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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Leiner Health Products, LLC 28-Aug-07

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

Public Health Service
Food and Drug Administration


Atlanta District Office
60 8th Street, N.E.
Atlanta, Georgia 30309

August 28, 2007




Robert Kaminski, CEO
Leiner Health Products, LLC
901 E. 233rd Street
Carson, CA 90745-6204

Dear Mr. Kaminski:

On January 22 through March 16, 2007, the Food and Drug Administration (FDA) conducted an inspection of your manufacturing facility located at 355 Crestmont Drive, Fort Mill, SC. The inspection revealed significant deviations from Current Good Manufacturing Practice (CGMP) regulations (Title 21 Code of Federal Regulations (21 CFR Parts 210 and 211) in the manufacture of drug products such as [redacted] and [redacted]. These CGMP deviations were listed on an Inspectional Observations (Form FDA 483) issued to Mr. Patrick Dunn, Vice President/Chief Science Officer at the close of the inspection. These CGMP deviations cause your drug products to be adulterated within the meaning of section 501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic Act ((the Act) 21 U.S.C.§ 351(a)(2XB)).

We acknowledge your corrective action plans. You have suspended production and distribution of drug products at [redacted] sites [redacted] and [redacted] and committed not to resume those operations until you have satisfactorily demonstrated to Atlanta District that the CGMP compliance problems have been addressed and the recall of most products within expiry is complete. We agree with your decision to hire consultants to help you implement corrective actions.

However, the inspection found many serious deviations, some of which involved data manipulation and inadequate testing procedures. Your own review of your test data revealed a "highly unusual trend" for discrepancies and "numerous previously undetected failures", findings that prompted your decision to voluntarily recall your drug products. The products manufactured at your facility under these violative conditions put consumers at significant risk.

Also, you are continuing packaging operations at your [redacted] site. Under the law, packaging is also defined as a "manufacturing" operation. See 21 CFR Part 211, Subpart G. We understand that it is your intention to package and distribute bulk product currently on-hold that was manufactured at another Leiner facility. Because of the poor CGMP controls in the areas inspected, e.g., failure of your Quality Control Unit to fulfill its responsibilities, we have no assurance that your packaging operations will be properly controlled.

The CGMP deviations observed during the inspection include, but are not limited to, the following:

1) Failure to perform appropriate stability testing using reliable, meaningful, and specific test methods in determining appropriate storage conditions and expiration dates as required in 21 CFR § 211.166 to assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use as required by 21 CFR § 211.137.

For example, you failed to properly assess the stability characteristics of the drug products manufactured and/or repackaged at the site. There is no assurance that any of the firm's over-the-counter (OTC) products in distribution have adequate impurity stability data to support their expiration dates. Failing impurity test results during stability testing studies were noted for the following products:


Review of impurity testing (chromatography) for stability samples including [redacted] Tablets/Capsules, [redacted], Tablets/Caplets/Gelcaps, [redacted] Caplets, [redacted] Tablets, [redacted] Tablets, [redacted] Tablets and [redacted] Tablets revealed impurities which were consistently ignored. A large number of extraneous unidentified peaks were noted in chromatograms of standard, mobile phase, diluent, and/or placebo injections. These unidentified peaks were dismissed and not included in the calculations if they were also present in the diluent, placebo, standard or mobile phases. Therefore, there is no assurance that all impurities would be detected and/or quantified in any of the stability studies conducted by the firm.

2) Failure to have an adequate quality control unit and adequate laboratory facilities available for the quality control unit for the testing and approval (or rejection) of components, in-process materials, drug products, and all procedures or specifications impacting on the identity, strength, quality, and purity of the drug products as required by 21 CFR § 211.22(a), 211.22(b), and 211.22(c).

Your quality control unit (QCU) has allowed failing product to remain in distribution, released product to the market without adequate stability data to support the expiration dates, failed to conduct adequate investigations of discrepancies, failed to adequately review all analytical data prior to release, and failed to assure adequate analytical method validations were conducted for numerous finished product test procedures.

During the meeting conducted on June 12, 2007, at the Atlanta District's office your consultant stated that the result of the cultural assessment review conducted at the Fort Mill site revealed that upper management responsible for overseeing the QCU was "out of touch" with the events occurring, had "minimal presence", and was "largely unaware of the quality concerns in the laboratory" at the site.

In addition, an investigation of the test procedure LC-111-05, the impurity test method for [redacted] caplets, conducted by the Quality Control Director in October 2006 revealed that the procedure was unreliable and concluded that the method should be revalidated. Despite this finding, the Quality Control Director did not implement any corrective actions to remedy this deficiency and your company continued to use the inadequate test method. Your QCU was aware of these issues and took no corrective and preventive action with respect to the product on the market and other lots of this product which continued to be manufactured and distributed after testing the products with the unreliable finished product test method. The Senior Vice President and Chief Science Officer decided to recall all lots of this product only after this matter was brought to the firm's attention by our investigators.

Furthermore, our investigators found that numerous products were tested using analytical methods, provided by outside sources, which had not been validated/verified according to SOP CO-S850-001-03, "Laboratory Technology transfer of Analytical Methods" and SOP CO-S880-002-02, "Method Validation Requirements" to determine these methods suitability for their intended use.

In addition, our investigators documented many instances with extensive manipulation of data with no explanation regarding why the manipulation was conducted. This manipulation would include changing integration parameters or re-labeling peaks such that previously resolved peaks would not be integrated and included in the calculation for impurities.

