Inspections, Compliance, Enforcement, and Criminal Investigations
Prime Enterprises, Inc 1/29/09
Department of Health and Human Services
|Public Health Service
Food and Drug Administration
|555 Winderley Pl., Ste. 200
Maitland, Fl 32751
RETURN RECEIPT REQUESTED
January 29, 2009
Mohamed Barakat, President
Prime Enterprises, Inc.
16363 NW 49th Ave
Miami Lakes, FL 33014-6316
Dear Mr. Barakat:
An inspection of your drug manufacturing facility located at 16363 NW 49th Ave., Miami. Lakes, FL conducted by our Food and Drug Administration (FDA) investigator from July 28, 2008 through August 1, 2008, determined that you are a manufacturer of human and veterinary drug products and cosmetics. The inspection revealed significant deviations from the current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211, with regard to the manufacture of pharmaceutical products by your facility. The deviations reported by the investigator cause your finished drugs to be adulterated within the meaning of 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)].
In addition, this inspection also revealed that your firm is manufacturing and/or marketing unapproved drugs in violation of Section 505(a) of the Act [21 U.S.C. § 355(a)] and the drugs are also misbranded in violation of Section 502 of the Act [21 U.S.C. § 352].
1. 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, and to extend the investigation to other batches that may have been associated with the specific failure or discrepancies, and to create a written record of the investigation including conclusions and follow-up [21 CFR § 211.192].
Specifically, investigations into the failure of batches to meet specifications in response to out-of-specification (OOS) results were incomplete or not documented. In response to OOS results, your firm remixed batches and/or added further ingredients, and then resampled to obtain passing results without performing adequate investigations into the root cause of your manufacturing problems. Further, your firm failed to expand investigations to determine if other lots were possibly affected. For example:
a) OOS Report # 00S07003 was opened on February 1, 2007, to investigate an OOS Clotrimazole assay result of 0.87% (spec:[(b)(4)] for FXP Anti-fungal (7) Mousse, lot # 61212. The OOS review stated, "The batch was not mixed properly. The batch was remixed." After remixing a passing result was obtained, the OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.
b) OOS Report # 00S07014 was opened on June 11, 2007, to investigate an OOS Clotrimazole assay result of 0.79% (spec. [(b)(4)] for EXP Dry Skin Anti-Fungal 7E Mousse, lot # 70603. Results of the laboratory investigation were not documented. The OOS review stated, "The batch was not mixed properly. The batch was remixed." After remixing a passing result was obtained, the OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.
c) OOS Report # 00S08005 was opened on February 14, 2008, to investigate multiple OOS assay results for three active ingredients in the bottom sample of the blend of HT Sport Spray SPF 30, lot # 8294A. The batch was adjusted with [(b)(4)] and resampled to obtain a passing result. The OOS investigation was closed and the batch was released without conducting an investigation into the cause of the failure.
Please note that it is the responsibility of your firm to investigate the cause of the failure of a batch of a drug product to meet its specifications and to include conclusions and follow-up measures to prevent recurrence of such manufacturing problems.
This is a repeat observation from the August 2006 inspection.
2. Failure to reject drug products that did not meet established standards or specifications and other relevant quality control criteria [21 CFR § 211.165(f)].
For example, Penetran, lot 71011, manufactured in January 2008, revealed a laboratory OOS assay test result for the active ingredient Ammonia of 3.4 % (spec: [(b)(4)]). However, the batch was released, and no records provide a science-based rationale for the decision (such as a determination of laboratory error.) Rather, records indicate that your personnel suggested changing the specification so that the result obtained would be a passing value, but there are no records to support a scientific rationale for a change of specification and it does not appear that the specification was changed prior to release of this lot.
This is a repeat observation from the August 2006 inspection.
3. Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products [21 CFR § 211.166(a)]. Specifically, stability samples were not collected or tested as required per your firm's General Stability Protocol. For example:
a) PRO-900 General Stability Protocol, Rev. 0, effective July 3, 1996, Section 4.1, states "A minimum of [(b)(4)] samples will be collected for each production lot placed on stability testing." Your firm failed to follow the stability protocol in that only [(b)(4)] samples per production lot were collected.
b) The procedure for routine stability testing, PRO-900 General Stability Protocol, Rev. 0, effective July 3, 1996, stated stability testing requirements. Stability samples of Lidocaine Bum Relief Cream lot # 61058 were placed on stability on December 11, 2006, and all stability time points (3, 6, 9, and 12 months Room Temperature) were later tested at the same time (on April 2, 2008). In addition, stability samples of Lidocaine Bum Relief Cream lot # 70308 placed on stability on May 29, 2007, were not tested at the 9 month RT time point.
