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Department of Health and Human ServicesCERTIFIED MAIL
RETURN RECEIPT REQUESTED
WARNING LETTER
FLA-11-19
February 22, 2011
James Talton, Ph.D.
President and C.E.O.
Nanotherapeutics, Inc.
13859 Progress Blvd., Suite 300
Alachua, Florida 32615
Dear Dr. Talton:
During an inspection of your firm located in Alachua, Florida on August 30, 2010 through September 7, 2010, investigator(s) from the United States Food and Drug Administration (FDA) determined that your firm manufactures Origen™ DBM/NanoFUSE™ DBM with Bioactive Glass. 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.
The Origen™ DBM (NanoFUSE™ DBM) device is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. § 351(f)(1)(B), because you do not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. § 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act, 21 U.S.C. § 360j(g). The Origen™ DBM (NanoFUSE™ DBM) device is also misbranded under section 502(o) of the Act, 21 U.S.C. § 352(o), in that a notice or other information respecting the modification to the device was not provided to the FDA as required by section 510(k), 21 U.S.C. § 360(k), and 21 CFR 807.81(a)(3)(i). Specifically, the inspection revealed that you modified the Origen™ DBM device by adding (b)(4) to increase the melt temperature of the gelatin in the Origen paste. This modification represents a change to your device that could significantly affect the safety or effectiveness of the device and thus requires the submission of a new 510(k). For a device requiring premarket approval, the notification required by section 510(k) of the Act, 21 U.S.C. § 360(k), is deemed satisfied when a PMA is pending before the agency, 21 CFR 807.81(b). The kind of information you need to submit in order to obtain approval or clearance for your device is described on the Internet at http://www.fda.gov/cdrh/devadvice/3122.html.
The FDA will evaluate the information you submit and decide whether your product may be legally marketed This inspection revealed that these devices are also 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 Dr. James Talton, CEO and Dr. Barb Eppler, Sr. VP of Preclinical and QA, dated September 23, 2010 concerning our investigator’s observations noted on the Form FDA 483, List of Inspectional Observations that was issued to you. 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 review and evaluate the process and perform revalidation, where appropriate, when changes or process deviations occur and to document these activities, as required by 21 CFR 820.75(c). For example:
a) The length of time for (b)(4) of the production of your firm’s Demineralized bone matrix (DBM) with Bioactive Glass (Lot numbers 071043PB and 073751P) was changed from a minimum of (b)(4) to (b)(4) with different (b)(4) specifications, but no change control documentation was created to address this specific change. There was limited documentation as to specifically when this change occurred, who approved it, and the justification that it did not adversely affect the product or require additional validations.
b) An in-process variance was planned in August 2010 regarding the elevated ambient temperature in the manufacturing area which led to a problem cooling the gelatin solution. The resolution included the (b)(4) as well as the introduction of (b)(4). The justification and rationale for this modification were not fully documented. In addition, the cleaning of the relocated equipment, i.e., the (b)(4) was not documented.
We have reviewed your response and concluded that it is inadequate since the verification or validation activities have not yet been conducted for these changes involving the reduction in drying time of the DBM with Bioactive Glass and the changes implemented due to increased temperatures in the manufacturing area. Your response does discuss the corrective actions to be implemented in order to prevent the recurrence of this deficiency. These corrective actions include: revising the form NT-FCC-001 used to document the review and evaluation of changes; revising SOP NT-CC-001, the Change Control SOP; revising SOP NT-CC-002, Planned and Unplanned Deviations, to add specific instructions for review and evaluation; and training the appropriate personnel on these revisions. Additionally, instructions on documentation for evaluation, justification, and rationale of the change, as well as the evaluation of potential verification or validation activities, or the lack thereof with justification, will be implemented as well. These revised documents were not provided for review.
2. Failure to establish and maintain procedures for the identification, documentation, validation, or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). For example: Neither the current Design Control SOP nor the Change Control System SOP addresses design change. Three design changes were observed and involved:
a) The addition of (b)(4) in the manufacturing process;
b) The use of (b)(4) DBM in place of (b)(4) DBM (raw material) and;
c) The size of the finished product packaging (both inner and outer pouches).
The two changes involving the (b)(4) DBM raw material and the packaging size, lacked documentation such as review and approval of these changes. The change involving the addition of the (b)(4) process was documented per the (b)(4) procedures but was not evaluated within the design control/process change system. There were no stability studies conducted for the addition of (b)(4). The data used to support this change was based on finished product made prior to the addition of (b)(4).
