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U.S. Department of Health and Human Services

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Enforcement Actions

GDMI, Inc 11/27/09

 

 

   

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

Public Health Service
Food and Drug Administration
  Dallas District
4040 North Central Expressway
Dallas, Texas 75204-3128

November 27, 2009

2010-DAL-WL-04

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED


Ms. Gina M. Ferrall, Vice President and C.O.O.
GDMI, Inc.
2763 Marquis Drive
Garland, TX 75042

Dear Ms. Ferrall,


This is regarding a June 11-29, 2009 inspection of your pharmaceutical manufacturing facility, GDMI, Inc., 2763 Marquis Drive, Garland, Texas, conducted by Food and Drug Administration investigators. The inspection identified significant violations of the Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), 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 regulations.

The inspection also revealed that over-the-counter (OTC) drug products being manufactured and marketed by your firm are unapproved "new drugs" in violation of Section 505(a) of the Act [21 U.S.C. § 355(a)] and/or misbranded drugs in violation of Sections 502(c) and 502(f)(1) of the Act [21 U.S.C. §§ 352(c) and 352(f)(1)].
We have received your firm's response of June 30, 2009, and note that it lacks sufficient corrective actions.

Good Manufacturing Practice Deviations

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

1. Reports of analyses from component suppliers are accepted in lieu of testing each component for conformity with all appropriate written specifications, without conducting at least one specific identity test on each component and establishing the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals [21 CFR § 211.84(d)(2)].

Your firm accepts suppliers' certificates of analysis (COA) without having qualified the vendor, and you do not conduct identity testing on all components received, such as epinephrine, hydrocortisone, hydroquinone, clotrimazole, lidocaine, tetracaine, and methylparaben.

We acknowledge the commitment in your response of June 30, 2009, to establish procedures for the identity testing of each raw active ingredient and audits of vendors. However, this response does not address identity testing of other drug product components. In addition, it gives no specific timeframe for completion and your proposed overall timeframe of one year for completion of all corrective actions is not acceptable.

2. Adequate written procedures for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of drug products have not been established or followed [21CFR § 211.67(b)]. For example, your firm has not validated all of the procedures used to clean equipment and containers (storage drums) used to manufacture and hold in-process and finished OTC drug products. The Vice President and Director of Plant Operations stated that cleaning validations had not been completed for most products. During the current inspection, we observed processing equipment tagged as cleaned that contained product in the drain area of the equipment, and finished product residue around the mixing blade and side of kettles. However, your SOP 1101, "Manufacturing and Equipment Cleaning," requires that any equipment still showing visible residues after the cleaning process be recleaned. In addition, this SOP was not followed in that hoses were stored touching the floor after cleaning.

We acknowledge your response of June 30, 2009, which states that all cleaning procedures are validated. However, as noted above, management indicated that not all cleaning validations were complete. In addition, the response did not include any documentation of these validations.

3. Records of maintenance, cleaning, and sanitization are not kept as specified in 21 CFR §§ 211.180 and 211.182 [21 CFR § 211.67(c)]. For example, written records of major equipment cleaning and maintenance are not included in individual equipment logs. In addition, cleaning and maintenance records do not identify the products processed in each piece of equipment.

We acknowledge the commitment in your response of June 30, 2009, to create new log sheets specific to each piece of equipment. However, this response gives no specific timeframe for completion and your proposed overall timeframe of one year for completion of all corrective actions is not acceptable.

4. Appropriate procedures designed to prevent objectionable microorganisms in drug products not required to be sterile have not been established [21 CFR § 211.113(a)].For example, your firm's purified water system that provides water for the production of liquid and semisolid drug products has not been validated to show that it produces water that meets the necessary specifications for objectionable microorganisms with sufficient consistency to justify the sampling frequency employed. In addition, there has been no preservative effectiveness testing for the methyl paraben and propyl paraben, used as preservatives, in the finished products and there is no testing of the finished products for the quantities of these compounds.

We acknowledge the commitments in your response to create new SOPs to address maintenance of the purified water system and to conduct preservative effectiveness testing on a limited number of products. However, this response gives no specific timeframe for completion and your proposed overall timeframe of one year for completion of all corrective actions is not acceptable.