This is a repeat observation from the August 2006 inspection.
4. Failure to establish written procedures for production and process control designed to assure that drug products have the identity, strength, quality and purity that they are represented to possess [21 CFR § 211.100(a)].
For example, the validation for the Flexitol anti-fungal liquid product manufacturing process is inadequate. Specifically, the Flexitol validation batches lacked sufficient manufacturing instructions such as mixing times to establish appropriate process controls and demonstrate the process is reproducible. Further, process validation studies were not performed for the following drug products: sunscreens, Lidocaine cream, Psoriaway, and Penetran Plus. Your firm failed to identify process parameters, write validation protocols, and show that product performance is consistent and reproducible from batch-to-batch for these above human and veterinary drug products. Demonstrating reproducibility of the manufacturing process at commercial scale is a fundamental and meaningful part of process validation. After establishing a validated manufacturing process, you must follow your written procedures to maintain the process in a state of control. (See 21 CFR §211.100(b)) We further note that this obligation to establish and follow such procedures is ongoing over the life of the product/process, even as materials, equipment, production environment, personnel, and manufacturing procedures change. Your response dated September 7, 2006, for this same observation from the previous inspection states "We anticipate starting these validations within the next two or three months." Please provide the reason for the failure to fulfill this commitment to the Agency, explain the latest status of validation activities for your drug products, and your plans for future distribution while validation studies are pending.
This is a repeat observation from the August 2006 and June 2005 inspections.
5. Failure to follow written procedures for evaluating at least annually, the quality standards of each drug product to determine the need for changes in specifications or manufacturing or control procedures [21 CFR § 211.180(e)]. For example:
a) No annual product review has been completed for drug products produced in calendar year 2007.
b) The 2006 annual product review is insufficient in that it addresses all products together, without identifying each specific drug product.
This is a repeat observation from the August 2006 inspection.
6. Failure to include complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed in the master production and control records [21 CFR § 211.186(b)(9)]. Specifically, master production records lack mixing times. For example:
a) MBR-BFCR50, Lidocaine Burn Relief Cream, Rev. No. 0, Effective: 08/09/05, [(b)(4)] batch size), contains the following instructions under batching times: Step No. 11 states, "Mix thoroughly until all the components are completely [(b)(4)]:" Step No. 12 states, "Mix thoroughly until [(b)(4)];" Step No. 15 states, "Mix thoroughly until [(b)(4)]. Avoid [(b)(4)] at all times;"Step No. 18 states, "Mix thoroughly until [(b)(4)]" The mixing times are not documented in the batch record.
b) MBR-BFNO1 Eulactol Antifungal Liquid, Rev. No. 4, Effective 12/10/07, [(b)(4)] lb batch size) contains the following instructions under batching times: Steps No. 13 and No. 15 state, "Mix thoroughly until [(b)(4)]" Step No. 17 states," Mix the Main Tank thoroughly until [(b)(4)]." The mixing times are not documented in the batch record.
7. Failure to determine actual yields at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the human drug product [21 CFR § 211.103].
Specifically, the actual yield is not determined by your firm after the blending phase prior to filling of each of your drug products. Review of your firm's batch records revealed batch reconciliation's, for the following lots: 1) MBR-BFGEL07 for Penetran cream, lot 71011; 2) MBR-BFCR50 for Lidocaine Burn Relief Cream, lot 70308, and; 3) MBRBFNO1 for Antifungal Liquid, lots 70829 and 80603. These above batch records incorrectly documented only estimated amounts for the actual yield determinations. These estimated amounts, which are entitled "Batch Quantity to Inventory" on page 5 of each of the above batch records, are calculated by subtracting the estimated product loss (whether due to spills, lines purges, Quality Control samples, etc.) from the theoretical yield. This is not an adequate method to determine actual yield. We are concerned that the value of 100%, as documented for each of these able lots, is not an accurate reflection of the percent yield (actual yield/theoretical yield [(b)(4)]. Please provide your rationale for the methodology to determine the actual yield. Among the reasons for accurate percent yield calculations is its value as a process monitoring tool that indicates if a manufacturing process is drifting. Yield calculations are a valid means of uncovering errors, which, if left undetected, may affect drug product quality.
Misbranded and Unapproved New Drugs
Based on the labeling collected during the inspection of your facility, Flexitol and Lidocane Plus, manufactured by your firm, 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 disease, or to affect the structure or any function of the body of man. As explained further below, Flexitol and Lidocane Plus do not conform to the formulation and labeling provisions of relevant OTC monographs. Therefore, these products are new drugs, as defined by 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) respectively], a new drug may not be introduced or delivered for introduction into interstate commerce unless an FDA-approved application is in effect for the drug. Based on our information, you do not have any FDA-approved applications on file for these drug products.
