Inspections, Compliance, Enforcement, and Criminal Investigations

RTI Surgical, Inc. 11/8/17



Black HHS-Blue FDA Logo


Office of Biological Products Operations
Division I



OBPO– 1 18-01
November 8, 2017
Mr. Camille Farhat
President and CEO
RTI Surgical, Inc.
11621 Research Circle
Alachua, FL 32615
Dear Mr. Farhat:
During an inspection of your firm, RTI Surgical, Inc. (RTI), located at 11621 Research Circle, Alachua, FL 32615, conducted between April 3 and 28, 2017, the Food and Drug Administration (FDA or agency) found that your firm continues to manufacture the (b)(4) Bone Graft Product (b)(4). The (b)(4) consists of a scaffold composed of human demineralized bone matrix and cortical cancellous chips or strips, co-packaged with (b)(4) isolated from bone marrow, cryopreserved in a suspension. All of these constituents are processed from the same human donor. The final packaged product includes the demineralized bone matrix, cortical cancellous chips or strips, and (b)(4).
Your (b)(4) is a human cell, tissue, or cellular or tissue-based product (HCT/P) as defined in 21 CFR 1271.3(d), and is subject to regulation under 21 CFR Part 1271, issued under authority of section 361 of the Public Health Service Act (PHS Act [42 U.S.C. 264]). HCT/Ps that do not meet all of the criteria in 21 CFR 1271.10(a), and do not qualify for any exception in section 1271.15, are regulated as a drug, device, and/or biological product under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and/or section 351 of the PHS Act.
This letter follows several earlier communications between FDA and RTI regarding the (b)(4). On September 26, 2014, FDA issued your firm an Untitled Letter stating that the (b)(4) does not meet all of the criteria in 21 CFR 1271.10(a) and is not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. FDA reviewed RTI’s responses to the Untitled Letter as well as the information presented and discussed at a meeting with FDA on December 11, 2014. FDA sent a written response to counsel to RTI on April 2, 2015, reiterating the conclusions the agency communicated in the Untitled Letter. On April 24, 2015, FDA also reminded counsel that RTI could file a Request for Designation to obtain a formal Agency decision regarding the classification of the (b)(4).  
Subsequently, RTI filed an informal submission to FDA’s Office of Combination Products, and on August 12, 2016, OCP informed you of its preliminary conclusion that, based on information you submitted to OCP, the (b)(4) “is not eligible for regulation solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271.” [1]
The April 2017 inspection found that you continue to manufacture the (b)(4), which fails to meet all the criteria in 21 CFR 1271.10(a). Therefore, you are again advised that the product is not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. Specifically, your processing of the (b)(4), which you refer to as an (b)(4) and (b)(4). This process utilizes (b)(4) and (b)(4) to (b)(4) which alters the relevant biological characteristics of the cells.  Therefore, your processing does not meet the definition of minimal manipulation for cells or nonstructural tissues in 21 CFR 1271.3(f)(2), and the (b)(4) fails to meet the criterion in 21 CFR 1271.10(a)(1). 
Furthermore, as explained in the Untitled Letter and in FDA’s letter to your firm, dated April 2, 2015, the (b)(4) are living allogeneic cells, (b)(4), (b)(4), and stored under conditions (b)(4). Therefore, the (b)(4) are dependent on metabolic activity of living cells for their primary function. The agency further noted and notes now again, that the addition of the (b)(4) to the product is to provide (b)(4). The product is therefore dependent on the metabolic activity of these living cells. This cellular product is also not intended for autologous use or allogeneic use in a first or second degree blood relative. Accordingly, for those same reasons, it does not meet the criterion in 21 CFR 1271.10(a)(4)(ii)(b).
Because it does not meet the criteria in 21 CFR 1271.10(a), the (b)(4) is subject to regulation as a drug as defined under section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and a biological product as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)].
