D.    Corrective Actions
 
We have reviewed your firm’s response to the Form FDA 483. We acknowledge your statement that your firm is “[c]easing the practice of compounding for ‘office use’ only for physicians.” 
 
We are unable to fully evaluate the following corrective actions due to a lack of adequate supporting documentation:
  1. Your response stated that you committed to instituting additional training on aseptic technique for your staff. However, you did not provide details on the aseptic training provided to your employees, especially in regards to your employees’ practice of placing their ungloved hands within the ISO 5 hood to don sterile gloves. 
  1. Your response stated that environmental surface sampling is performed (b)(4). However, it is not clear if surface sampling will continue to be performed after disinfection of the sample site. This practice could potentially bias the results received. 
  1. Your response stated that you use (b)(4) as your sporicidal agent to disinfect the aseptic processing areas. However, you did not provide supporting documentation for our review, such as the concentration of (b)(4) used and the contact time applied to ensure adequate levels of disinfection. 
  1. Your response stated that your firm has a handwritten policy for media fill simulations. However, you did not provide this policy for our review. Therefore, we remain concerned that your media fills do not closely simulate aseptic production operations, including worst-case activities. Specifically, your media fill does not utilize the same equipment, glassware, and container closure used by your firm and does not represent the largest volume of drug products that you aseptically produce. 
The following corrective actions appear inadequate:
  1. Your response did not commit to using sterile wipes within the ISO 5 hood and did not address our concern about the use of a non-sterile spray bottle to apply sterile water to equipment used during aseptic production. The use of non-sterile materials increases the potential for contamination to be introduced into the aseptic processing areas. 
  1. Your response did not indicate whether your firm will disinfect components and materials at each transfer step from areas of lower quality air to areas of higher quality. 
  1. Your response stated that you conduct (b)(4)-filtration integrity testing ((b)(4) testing) when indicated on the formula. However, filter integrity testing should be performed on each sterilizing filter, regardless of the formula worksheet, to ensure each filter remained integral throughout the process. This is of particular concern as it appears that the volume capacity of some of your sterilizing filters was exceeded during production. 
  1. Your response stated that the white residue on the face panel of the HEPA filter supplying air to the ISO 5 area was from your (b)(4) disinfectant. However, you provided no documentation to support this statement and we remain concerned as it is not clear if you have removed the residue or evaluated the impact of this residue on product quality.
For more information, we refer you to FDA’s draft guidance “Insanitary Conditions at Compounding Facilities.” http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM514666.pdf.
 
Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether drug products you compound meet the conditions of section 503A, including the condition on receipt of a prescription for an identified individual patient prior to compounding and distributing drug products. 
 
Should you continue to compound and distribute drug products that do not meet the conditions of section 503A, the compounding and distribution of such drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the drug CGMP regulations. Before doing so, you must comply with the requirements of section 505 and 502(f)(1) and fully implement corrections that meet the minimum requirements of the CGMP regulations. 
 
FDA strongly recommends that your management first undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, materials, and systems for the production of human and animal drugs.  In particular, this review should assess your aseptic processing operations.  A third party consultant with relevant sterile drug processing expertise could be useful in conducting this comprehensive evaluation.
 
E.     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 the 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 you cannot complete corrective action within 15 working days, state the reason for the delay and the time within which you will complete the correction. 
 
Your written notification should refer to the Warning Letter Number above, 17-PHI-08. Please address your reply to:
 
                                    Yvette I. Johnson
                                    US Customs House, Room 900
                                    200 Chestnut Street
                                    Philadelphia, PA 19106
 
If you have questions regarding the contents of this letter, please contact Ms. Johnson via email at Yvette.Johnson@fda.hhs.gov or by phone at (215)-717-3077. 
 
 
Sincerely,
/S/                                                            
Anne E. Johnson
District Director
Philadelphia District


 

______________________________


[1] We remind you that there are conditions other than those discussed in this letter that must be satisfied to qualify for the exemptions in section 503A of the FDCA.

 

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