| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Baltimore District Office
6000 Metro Drive, Suite 101
Baltimore, MD 21215
Telephone: (410) 779-5455
FAX: (410) 779-5707
April 26, 2013
Return Receipt Requested
James DeFrancesco, CEO
6640 Eli Whitney Drive, Suite 200
Columbia, MD 21046
Dear Mr. DeFrancesco:
During an inspection of your firm located in Columbia, Maryland on November 28 through December 20, 2012, investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures MatriStem® Surgical Matrix Thick (PSMT). 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 are intended to affect the structure or 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 (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (C.F.R.), Part 820.
We received a response from Mr. Rodney W. Bosley, Jr., President, dated January 11, 2013 concerning our investigators’ observations noted on the Form FDA 483 (FDA 483), List of Inspectional Observations, that was issued to your firm. We address this response below, in relation to each of the noted violations. These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures to control the design of the device in order to ensure that specified requirements are met, as required by 21 CFR § 820.30(a). For example:
a. Several design inputs were identified from scientific articles and promotional material for similar devices. For example, tensile burst strength identified in a research article should be greater than (b)(4). The design input for MatriStem® Surgical Matrix Thick as documented in “Input/Output Traceability Matrix” (dated 16Dec10 and November 14, 2012) for tensile burst strength is greater than (b)(4). There is no rationale for the “safety margin for the device” that increased the design input value from (b)(4) to (b)(4).
We reviewed your response and have concluded that the adequacy of your response cannot be determined at this time. According to your firm’s Document Number Q-0011, “Design Control”, the Design History File (DHF) Deliverables – Design Input is comprised of several documents to include the Design Inputs/Outputs Matrix (Q-0011-05) and Preliminary Risk Assessment (Q-0011-04). These documents were not included in your firm’s response.
b. Design validation has not been conducted. The objective of your firm’s report # V-0221 “Final Report: Design Validation: PreClinical data Review – MatriStem Surgical Matrix” (Date: August 8, 2012 Revision 0) is “(b)(4)”. However, the design validation literature review did not include production equivalents of the MatriStem® Surgical Matrix Thick device.
We reviewed your response and concluded that it is inadequate. Your firm’s response states that Design Validation testing is planned and the validation report will be prepared with approval of the report anticipated by the end of February 2013. However, your firm did not indicate whether the report will be submitted to the FDA for review.
c. The two year expiration date is not supported by stability data. Your firm had data to support the two-year expiration date for your Single Layer Lyophilized and Hydrated Sheets of UBM, but not for the Multi-Layer Vacuum Pressed product. Page 2 of the “memo to DHF” contains conflicting information regarding the applicability of shelf-life testing for both types of products.
We reviewed your response and concluded that it is inadequate.
1. Your firm indicated that it will use accelerated aging conditions to initially establish expiration dates for the multi-laminate product formulations. The product consists of various proteins, and other (b)(4) entities, e.g., (b)(4) components, etc…, which cannot be assumed to follow linear degradation kinetics. Linear degradation kinetics are necessary for manufacturers to use the Arrhenius equation as part of the accelerated aging evaluation, i.e., presumption that as temperature is increased, there is a linear relationship to material breakdown effects. This assumption can be used most easily for single component materials; your firm’s product is a complex combination of (b)(4) which could influence each other’s degradation kinetics. The product expiration date must be based upon real time data, or accelerated aging-based data that was previously validated by real time data on your firm’s product. To support the use of accelerated aging results, your firm may cite published literature information regarding the possibility that its material follows linear degradation kinetics, however, the published literature would need to be based on a material that is identical to your firm’s product. Believing that this information does not exist, FDA requires that the expiration date of your firm’s product be revised to what was obtained from real time expiration analysis. It can be subsequently revised as new additional real time data is obtained.
2. The parameters identified for assessing product stability are based solely on (b)(4) attributes of the product. The two parameters which are surrogates for determining whether the biochemistry of the material remains stable, i.e., onset temperature via DSC and hydration, are indicated as “informational only”. The protocol is inadequate in assessing product stability and should be revised to at least have specifications for onset temperature and hydration. Other assessments like SDS-PAGE or other electrophoretic/chromatographic analyses regarding ECM components, e.g., GAGs, etc., would better demonstrate product biochemistry stability. Please revise the protocol accordingly and implement these measures for establishing the real time-based, expiration date for the multi-laminate product formulations.
Our inspection also revealed that your firm’s MatriStem® Surgical Matrix Thick devices are misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 - Medical Device Reporting. Significant deviations include, but are not limited to, the following:
1. Failure to report to FDA no later than 30 calendar days after the day that your firm received or otherwise became aware of information, from any source, that reasonably suggests that a device that it markets may have caused or contributed to a death or serious injury, as required by 21 CFR § 803.50(a)(1).
For example, complaints (b)(6) and (b)(6) reference events where your firm’s implantable device may have contributed to patient infections that necessitated surgical or medical intervention to preclude permanent impairment of a body function or permanent damage to a body structure. Your firm failed to submit the MDR associated with complaint (b)(6) to FDA within the 30 calendar day timeframe. Your firm has not yet submitted an MDR for the event described in complaint (b)(6).
We reviewed your response and concluded that it is inadequate. Your response dated January 11, 2013 stated that you recognize the complaint investigations of these events were inadequate. However, as of 3/6/13, your firm has failed to submit MDRs for these events. In addition, your firm’s revised Document Numbers Q-0037, “Medical Device Reporting and Vigilance”, approved 1/10/13, and Q-0014, “Product Complaint Handling”, approved 1/10/13, do not describe the criteria by which your firm determines a reportable event.
If your firm wishes to discuss MDR reportability criteria or to schedule further communications, it may contact the Reportability Review Team by email at email@example.com
You 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 Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, no premarket submissions for devices to which the Quality System regulation deviations are reasonably related will be cleared 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 fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
You should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality management systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
Your response should be sent to:
U.S. Food and Drug Administration, Attention: Cherlita Honeycutt, Compliance Officer, 6000 Metro Drive, Suite 101, Baltimore, MD 21215. If you have questions regarding this letter, please contact Ms. Honeycutt at (410) 779-5412 or via e-mail at firstname.lastname@example.org
Baltimore District Office