5. A quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred, has not been established [21 CFR § 211.22(a)]. For example, there are no procedures establishing a quality control unit or designating its personnel. Also, individuals and organizational units within your firm that perform some of the functions of a quality control unit are not independent from the management in charge of production. In addition, the inadequacy of your firm's quality oversight is demonstrated by the failure to perform thorough investigations of product failures and complaints.

We acknowledge the commitment in your June 30, 2009 response to develop a new SOP defining a quality control unit. However, this response gives no specific timeframe for completion and your proposed overall timeframe of one year for completion of all corrective actions is not acceptable.

6. Thorough investigations of unexplained discrepancies and failure of batches or any of their components to meet any of their specifications are not performed [21 CFR § 211.192].

Specifically, your firm failed to investigate (b)(4) Wound Gel (b)(4) test failures obtained for 5 of (b)(4) lot during release testing of the drug product. For example, 5 batches of (b)(4) Wound Gel failed your release test for (b)(4). One lot out of 5 was destroyed and the other 4 lots were reworked. We noted that out-of-specification (ODS) forms were not completed as per SOP #1608, section 4, titled, "Production and Process Controls: OOS for OTC drugs," and individual investigations were not conducted.

We acknowledge the commitment in your response to revise your OOS SOP and related forms to better document complete investigations of unexplained discrepancies. However, this response gives no specific timeframe for completion and your proposed overall timeframe of one year for completion of all corrective actions is not acceptable.

7. Written procedures for production and process control designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess have not been established (21 CFR § 211.100(a)]. For example, your firm's manufacturing processes have not been validated. There is no documentation to show that any of your firm's manufacturing processes have been validated in accordance with your SOP 1603, "Concurrent Manufacturing Process Validation." In addition, your firm failed to establish a written change control procedure that documents changes in procedures, formulations, manufacturing processes and test methods.

We acknowledge the commitment in your response to create a new SOP to address change control and documentation of changes. However, this response gives no specific timeframe for completion and your proposed overall timeframe of one year for completion of all corrective actions is not acceptable.

8. The procedures in the written testing program designed to assess the stability characteristics of drug product are not followed [21 CFR § 211.166(a)]. For example, your SOP 1607, "Production and Process Controls: Stability Testing," is not followed in that accelerated and real time stability testing is not performed on samples from (b)(4) full-scale production batches of drug product.

We acknowledge the commitments in your response to establish new procedures to require quality control unit review of stability data submitted by client firms and improve laboratory equipment used for stability testing. However, the response does not address your firm's failure to follow your own procedures for stability testing.

9. Employees engaged in the manufacture, processing, packing, and holding of a drug product have not been trained in the particular operations they perform, or in the current good manufacturing practices as they relate to the employee's functions [21 CFR § 211.25(a)].Your employee training program addresses CGMP during the (b)(4) of employment and requires that refresher training be provided (b)(4). However, the written training logs do not specify the type of training employees were given other than 21 CFR Parts 210 and 211. There are no records that show that CGMP training specific to the employees' duties was performed, as required by your SOP 1200, "Personnel Training." Employees were observed during the inspection to be handling drug products and drug components without proper protective apparel to protect drug products from contamination, contrary to the your firm's written procedures and CGMP. This demonstrates that the training that took place was ineffective.

We acknowledge the assertion in your June 30, 2009 response that employees will be retrained during the month of August. We will review the results of this training at the next scheduled inspection.

Unapproved and Misbranded Over-the-Counter (OTC) Drugs

Your firm manufactures numerous drug products for over-the-counter (OTC) use,including those noted above. During the inspection noted above the investigators collected your labeling for the following products: (b)(4) Antiseptic Wound and Skin Cleanser" (b)(4) Antifungal Cream(b)(4) Antifungal Treatment" (b)(4) Fire Ant (b)(4) Bite (b)(4) all of which are manufactured and distributed by your firm. As presently labeled and promoted, these products are unapproved and/or misbranded drugs distributed by your firm in violation of Sections 505(a), 502(c) and 502(f)(1), respectively, of the Act [21 U.S.C. §§ 355(a), 352(c) and 352(f)(1)]. These violations are described in more detail below.