As you are aware, to lawfully market a drug that is also a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after a showing that the product is safe, pure, and potent for the product’s intended use. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug (IND) application in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]. The (b)(4) is not the subject of an approved biologics license application (BLA) nor is there an IND in effect. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.
During the April 2017 inspection, FDA investigators also documented evidence of significant deviations from current good manufacturing practice (CGMP) and the general biological products standards in the manufacture of the (b)(4) and (b)(4), including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210, 211, and 610. The deviations in procedures observed as well as the those noted in documents collected during the inspection indicate that the use of the (b)(4) raises potential significant safety concerns. For example, RTI’s unvalidated processes and inadequately controlled environment pose a product contamination risk. Use of contaminated product could cause a range of adverse events, from infections to death. In addition, the high rejection rate of manufactured product demonstrates that your process is not consistent, validated or in a state of control. This serious lack of control poses a potential significant safety risk for consumers using these products.      
At the close of the inspection, the investigators issued a list of inspectional observations (Form FDA 483), which described a number of significant objectionable conditions relating to your firm’s compliance with CGMP.  The CGMP deviations documented on the Form FDA 483 were presented to, and discussed with you at the conclusion of the inspection.  FDA has found a number of additional significant deviations upon further review of the documents collected during the April 2017 inspection, as discussed below.  The deficiencies found during the April 2017 inspection include, but are not limited to, the following:
1.    Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR 211.113(b)].  For example:
a.  Written procedures were not established for simulated media fills for filling of the (b)(4) in order to evaluate the state of control of the aseptic process.
b.  Your firm performed simulated media fills for filling of the final drug product as part of the initial qualification for the (b)(4); however, your firm was not performing routine qualifications for each filling line that would evaluate the ongoing state of control of the aseptic processes.
c.  Your simulated media fills performed as part of the initial qualification for the (b)(4) had a maximum of (b)(4) filled; however, you have manufactured (b)(4) batches that exceeded your qualified maximum of (b)(4).
2.    Failure to establish written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)].  Specifically, your Process Validation Summary for (b)(4) describes that the purpose of the process validation is to demonstrate that the (b)(4) is not contaminated or cross-contaminated and that no communicable disease is introduced, transmitted, or spread through its use.  You have not validated your manufacturing process for the (b)(4) with respect to identity, strength, quality, and purity.
3.    Your firm’s aseptic processing areas are deficient regarding the system for monitoring environmental conditions [21 CFR 211.42(c)(10)(iv)]. For example:
a.  The frequency of monitoring conducted in the critical aseptic areas is insufficient to detect problems and establish control.  For example, (b)(4), entitled (b)(4),” states that (b)(4) active air sample is taken (b)(4) at a specified time and rate utilizing the (b)(4).
b.  Surface Sampling of the (b)(4) cell processing areas is only performed on a (b)(4) basis after cleaning and is solely intended to verify the efficacy of your firm’s cleaning methods.
c.  The alert (b)(4) and action (b)(4) limits established for surface and personnel sampling in critical aseptic areas could contribute to product contamination.
4.    Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods utilized for lot release of the (b)(4) [21 CFR 211.165(e)].  For example:
a.  You have not revalidated your sterility test method for (b)(4) including bacteriostasis/fungistasis testing of the final drug product since making changes to the composition of the sterility test media. 
b.  (b)(4) vial sterility samples are stored in (b)(4) for (b)(4) days prior to being sterility tested which has the potential of destroying any microbial content in the samples before they are tested. This (b)(4) step was not included as part of your sterility test validation.
5.    Failure to take into account the size and volume of the final product lot during sterility testing [21 CFR 610.12(d)(1)]. Specifically, you were not testing a statistically significant sample of containers from each batch.
6.    Failure to test the (b)(4) for the presence of (b)(4) although a reasonable possibility exists that the drug products have been exposed to cross contamination with (b)(4) [21 CFR 211.176].  Specifically, your firm pipettes (b)(4) into the (b)(4), which is used throughout the processing of the (b)(4).   You do not perform testing for (b)(4) prior to final product release.