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since supporting documentation of the corrective actions was not provided. The corrective action includes retroactively justifying, evaluating, and documenting the above changes as well evaluating other possible changes to determine if they were improperly documented. Revisions to procedures and forms such as the Control SOP (NT-CC-001) and associated form (NT-FCC-001), Design Control SOP (NT-DR-017), and the Design History File SOP (NT-DR-020), will ensure that adequate instructions and documentation are maintained for the change type, a detailed description of the change, justification, and evaluation to include any impact the change may have on other systems or processes. The revised procedures will also ensure an evaluation on updating other connected documents and a time limit for completion and approval of the change. The validation procedures will be revised as well to emphasize the approval of the validation studies prior to distribution. Training on the revised processes will be scheduled as well.
3. Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished devices, as required by 21 CFR 820.100(a)(4). For example: Verification activities are not routinely conducted nor required in the CAPA SOP NT-QM-014, Corrective and Preventive Actions. In addition CAPA #08-002 was created due to nonconforming packaging that resulted in returned products. The corrective action implemented was 100% in-house inspection of (b)(4) packaged product. The continuing nonconformances observed during the 100% inspection are not fed back into the CAPA system to determine if additional actions are required in-house or at the contract packaging facility.
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since all supporting documents were not provided with the response. Your response indicated that your firm has revised the form to document and investigate CAPAs and added a Verification Section to the form in June 2010. The response indicated that effectiveness verification and documentation is also covered in the Quality Investigations and Corrective Actions SOP, NT-QM-014, in sections 8.11 – 8.11.2. The non-conforming packaging example discussed above, will be addressed in the updated Vendor Review and Approval system and any other non-conformances will be investigated through your firm’s out of specification, non-conforming and quality investigation and corrective action procedures. The response also stated that nonconformances will be trended in accordance with the Trending of Laboratory Data, NT-QM-024 SOP.
4. Failure to maintain complaint files and establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a). For example: All complaints are not processed in a uniform and timely manner since complaints from end-users are not being captured. A marketing partner is responsible for relaying complaints from the end users and no complaints were found on file at your firm However, the (b)(4) design change was found to be the result of an email from a marketing supervisor that summarized concerns heard by sales representatives about the melting property of the product, rather than being documented in the complaint system.
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since the supporting documentation was not provided. Your response stated that the end user communications such as preferences in handling characteristics and melt temperature can vary significantly therefore you did not consider these communications as complaints. However, the complaint system would be adjusted to capture such comments or complaints into the complaint handling system (Complaint Handling, Reporting, and Recalls SOP, NT-CR-001; Complaint Information Form NT-FCR-001; Medical Device Report Determination Form, NT-FCR-002). Your response also stated your firm had initiated communication with the distributor to seek a formal process to capture and document end-user complaints using a form that will capture information that must then be forwarded to the firm in a systemic manner or a prescribed time frame for evaluation. Your response indicated that you will make decisions internally as to whether or not the comments are actionable complaints. Your firm will also be requesting other end user comments that may have been documented by the distributor, for evaluation of other potential complaints. Additionally, future distributors and their complaint handling system will be evaluated prior to conducting business through NT-FQM-031 Quality Questionnaire for Nanotherapeutics Distributors.
5. Failure to establish and maintain records of acceptable suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)(3). For example:
a) Vendor qualification has not been completed as outlined in the Vendor Review and Approval Procedures. The SOP requires audit visits of all “critical” vendors/suppliers, however, at least 5 suppliers deemed critical by the firm have not been audited (or other justification documented).
b) The incoming material inspections of the pouches are performed by the contract packager and those results or non-conformances are not conveyed back into the supplier qualification process.
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since supporting documentation was not provided. Your response stated that all vendors have updated quality questionnaires on file. In addition, you revised SOP NT-QM-015, Vendor Review and Approval, so that on-site visits of vendors with a high criticality ranking, are not required, but rather recommends these on-site visits. A schedule was made for on-site audits of critical vendors and of the 7 vendors considered “critical”, all have completed initial mail audits and follow up audits were either received or pending. Your response indicated that scheduling of on-site visits of the remaining vendors was underway at the time of the inspection. Additionally, the Vendor Review and Approval procedure will be updated to more clearly establish what review steps are needed and allowable for different types of vendors and the timelines to be able to utilize a vendor. A form will serve to document and summarize the review and approval process specific to the vendor and document criticality of the vendor. An additional form will be created to document annual reviews of the vendor where vendors will be re-evaluated based on non-conformances or other documented issues.
