Company: Ben Venue Laboratories, Inc.
Subject: CGMP/Deviations/Adulterated
Issuer: Cincinnati District Office
Issued: Nov. 16, 2007 Closed:
Not applicable.
Source ucm076574 Archive Code:

Ben Venue Laboratories, Inc. 16-Nov-07

Department of Health and Human Services

Public Health Service
Food and Drug Administration

Cincinnati District Office
Central Region
6751 Steger Drive
Cincinnati, OH 45237-3097
Telephone: (513) 679-2700
FAX: (513) 679-2771

November 16, 2007

Via Fax: 440-439-6798 and Federal Express


Thomas J. Murphy, President
Ben Venue Laboratories, Inc.
300 Northfield Road
Bedford, Ohio 44146

Dear Mr. Murphy:

During an inspection of your manufacturing facility conducted May 7, 2007, through June 15, 2007, the Food and Drug Administration (FDA or Agency) documented significant deviations from the current good manufacturing practice (cGMP) regulations (Title 21, Code of Federal Regulations (C.F.R.), Parts 210 and 211) for the manufacturing of Propofol Injectable Emulsion (Propofol). Such deviations cause the drug product to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (Act) [21 U.S.C. §351 (a)(2)(B)] as follows:

1 . There was a failure to establish written control procedures to monitor the output and validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. [21 C.F.R. § 211.110(a)]. In addition, there was a failure of the quality control unit to reject in-process materials during the production process that were tested for identity, strength, quality and purity. [21 C.F.R. § 211.110(c)]. For example:

Despite the fact that some lots passed finished product testing, your firm does not have valid scientific data to demonstrate that endotoxin present at the in-process stage is reduced to an acceptable level in the finished product. In March 2006, three lots of Propofol exceeded the finished product specification for endotoxins ([redacted] /ml). As a result of an investigation into these failures, a [redacted] test for endotoxin was added to the master production record (MPR). The limit in the MPR is consistent with final product specifications. Your firm indicated that the results of this in-process test would provide an early indicator of objectionable endotoxin levels and provide pertinent investigational information. Our inspection found that lots included endotoxin at levels above the in-process limit. Although these lots had endotoxin levels above the in-process limit, your firm released these same lots, on the basis of passing finished product testing . Your quality control unit should have, during the production process, rejected the in-process materials that had the elevated endotoxin levels.

In response to current inspection findings, your firm conducted studies that were intended to demonstrate the ability of the sterilization process to achieve significant endotoxin reduction in the final product. However, as explained further below, your studies lacked adequate information to support this assertion.

In addition, your firm does not have data to support that endotoxin (when present) is uniformly distributed in Propofol vials . Due to the nature of the product (a non-aqueous emulsion) and non-uniform endotoxin content from unit to unit upon retest (e.g., lot 919086), we are led to the conclusion that end-product testing alone is insufficient to assure that your firm's finished product meets its endotoxin specifications. For example, the original finished product endotoxin testing result (from [redacted] vials) for lot 919086 was [redacted] EU/ml (below the ( [redacted] EU/ml limit). However, since lot 919086 was manufactured during the same time period as two (919087/88) rejected lots (for high endotoxin results) your firm properly performed additional testing on lot 919086. Upon retest, all [redacted] additional vials from lot 919086 were above the [redacted] EU/ml limit. Consequently, the lot was rejected.

We are also concerned with your quality control unit's (QCU) decision to eliminate the practice of taking in-process samples of the bulk Propofol emulsion for endotoxin testing during the inspection. Your QCU explained to FDA investigators that since this in-process testing for endotoxin was not a commitment in a drug application, it would be eliminated (despite previous failing of in-process limits of some lots). Please note that in-process controls beyond those described in submissions to FDA are a routine aspect of a firm's quality program to assure compliance with the cGMP regulations. Because we think that it would be appropriate to test your in-process materials for identity, strength, quality, and purity, we believe that eliminating this in-process endotoxin test would be in violation of 21 C.F.R. § 211.110(c).

2. There was a failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example:

a. Your firm did not conduct a thorough investigation to determine the source of endotoxin contamination.

(1) Your firm failed to conduct thorough investigations into the failure of multiple lots of Propofol (958302, 958364, 958438, 958445, and 968716) that significantly exceeded in-process levels for endotoxin ( [redacted] EU/ml) during [redacted] testing, but later passed final product testing for endotoxin. Your quality control unit (QCU) determined these lots to be acceptable for release without determining the source of the contamination.

(2) Your investigation of these lots concluded that since the in-process test for endotoxin was for investigational purposes, full investigations were not required. A root cause for the high [redacted] results for endotoxin was not identified, and the results were not scientifically invalidated by any of your firm's investigations.