(b)(4)"Antiseptic Wound and Skin Cleanser"

The package labeling for "(b)(4) Antiseptic Wound and Skin Cleanser" identifies benzethonium chloride 0.1% as the sole active ingredient. This product is labeled for use, among other things, as an "Antiseptic ... SKIN CLEANSER" to be "Spray[ed]on infected area up to 3 times daily. May be covered with a sterile bandage. If bandaged let dry first." In addition, the product label  bears the reference (b)(4). The distributer, (b)(4), for whom you manufacture (b)(4) Antiseptic Wound and Skin Cleanser," describes this product on its Internet website, as effective against "MRSA (Methicillin Resistant Staphylococcus Aureus) • VRE (Vancomycin Resistant Enterococcus)" and the diseases caused by infection with these microorganisms. While these claims do not appear directly on the label of this product, they do appear in the labeling (website). Under regulation 21 CFR § 201.128, intended uses for a product manufactured by you include those uses for which you are aware and such intent "may be shown by the circumstances surrounding the distribution of the article" as discussed above and make you liable for these claims.

Based on these uses "(b)(4) Antiseptic Wound and Skin Cleanser" is a "drug," as defined by section 201(g)(1) of the Act (21 U.S.C. § 321(g)(1)), because it is intended to prevent diseases caused by pathogenic microorganisms.

Although benzethonium chloride at this concentration (0.1 %) is covered under FDA's OTC Drug Review for certain uses, it is not covered by that review when offered as an antiseptic cleanser in a leave-on/no-rinse ("Spray on ... let dry first."). Nor is this ingredient covered by the OTC Drug Review for use in preventing MRSA or VRE infections. See the Tentative Final Monograph (TFM) for OTC Health-Care Antiseptic Drug Products (59 FR 31402) and the TFM for OTC First-Aid Antiseptic Drug Products (56 FR 33644). These TFMs are available on FDA's Internet website at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentReso urces/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/UCM107143.pdf

Based on the above mentioned indications, (b)(4) Antiseptic Wound and Skin Cleanser" is a "new drug" as defined by section 201(p) of the Act (21 U.S.C. § 321(p)) because we are not aware of sufficient evidence to show that it is generally recognized as safe and effective for these labeled uses. We are also not aware of products like (b)(4) Antiseptic Wound and Skin Cleanser" having been marketed on or before the inception of the OTC Drug Review; nor is this product the subject of a final determination by FDA under 21 CFR § 330.14. Accordingly, it is not covered by that review.

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 or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. (b)(4) Antiseptic Wound and Skin Cleanser" does not have an approved application, and its introduction and delivery for introduction into interstate commerce violates these provisions of the Act. In addition, because (b)(4) Antiseptic Wound and Skin Cleanser" is offered for uses not described on the package labeling ("MRSA (Methicillin Resistant Staphylococcus Aureus) • VRE (Vancomycin Resistant Enterococcus)"), it is misbranded under section 502(1)(1) of the Act as further described under 21 CFR § 201.5(a) because the package labeling fails to provide directions for those uses.

"(b)(4) Antiseptic Wound and Skin Cleanser" is also being marketed in violation of section 502(c) of the Act, (21 U.S.C. § 352 (c)) because it does not fully comply with the "Drug Facts" labeling requirements under 21 CFR § 201.66. For example, "Purpose" or "Purposes" followed by the general pharmacological category(ies) or the principal intended action(s) of the drug (i.e., antimicrobial) is a required heading under 21 CFR § 201.66(c)(3).

Pending a final monograph for OTC first aid antiseptics, we would not object to the marketing of a benzethonium chloride 0.1% containing OTC skin wound cleanser that meets the provisions of the TFM for OTC First-Aid Antiseptic Drug Products, described above, and is offered as follows: "To clean superficial wounds," "for washing small superficial wounds," "aids in removal of foreign material such as dirt and debris," or "first aid product." Such marketing, however, is subject to the risk that a final monograph or rule may require reformulation and/or relabeling or FDA approval through the "new drug" procedures of the Act (section 505 of the Act; 21 U.S.C. § 355).