6. Failure establish and maintain adequate procedures for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria and finished devices shall not be released for distribution until: (1) the activities required in the Device Master Record (DMR) are completed; (2) the associated data and documentation is reviewed; (3) the release is authorized by the signature of a designated individual(s); and (4) the authorization is dated, as required by 21 CFR 820.80(d). For example:
a) There was no procedure or work instruction that addresses the 100% inspection of pre-sterilized finished product for packaging and labeling. Acceptance criteria, specifically for “Integrity of Packaging – Pass/Fail” is not defined.
b) Instructions on how to document these packaging failures (i.e. as non-conformances) is not addressed.
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since supporting documentation was not provided with the response. The response stated that the Master Batch Record for bone paste product final assembly and tracking includes instruction for inspection such as the legibility of the label, integrity of package and the absence of foreign matter. Your response indicated that a work instruction with more detailed instructions for the inspection of final product will be written and personnel will be trained prior to any product release. Additionally, non-conformances found during the 100% inspection would be documented and investigated according to your Out-Of Specification Investigations and Non-Conforming Product SOP, NT-QM-021 and the Quality Investigations and Corrective Actions SOP, NT-QM-014. Changes resulting from the investigation would be documented using the revised Change Control System.
7. Failure to establish and maintain an adequate Design History File (DHF) for each type of device to demonstrate that the design was developed in accordance with the approved design plan and design control requirements, as required by 21 CFR 820.30(j). For example: The design history file did not contain or reflect the three design changes observed:
a) The addition of (b)(4) to the process;
b) The replacement of (b)(4) DBM with (b)(4) DBM; and
c) The change in packaging size.
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since the response did not include supporting documentation to demonstrate the implementation of the correction and corrective action to satisfy design control requirements. The response stated the issue was the result of a missing link between the Design History File and the Change Control System. You state that you intend to revise your current Change Control SOP (NT-CC-001) and associated form (NT-FCC-001). These revisions would include instructions and documentation for the change type, a detailed description, justification, and evaluation to include any impact the change may have on other systems or processes, an evaluation on updating other connected documents and a time limit for completion and approval of the change. The Design Control SOP (NT-DR-017), and the new Design History File SOP (NT-DR-020) will be revised to include instructions that will reference the Change Control System for documentation and evaluation of any design changes. Training of the revised processes will be conducted as well. You also state that the Design History File for Origen™ will be updated to include the addition of (b)(4) to the process, the replacement of (b)(4) DBM with (b)(4) DBM, and the change in packaging.
8. Failure to establish and maintain adequate procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system. These quality audits shall be conducted by individuals who do not have direct responsibility for the matters being audited, as required by 21 CFR 820.22. For example: Quality audits were not performed at defined intervals to determine whether the quality system activities and results comply with quality system procedures. Specifically, no audits were conducted in 2008; documentation of audits conducted included August 2001 and focused audits between November 2009 and June 2010.
We have reviewed your response and concluded that it is adequate. You revised SOP Internal Audits, QA Inspection & Reporting Procedures which was made effective October 2009. Internal Audit dates have been provided that demonstrates compliance with your internal audit SOP and that satisfies 21 CFR 820.22.
9. Failure of management with executive responsibility to review the suitability of the quality system at defined intervals and with sufficient frequency according to established procedures to ensure that the quality system satisfies the requirements of this part, as required by 21 CFR 820.20(c). For example: The Quality Manual calls for semi-annual management review meetings, but documentation indicated no meetings were convened in late 2007 or in 2008 (following the August 2001 external audit performed); subsequent meetings were held March and September 2009 and May 2010.
We have reviewed your response and concluded that the adequacy of your response cannot be determined at this time since supporting documentation was not provided. Your response stated that two Management Review Meetings were held in 2007, on February 23, 2007 and July 25, 2007 in accordance with your Quality Manual. You indicated that you have corrected this issue by conducting semi-annual Management Review Meetings on a defined schedule since March 2009. Additionally, you stated that the second meeting of 2010 was held on 9/17/2010. However, you did not provide evidence to support the management review meeting requirement as outlined in your Quality Manual and to satisfy 21 CFR 820.20(c).
A follow up inspection will be required to assure that corrections and/or corrective actions are adequate.
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, premarket approval applications for Class III devices to which the Quality System regulation deviations 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 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, stated the reason for the delay and the time within which the corrections will be completed. Your response should be comprehensive and address all violations included in this Warning Letter.Your response should be sent to:
Salvatore N. Randazzo
Compliance Officer
555 Winderley Place, Suite 200
Maitland, Florida 32751
If you have any questions about the content of this letter please contact: Mr. Randazzo at (407) 475-4712.
Finally, 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.
Sincerely yours,
/s/
Emma R. Singleton
District Director
