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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Nexgen Pharma Inc


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

Public Health Service
Food and Drug Administration
 Los Angeles District
Pacific Region
19701 Fairchild
Irvine, CA 92612·2506
Telephone: 949·608·2900
FAX: 949·608-4415



W/L 45-10

September 27, 2010

Steven R. Brown, President & CEO
NexgenPharma, Inc.
17802 Gillette Avenue
Irvine, CA 92614

Dear Mr. Brown:

During our March 1 to April 2, 2010, and April 19 to May 25, 2010 inspection of your pharmaceutical manufacturing facilities, Nexgen Pharma, Inc., located at 17802 Gillette Avenue, Irvine, California, and 1835 East Cheyenne Road, Colorado Springs, Colorado, investigators from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations 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)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.

In addition, your drug products are unapproved new drugs in violation of section 505(a) of the Act [21 U.S.C. § 355(a)]. These unapproved new drugs are also misbranded in violation of 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)].

We have reviewed your firm's responses (b)(4), and note that they lack sufficient corrective actions.

Specific violations observed during the inspections include, but are not limited, to the following:

CGMP Violations

A. Irvine, California, Facility

1. Your firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, or quality of the drug product [21 C.F.R. § 211.67(a)]. For example,

a. Your firm has not conducted adequate cleaning validation or provided scientific justification for a (b)(4) of the following drug products:

(b)(4) Tablet
(b)(4) Tablet
(b)(4) capsule
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Capsule
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Capsule
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Tablet
(b)(4) Tablet

In your response, you state that you have cleaning procedures for all equipment and have employed the same cleaning procedures for the past (b)(4) You also state that your Cleaning Validation Procedure, (b)(4) However, your response fails to establish that existing studies support these products can be reproducibly cleaned using your existing cleaning procedures.

b. Your firm has not provided any documentation to demonstrate that trays used in (b)(4) for the (b)(4) of drug products (i.e., (b)(4) are adequately cleaned.

In your response, you state that the original (b)(4) reports contain the swabbing results for several pieces of equipment, including the (b)(4) Your response is inadequate because it is not clear if the study supports adequate cleaning and removal of all products or whether you are currently using the same (b)(4) equipment.

2. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release [21 C.F.R. § 211.165(a)].

For example, your firm did not determine the strength for (1) (b)(4); (2) (b)(4) and; (3) (b)(4) which are components in finished drug products such as (b)(4) Tablets, (b)(4) Tablets, and (b)(4) Tablets.

In your response, you state that (b)(4), (b)(4) and (b)(4) are closely related in structure and thus, do not necessitate individual testing for strength. These components are individual active components in the formulations of (b)(4) Tablets, (b)(4) Tablets, and (b)(4) Tablets. As such, you are required to test each of these components for conformance to final specifications. We find your failure to test especially notable since your firm was observed to add up to (b)(4) in overages of the described components into these formulations.

3. Your firm has failed to justify deviations from written production and process control procedures [21 C.F.R. 211.100(b)].

For example, your firm manufactured a reduced batch size of (b)(4) Tablets ((b)(4)) and released the lot based upon finished product testing. Specifically, your deviation report, (b)(4), indicated that you did not manufacture a full batch of (b)(4) tablets due to insufficient materials. Your firm allowed this deviation from the usual validated manufacturing process and justified the release of the lots on passing finished product testing. It is a fundamental concept of CGMP that finished product testing alone is not an adequate control to assure that finished product have the necessary quality attributes.

In your response, you state that a (b)(4) becomes more efficient with (b)(4). Your response is inadequate because you do not provide adequate justification to demonstrate how manufacturing a smaller batch, using the process parameters for a large batch, did not impact the quality of the finished product.

4. Your firm has failed to provide justification, in the master production and control records, for reasonable variations in the amount of components necessary for the preparation in the dosage form [21 C.F.R. § 211.186(b)(4)].

For example, your firm adds overages up to (b)(4) of, but not limited to, the following components: (1) (b)(4) (2) (b)(4) (3) (b)(4), and; (4) (b)(4). These components are added in various combinations to the (b)(4) Tablets, (b)(4) Tablets, and (b)(4) Tablets formulations without justification.

In your response, you state that the overages are considered appropriate, and that the amounts of the components are so small that losing even a few milligrams would render the final drug product Out-of-Specification (OS) as a result of processing. Your response is inadequate because you do not test the strength of each individual active ingredient in the finished product. There are no assurances that the overages used are appropriate.

5. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)].