(b)(4) "Anti-Fungal Cream"

The package labeling for "(b)(4)Anti-Fungal Cream" identifies clotrimazole 1% as the active ingredient and claims that this product is intended "For the cure of athlete's foot (tinea pedis), jock itch (tinea cruris) and ring worm (tinea corporis). For the relief of itching, scaling, burning and discomfort that accompany these conditions,"Clotrimazole 1%, for these uses is covered by the Final OTC Monograph for Topical Antifungal Drug Products (21 CFR Part 333, Subpart C). However, the ingredients "Vitamins A. D, & E," are prominently featured on the principal display panel in such a manner as to suggest that they are "active ingredients," as described in 21 CFR § 201.66(b)(2). The  combination of c1otrimazole 1% with Vitamins A, D, and E are not permitted by the final monograph for OTC topical antifungal drug products (see 21 CFR 333.210). Therefore, "(b)(4) Anti-Fungal Cream" is a "new drug" as defined by section 201(p) of the Act (21 U.S.C. § 321(p)) because we are not aware of sufficient evidence to show that it is generally recognized as safe and effective when so formulated. 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 or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. "(b)(4) Anti-Fungal Cream" does not have an approved application and its introduction and delivery for introduction into interstate commerce violates these provisions of the Act.

Additionally, "(b)(4) Anti-Fungal Cream" violates section 502(c) of the Act, (21 U.S.C. § 352(c)) because it does not fully comply with the "Drug Facts" labeling requirements under 21 CFR § 201.66. For example, under 21 CFR § 201.66(d)(4), "When there is more than one statement, each individual statement listed under the headings and subheadings in paragraphs (c)(4) through (c)(7) of this section shall be preceded by a solid square or solid circle bullet of 5-point type size. Bullets shall be presented in the same shape and color throughout the labeling."

(b)(4) "Antifungal Treatment"

(b)(4) Antifungal Treatment' identifies miconazole nitrate 2% as the sole active ingredient. The indication that appears on the immediate container label claims that this product is "Proven clinically effective in the treatment of athlete's foot & ringworm. For the effective relief of itching, scaling, cracking, burning, redness, soreness, irritation, itchy, scaly skin between the toes, chafing associated with itching, burning feet." The immediate container label also identifies the (b)(4) Internet website, (b)(4). This website promotes an additional indication for (b)(4) Antifungal Treatment." The indication, "Kills fungus around and under the nails," appears on the website labeling along with a package label that shows the application of "(b)(4) Antifungal Treatment" to toenails. Under regulation 21 CFR § 201.128, intended uses for a product manufactured by you include those uses for which you are aware and such intent "may be shown by the circumstances surrounding the distribution of the article" as discussed above and make you liable for these claims.

The active ingredient, miconazole nitrate 2%, as formulated and labeled, and the indication that appears on the immediate container label are covered under the Final OTC Monograph for Topical Antifungal Drug Products (21 CFR 333, Subpart C). However. the Final OTC Monograph for Topical Antifungal Drug Products does not allow for the claim, "Kills fungus around and under the nails." This claim is specifically prohibited by regulation 21 CFR § 310.545(a)(22)(iii) no matter what active ingredient is used.

Based on the above mentioned indication, "(b)(4) Antifungal Treatment" is a "new drug" as defined by section 201(p) of the Act (21 U.S.C. § 321(p)) because we are not aware of sufficient evidence to show that it is generally recognized as safe and effective for this labeled use.

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 or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. "(b)(4) Antifungal Treatment" does not have an approved application, and its introduction and delivery for introduction into interstate commerce violates these provisions of the Act.

In addition, because "(b)(4) Antifungal Treatment" is offered for a use that is not described on the immediate container labeling ("Kills fungus around and under the nails,"), it is misbranded under section 502(1)(1) of the Act as further described under 21 CFR § 201.5(a) because the immediate container labeling fails to provide directions for those uses.

(b)(4)

The package labeling for (b)(4) identifies Lidocaine HCL 4% as the sole active ingredient. The indication that is featured on the label's principal display panel claims that this product is intended for the "Immediate and complete relief from pain and itching associated with (b)(4) stings."

