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  5. Cytophil, Inc. - 04/01/2014
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Cytophil, Inc.

Cytophil, Inc.

United States

Issuing Office:
Minneapolis District Office

United States


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

Public Health Service
Food and Drug Administration
Minneapolis District Office
Central Region
250 Marquette Avenue, Suite 600
Minneapolis, MN 55401
Telephone: (612) 334-4100
FAX: (612) 334-4142


April 1, 2014
Via UPS Overnight Delivery                                 
Refer to MIN 14 – 13
William G. Hubbard
Cytophil, Inc.
2485 Corporate Circle, Suite 2
East Troy, Wisconsin  53120

Dear Mr. Hubbard:
During an inspection of your firm located in East Troy, Wisconsin, on January 27 through February 13, 2014, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures synthetic bone graft material, bone void fillers, and an intranasal splint. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body.
This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System regulation found at Title 21, Code of Federal Regulations (21 CFR), Part 820.  We received your response dated March 6, 2014, concerning our investigator’s observations noted on the Form FDA-483 (FDA 483), List of Inspectional Observations, which was issued to your firm.  We address your response to the noted violations below.  These violations include, but are not limited to, the following:
1.    Failure to adequately establish procedures to control environmental conditions, as required by 21 CFR 820.70(c). 
a.    Your firm failed to investigate clean room environmental monitoring results that reached the alert or action limits as required by your procedures:
  • “Air Particle Monitoring,” Doc # CR 02-001, Revision 08, Effective 3/4/2013;
  • “Air Microbial Monitoring,” Doc # CR 02-002, Revision 07, Effective 3/4/2013;
  • “Contact Microbial Monitoring,” Doc # CR 02-005, Revision 05, Effective 3/4/2013.
The procedures require QA and/or Executive Management notification if results are above the limits and an investigation must be conducted. When the action limit is reached, a start-up cleaning procedure must be performed and re-testing completed prior to production resuming.
The following results were observed to have reached the action or alert limits. An investigation was not performed; nor was the start-up cleaning procedure and re-testing completed prior to production activities resuming when the action limits were reached.
  • Air Particle:  (b)(4) out-of-specification result for alert limits reached 1/10/2014 for (b)(4) testing;
  • Air Microbial:  (b)(4) out-of-specification result for bacteria action limits reached 1/16/2014; one out-of-specification result for bacteria alert limits reached 12/23/2013;
  • Contact Microbial:  (b)(4) out-of-specification results for bacteria alert limits reached 11/18/2013 and 12/23/2013.
b.    Your firm failed to establish parameters for monitoring room temperature and humidity in your clean room. Your procedure “Temperature and Humidity Monitoring,” CR 02-003, Revision 03, lacks acceptance criteria to ensure the clean room is operating in a controlled environment.
c.    Your firm failed to establish alert limits and action limits for air particle, air microbial and contact microbial testing performed in the “Gowning Room.” The Gowning Room is part of your firm’s clean room environment.
2.    Failure to adequately validate a process whose results cannot be fully verified by subsequent inspection and test according to established procedures, as required by 21 CFR 820.75(a).
Specifically, your firm failed to validate the sterilization process to ensure the following parameters were included, per the ISO 11137 standard, which you referenced as following in the validation plan “(b)(4) Validation Plan for the Bone Void Filler” approved 4/19/2010.
  • Dose mapping was not performed;
  • (b)(4) production units were not submitted for dosing at (b)(4) to substantiate the minimum sterilization dose of (b)(4);
  • Product was not submitted for testing in August 2010 to maintain assurance that a change in product bioburden did not occur as required by the standard.
     Your firm lacks the following specifications for your sterilization process as required by the standard:
  • The description of packaged product, including dimensions, density and orientation of product within the package and acceptable variations;
  • The loading pattern of product within the irradiation container;
  • The conveyor path(s) to be used;
  • For product that supports microbial growth, the maximal interval of time between manufacture and completion of irradiation;
  • The routine dosimeter monitoring position(s);
  • The relationships between the dose at the monitoring position(s) and the minimum and maximum doses;
  • For product that is to be given multiple exposures to the radiation field, any required re-orientation between exposures.
3.    Failure to adequately establish procedures for changes to a specification, as required by 21 CFR 820.70(b).
Specifically, your firm made changes to product or process specifications without verifying or validating that the changes would have no adverse effect on the final product. For example:
a.    You made a change to the (b)(4) raw material specifications for porosity, bulk density, and pH on 6/21/12; (b)(4) is the granular material used to manufacture bone void fillers.
Your design input/output requirements approved 4/25/2011 for the Osteophil β-TCP requires:
  • Bulk Density:  (b)(4)
  • Porosity that allows bone filtration:  (b)(4)
  • pH:  (b)(4)
The raw material specification for (b)(4), RM 20-003, Rev. 4, Approved/Effective 6/21/2012 lists the specifications as:
  • Bulk Density:  (b)(4)