In light of the high endotoxin test results seen at your facility during the manufacturing of Propofol, we are concerned that your firm may lack an adequate understanding of the product and the process for manufacturing Propofol. We strongly recommend that your firm review your process design and endotoxin controls for the entire manufacturing process, e.g., prior to the filtration and terminal sterilization. Some considerations may include the raw materials used in the process and the lengthy compounding process.

We acknowledge receipt of your firm's responses dated July 11, 2007, August 3, 2007, August 6, 2007, September 13, 2007, October 4, 2007 and October 25, 2007. While your responses appear to partly address the deficiencies on the FDA-483, major concerns remain with respect to your manufacturing practices and quality assurance program. In this regard, we would like to share two significant concerns regarding your written response.

First, as mentioned above, your firm stated that in-process testing for endotoxin will be eliminated. Because of the failing endotoxin results in 2006, we believe that establishing an in-process control for endotoxin was appropriate and required by 21 C.F.R. § 211.110. Given the findings of significantly elevated levels of endotoxins during processing in several cases, there does not appear to be a sound scientific rationale to eliminate this in-process control.

Next, your responses contained two studies, Study #SP07016 [redacted] and [redacted] Study No: S12807M, [redacted] which where conducted in response to current inspectional findings. We have the following concerns with both of the studies.

(1) Your studies showed that filtration did not reduce the levels of endotoxin.
(2) Your studies were not sufficiently representative of production conditions and did not provide for a safety margin. For example, they were conducted using a minimum load, rather than a production load. Acceptance criteria should have a safety margin built in to provide adequate process assurance (analogous to depyrogenation validation studies, which demonstrate a minimum three log endotoxin reduction). A study that demonstrates only a [redacted] log endotoxin reduction under production conditions would be insufficient to support release of Propofol lots that have high in-process endotoxin loads.

During the course of the inspection, FDA investigators also noted that your firm produces drug Products that do not have FDA approval. These include: Levothyroxine Sodium for Injection, Colchicine Injection USP, Ephedrine Sulfate Injection USP, Papaverine HCl Injection USP, and Caffeine and Sodium Benzoate Injection. According to FDA investigators, your firm indicated that it believed that these products were grandfathered.


In regard to your contention that your products are grandfathered, although there were numerous drug products marketed before the enactment of the Act in 1938 and its amendment in 1962, FDA believes that it is unlikely that currently marketed products such as yours are grandfathered or otherwise not a new drug. The grandfather clauses have been construed very narrowly by the courts and drug products on the market would not be entitled to grandfather status if they differed from the previous version in some respect, such as formulation, dosage or strength, dosage form, route of administration, indications, or intended patient population. Only drugs that are, at a minimum, identical in formulation and conditions of use as their predecessor pre 1938 or 1962 drugs, can be grandfathered. For additional information concerning grandfather status, please see 21 C.F.R. § 314.200(e)(2) and the appendix of our Compliance Policy Guide Marketed Unapproved Drugs at , lines 323-329.

Further, it is FDA's view that companies claiming that their products are grandfathered bear responsibility to fully document their products' grandfathered status. Any company marketing products on this basis should have available documentation to demonstrate the market presence of the product prior to the enactment of the new drug requirements that were established in 1938 and 1962.

The issues and violations cited in this letter are not intended to be an all-inclusive statement of violations that exist 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 assure that your firm complies with all requirements of federal law and FDA regulations. For regulatory and scientific guidance, please refer to FDA's website at

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 limitat'ion, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug applications listing your facility as a manufacturer until the above violations are corrected .

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 violations (not included in previous correspondences). Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. If you no longer manufacture Propofol, your response should so indicate, including the reasons for, and the date on which, you ceased production. We will evaluate the adequacy of your corrective actions during our follow-up inspection of your facility. Your written response should be directed to the attention of Karen Gale Sego, Compliance Officer, at the address listed above. If you have any questions regarding any issue in this letter, please contact Karen Gale Sego at 513-679-2700 extension 164.

In addition, please contact Kennerly Chapman, Regulatory Project Manager, CDER Office of Compliance immediately at 301-827-9032 to schedule a regulatory meeting within five working days of the receipt of this letter. At the meeting, your firm should be prepared to discuss the specific steps taken to correct these violations, including a detailed explanation of each step taken to ensure that these types of violations do not recur. Please bring the necessary documentation to demonstrate that your firm has adequately effected systemic corrections to the above violations.



Carol A. Heppe
District Director

Enclosure: FDA-483

cc: w/FDA-483