Flexitol and Lidocane Plus are also misbranded under Section 502(o) of the Act, 21 U.S.C. § 352, because they have not been listed as required by Section 510(j) of the Act, 21 U.S.C. § 360(j). In addition, Flexitol and Lidocane Plus violate various other misbranding provisions of section 502 of the Act [21 U.S.C. § 352].
Flexitol is an OTC anti-fungal drug product with the declared active ingredient Undecylenic Acid 25%. As described in more detail below, your labeling of Flexitol is inconsistent with the labeling requirements under FDA's OTC Drug Review and violates various provisions of the Act.
Your labeling of Flexitol for fungal nail infections is not consistent with the
final monograph for Topical Antifungal OTC Drug Products at 21 CFR Part 333, Subpart C Topical Antifungal Drug Products. Your labeling insert states, "Treating Nail fungus infection with Flexitol Anti-Fungal Liquid"; in addition, the outer package includes before and after photos of nails that have been treated with Flexitol, accompanied by captions indicating that the product is for use to treat fungus. In order for OTC topical antifungal drug products to be generally recognized as safe and effective and not misbranded, and thus be marketed without an approved NDA, they must meet the requirements of the final monograph for Topical Antifungal OTC Drug Products [See 21CFR § 333.201(a)]. That monograph does not recognize any active ingredients for OTC use to treat fungal infections of the scalp or nails; according to 21 CFR § 333.250, the only indications for use permitted for the antifungal ingredient Undecylenic Acid, used in Flexitol, are athlete's foot, jock itch, and ringworm. In fact, the monograph requires such products to include a direction for use stating that the product is not effective on the scalp or nails [21 CFR § 333.250(d)(1)]. In addition, 21 CFR § 310.545(a)(22)(iii) indicates that no OTC antifungal drugs marketed without an NDA may make any claims for use on the nails.
Because Flexitol, as marketed for use in the treatment of fungal infections of the nails, is not generally recognized as safe and effective, it is a "new drug" as defined by section 201(p) of the Act, 21 U.S.C. § 321(p). Because Flexitol is a new drug, its marketing without approved applications causes it to violate sections 301(d) and 505(a) of the Act, 21 U.S.C. §§ 331(d), 355(a).
Flexitol is also misbranded under section 502(a) of the Act because, while its directions for use state that it is not effective on the nails, as described above, other materials accompanying the product and the promotional photos on the packaging clearly demonstrate that it is intended for use in fungal nail infections and the use of "before and after" photos indicate that it is effective for this use. The discrepancy between the statement of ineffectiveness included in the directions for use and the other promotional statements and photos causes the labeling to be false and misleading.
Your product is also misbranded under section 502(f)(2) of the Act, 21 U.S.C. § 352(f) (2), because Flexitol is marketed without an approved NDA and its labeling does not include the warning, "Avoid contact with the eyes," as required by 21 CFR § 333.250(c)(1) (iii).
In addition, labeling for Flexitol lists Undecyclenic Acid 25% as the only active ingredient. However, based on the labeling insert which states, "Flexitol Anti-Fungal liquid includes tea tree oil which has a natural antifungal action, antibacterial and antiseptic properties to help protect the skin from further infection," tea tree oil is also an active ingredient. Under 21 CFR § 201.66(b)(2), any component in a drug that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the body of humans, is considered an active ingredient. The failure to declare the presence of tea tree oil as an active ingredient misbrands Flexitol under Section 502(e)(1)(A)(ii) of the Act.
B. Lidocane Plus
Lidocane Plus is an OTC drug product that contains the declared active ingredient Lidocaine Hydrochloride 4%. Your labeling of Lidocane Plus is inconsistent with labeling requirements under FDA's OTC Drug Review and violates various provisions of the Act.
In order for a drug to be included in FDA's OTC Drug Review, it must either comply with requirements under 21 CFR 330.14, or the product or similarly formulated and labeled products must have been marketed as OTC drugs at the inception of the OTC drug review on May 11, 1972. Lidocaine Plus does not meet these requirements, and thus cannot be marketed as an OTC topical analgesic product or OTC antiseptic product, types of drug products for which FDA has issued tentative final monographs under the OTC Drug Review.
As described further below, under the OTC Drug Review, FDA has issued tentative final monographs (TFMs) for OTC topical analgesic products and two types of OTC antiseptic products. As a general matter, FDA does not object to the marketing of products that comply with the formulation and labeling requirements described in tentative final monographs, along with any other regulations affecting these products. Marketing products in conformance with a TFM, 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). In this case, however, Lidocaine Plus does not comply with the formulation and labeling requirements of the TFMs.