Drug products intended for relieving pain and itching from insect bites and stings are being evaluated in the OTC Drug Review under External Analgesic Drug Products for OTC Human Use for Poison Ivy, Poison Oak, Poison Sumac, and Insect Bites Drug Products. See 54 FR 40818. At present, there is a proposed rule (TFM) for these. This TFM is available on FDA's Internet website through the following link:
htlp:/Iwww.fda.gov/downloads/Drugs/DevelopmentApprovaIProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/UCM077928.pdf. This TFM does not include indications related to (b)(4) stings and we are not aware of any OTC product formulated and labeled like (b)(4) having been available in the U.S. market on or before the inception of FDA's OTC Drug Review to be eligible for evaluation under that review. Accordingly, (b)(4) is a "new drug" as defined by section 201(p) of the Act (21 U.S.C. § 321(p)). 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 or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for it. (b)(4) does not have an approved application, and its introduction and delivery for introduction into interstate commerce violates these provisions of the Act.

Additionally, the product violates section 502(c) of the Act, (21 U.S.C. § 352(c)) because it does not fully comply with the "Drug Fact" labeling requirements under 21 CFR § 201.66. For example, under 21 CFR § 201.66(c)(4), "Use" or "Uses" followed by the indication(s) for the specific drug product" is required.

(b)(4) "Fire Ant (b)(4) Chigger (b)(4) and Bite (b)(4)

Drug products intended for relieving pain and itching from insect bites and stings are being evaluated in the OTC Drug Review under the External Analgesic Drug Products for OTC Human Use for Poison Ivy, Poison Oak Poison Sumac, and Insect Bites Drug Products, see 54 FR 40818. However,(b)(4) Fire Ant (b)(4) "Chigger (b)(4) and "Bite (b)(4) violate section 502(c) of the Act, (21 U.S.C. § 352(c)) because they do not fully comply with "Drug Fact" labeling requirements under 21 CFR § 201.66. For example, under 21 CFR § 201.66 (d)(4), 'When there is more than one statement, each individual statement listed under the headings and subheadings in paragraphs (c)(4) through (c)(7) of this section shall be preceded by a solid square or solid circle bullet of 5-point type size. Bullets shall be presented in the same shape and color throughout the labeling."

During the regulatory meeting conducted at the Dallas District's office on July 19, 2006, your management was informed of the need to revise the labeling for your OTC drug products to meet the pertinent OTC monograph requirements before marketing. Management committed to come into compliance with all applicable regulations, however, this compliance has not been attained.

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. 

Your firm also manufactures cosmetic products. Information from your company's emails shows that in March and April 2008 there was a problem with filth contamination in empty bottles provided for filling the (b)(4) product. The degree of filth appeared to be of unknown origin but possibly included dust or cardboard debris, which was determined to contaminate the bottles at levels mentioned, from fine to severe. The decision was made to fill these containers, even though contamination was evident. The investigation results noted from the March 10, 2008 Customer Complaint log states that "Fine debris appears to be from the cardboard that could have been floating in the air at the bottle manufacturer or even GDMI. GDMI filling reservoir is left uncovered, but heads are filtered. Boxes are broken down in filling area in proximity to open bottles. Bottles are dumped into trays during coding process and left uncovered." Trash and debris such as lint, dirt, grease, gasket material and cardboard may come into contact with the bottles under these conditions.

This above cosmetic product that was filled in contaminated containers could be considered adulterated under section 601(c) of the Act [21 U.S.C. § 361(c)] because it was prepared packed or held under insanitary conditions whereby it may have become contaminated with filth.

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 correction. Additionally, your response should state if you no longer manufacture or distribute Antiseptic Wound and Skin Cleanser with benzethonium chloride, or any other drug products, and provide the dates and reasons you ceased production. The response should contain any documentation, including any SOP regarding product container acceptability for receiving and rejection of contaminated lots. Further, we request in your written response a description of what corrective measures have been taken to eliminate possible sources of container contamination at your manufacturing facility.

Your reply should be directed to Thao Ta, Compliance Officer, U.S. Food and Drug Administration, 4040 N. Central Expressway, Suite 300, Dallas, Texas 75204. If you have any questions regarding any issue in this letter, please contact Mr. Ta at (214) 253-5217.

Sincerely,

/s/


Reynaldo R. Rodriguez, Jr.
Dallas District Director

 


cc: Mr. Terry Meacham, VP Director of Plant Operations
GDMI, Inc.
2763 Marquis Drive
Garland, Texas