7.    Your firm’s system for cleaning and disinfection of the room and equipment to produce aseptic conditions is inadequate [21 CFR 211.42(c)(10)(v)].  Specifically, your biological safety cabinets (BSCs) are cleaned with sporicide only monthly, even though sporeforming microorganisms are routinely detected in your environmental monitoring samples.
8.    Your firm failed to establish written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures [21 CFR 211.80(a)].  Specifically, during the April 2017 inspection, FDA investigators found no written procedures describing in sufficient detail the criteria for approval or rejectionof all components of the (b)(4), including, for example, (b)(4) and (b)(4).
9.    Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced [21 CFR 211.188].  Specifically, master production records have not been prepared to assure uniformity from batch to batch of the (b)(4) with complete information documenting each significant step that was accomplished in the manufacture, processing, packing, or holding of the batch.
Additionally, FDA observed significant deviations in the manufacture of your (b)(4) during the April 2017 inspection.  Specific areas of concern include, but are not limited to:
10.    You initially validated your aseptic processes for (b)(4) production, however routine re-validations are not conducted.  
11.    You have not validated the manufacturing process for your (b)(4) with respect to identity, strength, quality, and purity.  At the time of the inspection, RTI released and distributed (b)(4) of the (b)(4) but rejected more than (b)(4) for various failures during production, in addition to the (b)(4) RTI rejected for visible contamination. This represents an approximately 62% failure rate for your process. The high rejection rate demonstrates that your process is not consistent, validated or in a state of control.
12.    Environmental monitoring for the presence of microorganisms is inadequate in the manufacture of the (b)(4). For example:
a.  (b)(4) active air sample is taken (b)(4).
b.  Surface sampling of the (b)(4) processing areas is only performed (b)(4).
c.  The alert (b)(4) and action (b)(4) limits established for surface and personnel sampling in critical aseptic areas could contribute to product contamination.
13.    During the April 2017 inspection, FDA investigators found no procedures for receipt, identification, storage, handling, sampling, testing, and approval or rejection of the following supplies and components used to manufacture the (b)(4)
a.  (b)(4) used as a component of the (b)(4) to inhibit growth of microorganisms introduced during media preparation.
b.  (b)(4) used as a component of the (b)(4) for cultivation of the (b)(4).
c.  (b)(4) used as a component of the (b)(4) for cultivation of the (b)(4).
d.  (b)(4) used to harvest the (b)(4) from the (b)(4).
We received your written responses, dated May 18, June 28, July 26, August 18, September 22, and October 20, 2017, to the Form FDA 483 and have reviewed their contents.  We acknowledge the corrective actions that you have made to the April 2017, list of inspectional observations and provide specific comments and questions below.  We also recognize that you have not had an opportunity to respond to the additional deviations noted above that were not listed on the Form FDA 483.   However, in addition to the deficiencies noted below, your responses fail to address your continued distribution of the (b)(4) without an IND being in effect or an approved BLA. At the time of the inspection, your firm had distributed over (b)(4) from (b)(4) of the (b)(4) from your Alachua, Florida establishment.
Form FDA 483 Observation 1 & 2
We acknowledge your corrective actions to remediate your firm’s (b)(4) program. However, according to your responses and the SOPs provided, your new program does not include routine validation of the entire aseptic process. Instead, it appears limited to the vialing process.  In your May 18, 2017, response, you contend that validation of the entire aseptic process is unnecessary because, among other things, you test the product for sterility and mycoplasma and reject lots that are positive. We do not agree that you can test identity, strength, quality, and purity into a product. We also note that sterility testing is far from 100% effective and that, in addition to the final product sterility failures noted, you rejected approximately (b)(4) because of visible contamination with microorganisms that are also routinely isolated from the environment during (b)(4) processing, suggesting that your aseptic process is not in a state of control. 