For example, the Tentative Final Monograph (TFM) for External Analgesics (48 FR 5852, February 8, 1983), which is FDA's proposal for such products in the developing OTC monographs, does not include many of the indications listed on the labeling for Lidocane Plus. The Tentative Final Monograph for External Analgesics only includes indications for temporary relief of pain and itching associated with minor burns, sunburn, minor cuts, scrapes, insect bites, or minor skin irritations. Your product is indicated for relieving "pain and itching . . . from chemical bums, sun poisoning. Anti-itch for stings [sic] rashes & jock itch, hemorrhoids, dry & flaky skin, shingles/dermatitis, Poison Ivy, Oak & Sumac, athletes foot, Eczema/Psoriasis, chaffing." None of these aforementioned indications are included in the TFM for External Analgesics.
You also label your product as a "Burn & First Aid Cream" for use in preventing infection: "First Aid Power for prevention of infection of minor cuts, scrapes and abrasions, first & second degree burns, radiation dermatitis, wound care, bed sores. Avoids allergic reaction from antibiotic use." OTC health care antiseptics and OTC first aid antiseptics are being evaluated under FDA's OTC Drug Review. Tentative final monographs (TFMs) for these products were published in the Federal Register of June 17, 1994 (59 FR 31402) and July 22, 1991 (56 FR 336444). These TFMs are available on FDA's Internet website at www.fda.gov/cder/otcmonographs/category sort/antimicrobial.htm. However, none of the active ingredients and only some of the indications listed on your product's labeling conform to either of the TFMs for antiseptic products.
Because Lidocane Plus does not comply with the labeling and formulation requirements described in the TFMs described above, it is not generally recognized as safe and effective for these indications, causing Lidocane Plus to be a "new drug" as defined by section 201(p) of the Act, 21 U.S.C. § 32l(p). Because Lidocane Plus is a new drug, its marketing without approved applications causes it to violate sections 301(d) and 505(a) of the Act, 21 U.S.C. §§ 331(d), 355(a).
Furthermore, Lidocaine Hydrochloride 4% is listed as the only "active ingredient" on the label of Lidocaine Plus. However, based on the labeling declaration "Plus Aloe / Burn & First Aid Cream," aloe also appears to be an active ingredient, although it is unclear if it is indicated for use as an external analgesic or as a first aid antiseptic. As previously indicated, under 21 CFR § 201.66(b)(2), any component in a drug that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the body of humans, would be considered an active ingredient. The failure to declare aloe as an active ingredient in the label of Lidocane Plus causes the products to be misbranded under section 502(e)(1)(A)(ii) of the Act, 21 U.S.C. § 352(e)(1)(A)(ii).
We note, moreover, that aloe is not authorized as an active ingredient under the TFMs for external analgesics, healthcare antiseptics, or first aid antiseptics. In addition, on June 19, 2008 (73 FR 34895), the agency introduced a proposed rule that would amend the list of nonmonograph ingredients in 21 CFR 310.545, to indicate that aloe vera is not generally recognized as safe and effective for use as an external analgesic.
In addition, Lidocane Plus, as presently marketed, does not comply with the OTC Drug Facts Panel requirements under 21 C.F.R. §201.66. For instance, your product lacks a "Purpose" heading. Thus, your product is misbranded within the meaning of section 502(c) of the Act, 21 U.S.C. § 352(c) because the required OTC Drug Facts Panel information does not appear prominently on the labeling.
The issues discussed in this letter and on the Form FDA 483 are not intended to be an all-inclusive statement of the objectionable conditions that exist at your facility. You are responsible for investigating and determining the causes of the objectionable conditions identified above and for preventing their recurrence or the occurrence of other objectionable conditions. It is your responsibility to assure that your firm complies with all requirements of the Act and FDA regulations.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure and injunction. Also, federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when considering the award of contracts.
We also request that you outline the action you are taking to discontinue the marketing of the unapproved drug products produced at your facility. Also please note that if you are no longer marketing this (these) product(s), you must update the Drug Listing files in accordance with 21 CFR § 207.30(a)(2).
Within 15 working days of receipt of this letter please notify this office in writing of the specific steps you have taken to correct violations. Include an explanation of each step taken to prevent recurrence. of similar 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 or market any products, your response should so indicate, include the reasons for, and the date on which you ceased production.
Please send your reply to the U.S. Food and Drug Administration, Attention: Winston R. Alejo, Compliance Officer, 555 Winderley Place, Suite 200, Maitland, Florida, 32751. If you have questions regarding any issues in this letter, please contact Mr. Alejo at (407) 475-4731.
Emma R. Singleton
Director, Florida District