3) Failure to establish a stability testing program which includes reliable, meaningful, and specific test methods as required by 21 CFR § 211.166(a)(3).

For example, test methods for the following drug products have not been shown to be stability indicating through forced degradation and/or limit of detection (LOD) and limit of quantification (LOQ) determinations during method validations Is required by SOP CO-S880-002-02, "Method Validation Requirements": [redacted] Tabs; [redacted] Tabs; [redacted] Gel Caps; [redacted] Gel Tabs; and [redacted].

Also, analytical methods for several drug products instruct the analysts to ignore peaks associated with mobile phase, diluent, placebo and standard injections without prior identification of those peaks. Therefore, there is no assurance that all impurities would be detected and/or quantified in any of the stability studies conducted by the firm.

In addition, although your firm conducts impurity testing for [redacted] tablets, [redacted] softgels [redacted] caplets; and [redacted] mg tablets, it does not have written procedures for impurity testing as required by 21 CFR 211.160(a) and (b).

4) Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications as required by 21 CFR § 211.192.

For example, you failed to conduct adequate laboratory investigations for the following out of specification results, which is also required by our SOP for investigating out of specification analytical results of drug products. [redacted] mg tablets had four stability study lots with failing individual unknown impurities. The investigation into this matter was done a year later and did not adequately identify the cause of the failure in that the investigation concluded that the [redacted] buffer in the mobile phase was causing degradation of the active in the samples; however, the active in the standard, which was also in contact with the mobile phase, was not degraded.

Assay values of over [redacted] were obtained during the stability study for [redacted] mg. The sample was re-filtered and injected reportedly due to the use of a wrong syringe filter with the initial injection. No laboratory investigation was conducted into these events.

You failed to investigate failing content uniformity test results for [redacted] Caplets, Lot [redacted]. This product was recalled during the inspection after our investigators discussed the failing results with your firm's representatives.

In addition, manufacturing discrepancies such as broken tablets and incomplete coating were not investigated as instructed in your SOP CO-S150-003-05, "Non Conformance Report." During the last two years, over 100 lots of various products had to be screened for broken tablets, sticking, black specks, coating defects, and/or screened for potential metal contamination.

5) Failure to establish adequate controls and procedures to assure the authenticity, integrity, and security of all electronic records including data generated in the laboratory as required by 21 CFR § 211 .68(b).

System administrator privileges were to be assigned to validation chemists, lead chemists, and laboratory supervisors only. These privileges include the ability to modify and delete raw data files and to lock/unlock projects for reprocessing in the chromatographic data acquisitions system which is used in the laboratory for finished product release testing, stability testing, and method validation studies. Our investigators documented numerous instances where these privileges were reassigned to other chemists without documentation or justification some of which resulted in extensive manipulation of data with no explanation regarding why the manipulation was conducted.

We acknowledge receipt of your response to the FDA 483 dated April 9, 2007, and your May and June monthly status updates dated May 31, 2007, and June 28, 2007, respectively. We also met with you and other representatives from your firm on March 26, 2007, and June 12, 2007, at the Atlanta District office. We understand that you intend to move the [redacted] previously conducted at the Fort Mill site [redacted] to the [redacted] by the end of [redacted], at which time the Fort Mill site [redacted]. However, you expressed your intention to continue [redacted] at the Fort Mill site of those bulk products currently stored at the site. Please be aware that packaging is a manufacturing operation and therefore we expect you to implement and follow adequate controls as required by the regulations. In addition, because part of your corrective action plan is to [redacted] to your other sites, we request that you explain your plans for ensuring compliance with all laws and regulations governing the manufacturing of drugs at those sites.

Note that transferring of manufacturing operations of products pursuant to an Abbreviated New. Drug Application requires the submission of a supplement by the sponsor and a compliance check of the intended manufacturing site. Please submit evidence that the pertinent individuals were notified of the manufacturing site change.

Neither this letter nor the observations noted on the Form FDA 483 are intended to be an all-inclusive list of deficiencies that may exist at your facilities. It is your responsibility to ensure that all drug products manufactured and distributed by your firm comply with the Act and the regulations. You should take prompt action to correct these violations, and you should establish procedures whereby such violations do not recur. Failure to do so may result in regulatory action without further notice, including seizure and/or injunction.

Federal agencies are advised of the issuance of all Warning Letters pertaining to drugs so that they may take this information into account when considering the award of contracts. In addition, any pending New Drug Applications, Abbreviated New Drug Applications, or export certificate requests submitted by your firm may not be approved until the above violations are corrected.

Please respond to this office in writing within fifteen (15) working days of receiving this letter. Your response should describe any specific actions, other than those already submitted, you will take, or have taken, to correct the violations described above and include an explanation of how each action being taken will prevent recurrence of similar violations. As noted earlier, please furnish evidence that sponsors have been notified of manufacturing site changes and what specific steps you have taken to implement corrective actions at all Leiner sites. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the time within which corrections will be completed.

Your response should be sent to Serene N. Ackall, Compliance Officer, at the address noted in the letterhead. If you wish to discuss this letter you should contact Serene N. Ackall at 404-253-1296.



Mary H. Woleske, Director
Atlanta District

Cc: Jeff Lukens
Senior Director Quality Assurance/Quality Control (East Coast)
Leiner Health Products
355 Crestmont Drive
Fort Mill, SC 29708-8321