For more information, please see FDA’s “Guidance for Industry: Sterile Drug Product Produced by Aseptic Processing: Current Good Manufacturing Practice,” September 2004.  
In addition, please provide to FDA for review the validation reports of the three executed (b)(4) for the vial filling process, when available, including the growth promotion tests performed.
Form FDA 483 Observation 3 & 4
We acknowledge your commitment to detect residual (b)(4) in your product. Additionally, we acknowledge your commitment to add a cleaning validation addendum when these test methods are confirmed.   
Form FDA 483 Observation 5
We acknowledge your responses intended to address your firm’s environmental monitoring program (specifically, the inadequate frequency in critical areas) and your continued commitment to update (b)(4) However, the changes that you have proposed do not adequately respond to the deficiencies noted.  A robust environmental monitoring program provides important information about the environmental control of your manufacturing facility over time. Given the large number of failures for visible contamination and sterility and (b)(4) rejection rate, your program should include more active viable air monitoring and limits that will better assist you in establishing needed control. 
We also note that your BSCs, which should provide an ISO 5 environment, are placed in a surrounding area that is only expected to meet ISO 7 standards rather than the recommended ISO 6.  You also perform upstream operations in the same area and at the same time as filling of your final cell product.  These are basic design flaws that likely contribute to contamination and sterility failures.
Form FDA 483 Observation 6
We acknowledge that you have initiated testing for all materials outlined in this observation, with the exception of (b)(4), for which you are still in the process of determining an identify test.
Form FDA 483 Observation 7
We acknowledge your commitment to revise your (b)(4) entitled (b)(4) and increase the number of sterility samples based upon USP <71> so the sample size is representative of the lot size. We also acknowledge receipt of a summary report for (b)(4) that appears to address both the issue of (b)(4) samples supporting growth and bacteriostasis and fungistasis testing. However, it is unclear from the information provided how the study addressing the (b)(4) samples was conducted to demonstrate that microorganisms present in the in-process materials and final product can be recovered after (b)(4).   This would entail inoculation of these materials prior to (b)(4).   While we acknowledge that you are no longer (b)(4) samples prior to sterility testing, you released (b)(4) that were tested in this manner.
Neither this letter nor the observations noted on the Form FDA 483, which were discussed with RTI management at the conclusion of the April 2017 inspection, are intended to be an all-inclusive list of deficiencies that may exist at your facility.  It is your responsibility to ensure full compliance with the provisions of the FD&C Act and the PHS Act, and their implementing regulations.
You should take prompt action to correct the above-described deviations.  Failure to promptly correct these deviations may result in regulatory action without further notice.  Such actions include, but are not limited to, seizure and/or injunction.
Further information about IND requirements for biological products may be obtained through the Division of Regulatory Project Management, Office of Tissues and Advanced Therapies, (240) 402-8190 or Please include a copy of this letter with your initial submission to CBER.
Please notify this office in writing, within 15 working days of receipt of this letter, of any additional steps you have taken or will take to correct the above-noted violations and to prevent their recurrence.  Include any documentation necessary to show that correction has been achieved.  Corrective actions addressed in your prior response may be referenced in your subsequent response.  If you do not believe your product is in violation of the FD&C Act, PHS Act, or applicable regulations, include your reasoning and any supporting information for our consideration.  If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which all corrections will be completed.
Your response should be sent to the attention of Randall L. Morris, Compliance Officer, electronically at or to U.S. Food and Drug Administration, Florida District Office, 555 Winderley Place, Suite 200, Maitland, FL 32751.  If you have any questions regarding this letter, please contact Mr. Morris, at (407) 475-4741.
Elizabeth A. Waltrip  
Program Division Director, Acting

[1] The description of the (b)(4) in this letter is consistent with the product information you provided to the agency in your informal submission to OCP.

Page Last Updated: 11/14/2017
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