  • Porosity:  (b)(4)
  • pH:  (b)(4)
You also added a specification of (b)(4) for (b)(4) testing at (b)(4) for (b)(4) on 4/25/2011.
Your firm lacks objective evidence of verification and/or validation activities for all of these changes.
b.    You made several changes to the hyaluronan gelatin product and process specifications:
  • Addition of (b)(4)
  • Removal of (b)(4)
  • Change in (b)(4) testing to use (b)(4) instead of (b)(4)
  • Change in (b)(4)
  • Formulation change of (b)(4)
  • Change in (b)(4)
  • Addition of (b)(4)
  • Change in (b)(4)
  • Addition of (b)(4)
  • Change in (b)(4)
  • Change in (b)(4)
  • Change in (b)(4)
Your firm lacks objective evidence of verification and/or validation activities for these changes.
4.    Failure to adequately establish procedures for corrective and preventive action, as required by 21 CFR 820.100(a).
Specifically, your firm failed to follow your written procedure “Corrective and Preventive Action,” GP05-002, Revision 04, in that you failed to:
a.    Perform an adequate investigation for CAPA 13-018 initiated in response to your contract manufacturer’s (b)(4) Vendor Corrective Action Request #VCAR 003. The VCAR was initiated 07/22/2013 and has not been adequately investigated or addressed as of this inspection.
b.    Verify and/or validate corrective actions to ensure that such action is effective and does not adversely affect the finished device.
  • CAPA 13-009 was initiated 4/5/2013 in response to your contract customer’s (b)(4) complaint regarding product malfunctions of syringe plungers separating from the syringe and/or product leakage. The corrective action follow-up assignment required tracking (b)(4) lots of product manufactured with a (b)(4) which was determined to be the root cause of the product malfunctions. However, there is no objective evidence to support the tracking of (b)(4) lots. The CAPA was closed 7/16/2013.
  • CAPA 12-002 was initiated 1/9/2012 in response to a discovery that your firm distributed product labeled as sterile that did not receive the required dose of (b)(4) and resulted in a correction and removal. The CAPA was closed 3/29/2012 with no objective evidence to support the corrective actions were effective. Further, contrary to a statement in the CAPA record, a shipping configuration for sterilization does not exist.
5.    Failure to adequately establish process control procedures that describe any process controls necessary to ensure conformance to specifications, as required by 21 CFR 820.70(a).
a.    Your firm lacks procedures to ensure the temperature requirements are met for in-process product stored in your clean room refrigerator. For example, the raw material sodium hyaluraonate and the in-process sodium hyaluronan gelatin which are stored in this refrigerator have a temperature requirement of (b)(4)C. There is no evidence to support this requirement being met.
b.    Your firm’s procedure “(b)(4) Testing,” TM 03-005, Revision 04, references the ASTM standard (b)(4) for the performance of (b)(4). This standard requires pre-conditioning of test specimens prior to testing which your firm does not perform when conducting the (b)(4) test.
6.    Failure to adequately establish procedures for the control of storage areas and stock rooms, as required by 21 CFR 820.150.
Specifically, your firm lacks procedures to monitor and control the temperature of your storage areas and/or stock rooms that store temperature sensitive finished devices.
We have reviewed your response dated March 6, 2014. We acknowledge your commitment to addressing the observations cited on the FDA-483; however, the implementation of your corrective actions will require verification during our next inspection.
Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice.  These actions include, but are not limited to, seizure, injunction, and civil money penalties.  Also, federal agencies may be advised of the issuance of Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation violations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected. 
Please notify this office in writing within 15 business days from the date you receive this letter of the specific steps your firm has taken to correct the noted violations, as well as an explanation of how your firm plans to prevent these violations, or similar violations, from occurring again.  Include documentation of the corrections and/or corrective actions (including any systemic corrective actions) that your firm has taken.  If your firm’s planned corrections and/or corrective actions will occur over time, please include a timetable for implementation of those activities.  If corrections and/or corrective actions cannot be completed within 15 business days, state the reason for the delay and the time within which these activities will be completed. Your firm’s response should be comprehensive and address all violations included in this Warning Letter.
Your firm’s response should be sent to Melissa I. Michurski, Compliance Officer, at the address on the letterhead. If you have any questions about the content of this letter, please contact Ms. Michurski at (612) 758-7185.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your firm’s facility.  It is your firm’s responsibility to ensure compliance with applicable laws and regulations administered by FDA.  The specific violations noted in this letter and in the Inspectional Observations, FDA 483, issued at the close of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems.  Your firm should investigate and determine the causes of the violations, and take prompt action to correct the violations and bring the products into compliance.          
Michael Dutcher, DVM
Minneapolis District

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