For example, although you receive a Certificate of Analysis (COA) and confirm several of the test results through your own testing, you have not conducted an analysis of components to establish the reliability of the manufacturer's COA for those listed below:

(b)(4) for residual solvents and chromatographic purity

(b)(4) for related substances and residual solvents

(b)(4) for residual solvent

(b)(4) for residual solvents

(b)(4) for residual solvent

Your response is inadequate because you have not committed to conduct the testing or ensure the vendor results are reliable.

B. Colorado Springs, Colorado, Facility

1. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release [21 C.F.R. 211.165(a)).

For example, your did not determine the strength of 11 of the 13 components in your (b)(4) Capsules.

In your response, you state that you are going to test each drug product component at least once a year. We find your failure to test especially notable since your firm was observed adding up to (b)(4) in overages of the untested components in your (b)(4) Capsules.

2. Your firm does not have a written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expirations dates [21 C.F.R. 211.166(a)).

For example, your firm does not have adequate stability data to support the labeled expiry of (b)(4) Capsules. You indicated that stabilities studies are only performed if the customer pays to conduct the studies.

Unapproved and Misbranded Prescription Drugs

In addition to violating CGMPs, you manufacture and market unapproved new drugs in violation of the Act at your facilities at 17802 Gillette Ave. Irvine, CA 92614 and 1835 East Cheyenne Road, Colorado Springs, Based on the information your firm submitted to FDA's Drug Registration and Listing System and the information collected during the inspection of your facility, you manufacture the following prescription drugs, including, but not limited to:




These products are drugs within the meaning of section 201 (g) of the Act, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they are "new drugs" within the meaning of section 201(P) of the Act [21 U.S.C. § 321(P)] because they are not generally recognized as safe and effective for their labeled uses. Under sections 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under either section 505(b) or (j) of the Act [21 U.S.C. § 355(b) or (j)] is in effect for the drug. Based on our information, you do not have any FDA-approved applications on file for these drug products. The marketing of these products, or other applicable products, without an approved application constitutes a violation of these provisions of the Act.

Additionally, because the above products are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use this product safely for its intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing it to be misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)] Because your products lack required approved applications, they are not exempt under 21 C.F.R. § 201.115 from the requirements of section 502(f)(1) of the Act. The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the Act [21 U.S.C. § 331(a)].

You should discontinue manufacturing and distributing all of your unapproved drugs at all facilities immediately, with the exception of the products we have separately discussed. For questions about the regulatory status of your drugs, contact Kathleen Joyce, at 301-796-3329. For assistance in communicating with the FDA concerning the application process for your unapproved drug(s), contact FDA's unapproved drugs coordinator, Dr. Sally Loewke, at 301-796-0710.

To ensure that all drugs marketed in the U.S., prescription and over-the-counter, have been shown to be safe and effective, FDA published a Compliance Policy Guide (CPG) Section 440.100, Marketed Unapproved Drugs, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf. FDA expects manufacturers of products requiring approval to submit applications to the agency showing that their products are safe and effective. The CPG describes the very strict criteria under which the Act permits drugs to be marketed without approval. The CPG also outlines the Agency's enforcement policies aimed at efficiently and rationally bringing all drugs requiring approved applications into the approval process.

The 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 and the occurrence of other violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.

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 limitation, 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 drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.

We also noted that your did not conduct stability testing on two lots (b)(4) and two lots (b)(4). Your response states that you rely on stability data recorded in the years before and after to support the labeled expiry. It is FDA's expectation that you test an adequate number of batches of each drug product, at adequate intervals, as part of your stability program. A dosage form is a complex unit and there may be variables in the production process, such as changes in formulation, raw material lots and suppliers, and equipment. It is imperative that stability studies are not limited to what your current practice allows. A portion of annual production batches should be the subject of an ongoing stability program.

In addition, we remind you of your responsibility for ensuring that your firm's drug manufacturing operations comply with applicable requirements, including the CGMP regulations. FDA expects Nexgen Pharma, Inc., to undertake a comprehensive and global assessment of your manufacturing operations to ensure that drug products conform to FDA requirements.

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. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute the drug products manufactured at this facility, and provide the dates and reasons you ceased production.

Your reply should be sent to:

Blake Bevill, Director
Los Angeles District Domestic Compliance Branch
U.S. Food Drug Administration
19701 Fairchild
Irvine, CA  92612

If you have any questions regarding this letter, please contact John J. Stamp, Compliance Officer, at (949) 608-4464.

Alonza E. Cruse
District Director

Cc: Ingeborg Small, Branch Chief
Califomia Department ofPublic Health
Food and Drug Branch
1500 Capitol Avenue, MS-7602
P.O. Box 997413
Sacramento, CA 95899-7413