Inspections, Compliance, Enforcement, and Criminal Investigations
Selder S.A. de C.V. 4/27/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Silver Spring, MD 20993
VIA UPS MAIL
April 27, 2012
Mr. Alejandro Martinez Villarreal
Director General and Owner
Selder S.A. de C.V.
Fernando Villapando #48
Colonia Guadalupe Inn 01020
Dear Mr. Villarreal:
During our September 19 to 23, 2011, inspection of your pharmaceutical manufacturing facility, Selder S.A. de C.V. located at Fernando Villapando #48, Colonia Guadalupe Inn, 01020, Mexico, D.F., Mexico, 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 product(s) 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. These drugs are also misbranded under section 502(f)(2) of the Act.
We acknowledge your written response to the Form FDA 483, submitted on October 19, 2011. However, because this response was received more than 15 business days after the Form FDA 483 was issued, the response has not been considered. We plan to evaluate your response to the Form FDA 483, along with any other written material provided in response to this warning letter.
Specific violations observed during the inspection include, but are not limited to, the following:
1. Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates [21 C.F.R. § 211.166(a)].
Two examples of violations of § 211.166(a) are as follows:
a. Your firm did not perform stability studies to support the (b)(4)-year expiry period for the XL-3 Cold Medicine Tablets in the (b)(4)-tablet package presentation.
b. Your firm did not perform stability studies to support either the (b)(4)-year expiry period for the XL-3 Cold Medicine Tablets in the 20-tablet presentation or the (b)(4)-year expiry period for the XL-DOL Tablets.
In your response to this letter, please include a review of all of your products’ stability data and your proposed plan for all of your products that are currently within expiry and distributed to the U.S. for which you do not have adequate supporting stability data. You should also include copies of your revised procedures designed to ensure that you test all products according to an approved stability program.
2. Your firm has not established written procedures to monitor the output and to 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)].
For example, you did not perform adequate in-process tests for the Children’s XL-3 Chewable Tablets after the (b)(4) of the production runs for lots # A136, A137, and A138 to assure the process remains in a state of control throughout the run. In addition, you failed to follow your procedure INS-05-01, entitled “Controles en Proceso” section 188.8.131.52, approved on January 21, 2010 which requires (b)(4) samples be taken at the (b)(4) of the (b)(4) operation.
In your response to this letter please include provisions for frequent sampling of tablets throughout the (b)(4) operation, and include a strong scientific and quality assurance rationale for your in-process sampling and testing approach (e.g., including an understanding of variability in the process and use of suitable statistical procedures). In addition, please review all in-process test results for products distributed to the U.S. within expiry, and provide a risk assessment on all lots for which your firm can provide no evidence that you performed adequate in-process tests and obtained results that support release of your drug products.
3. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100(a)].
Two examples of violations of § 211.100(a) are as follows:
- Your firm failed to appropriately validate the manufacturing processes for the Children’s XL-3 Chewable Tablets, XL-3 Cold Medicine Tablets, and XL-DOL Tablets. You did not validate the (b)(4) processing step and you did not evaluate the (b)(4) time ((b)(4)), tablet (b)(4) speed, or the tablet (b)(4) feed rate. In addition, you failed to document in the batch records the equipment used during the validation studies.
- Your firm does not have validation protocols for the validation of Children’s XL-3 Chewable Tablets, XL-3 Cold Medicine Tablets, and XL-DOL Tablets.
In your response to this letter, you should include evidence that your firm has successfully validated the manufacturing process for Children’s XL-3 Chewable Tablets, XL-3 Cold Medicine Tablets, and XL-DOL Tablets.
4. Your firm does not have laboratory control records which include complete data derived from all tests necessary to ensure compliance with established specifications and standards [21 C.F.R. § 211.194(a)].
Three examples of violations of § 211.194(a) are as follows:
a. Your firm failed to include the required raw data, including the sample dilution, mobile phase preparation, equipment used, conditions of the chromatographic system, and the signature and date of the analyst who performed the tests, in the analytical documentation for Children’s XL-3 Chewable Tablets lots A136, A137, A138 and A218.
b. You firm failed to list a mathematical factor used for assay calculation in the test method procedure, EPT-010.
c. You failed to maintain important raw data, such as sample and standard preparation for the stability studies performed to justify the (b)(4)-year expiry period, in your analytical records for lot # A216 of Children’s XL-3 Chewable Tablets. Your firm exported this product to the U.S.
Please review all of your analytical records and calculations to ensure that your laboratory results are accurate and support the release for distribution in the U.S. of your products within expiry. In your response, provide a summary of your review and copies of all the SOPs that you have updated.
5. Your firm neither established nor documented the accuracy, sensitivity, specificity, and/or reproducibility of test methods [21 C.F.R. § 211.165(e)].
For example, you did not conduct a test for specificity in validation report #CC-VAL-02 for the HPLC method for Children’s XL-3 Chewable Tablets.
In your response, you should include a detailed review of all analytical test methods that you utilize to ensure that they have been properly validated and verified that they are adequate for actual conditions of use. You should also include a list of revisions you made to the analytical methods as a result of your review.
In addition to the items listed above, the investigators found other deficiencies that lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your facility. For example, there are several instances of incomplete qualification of equipment and incomplete laboratory data. We recommend that you seek the advice of a third-party consultant for assistance with a complete evaluation to determine the improvements that you will need to make at your firm in order to meet the CGMP requirements for the manufacture of OTC drug products.
XL-DOL, XL-3 Xtra, XL-3, and XL-3 for Children are drugs within the meaning of Section 201(g)(1)(B) of the Act, 21 U.S.C. § 321(g)(1)(B), because they are intended for use in the diagnosis, treatment, or prevention of disease, and under section 201(g)(1)(C) of the Act (21 U.S.C. § 321(g)(1)(C)) because they are intended to affect the structure or function of the body. These products are misbranded under section 502(f)(2) of the Federal Food, Drug and Cosmetic Act (the Act) because the products’ labeling does not comply with FDA’s organ specific labeling regulation for acetaminophen containing OTC drug products. Specifically, XL-DOL, XL-3 Xtra, XL-3 are misbranded because they do not include the required warning information described in 21 C.F.R. § 201.326(a)(1)(iii), and XL-3 for Children is misbranded because it does not include the required warning information described in 21 C.F.R. § 201.326(a)(1)(iv). Please note, this warning is required to be on both outer and immediate container labeling if there is both an outer and immediate container.
XL-3 Xtra, XL-3, and XL3 for Children are also misbranded under section 502(f)(2) of the Act because the products’ labeling fails to bear all the required warning information for antihistamine drug products described in 21 CFR 341.72(c) including, but not limited to, the warning “May cause excitability especially in children.” Furthermore, XL3 for Children does not include the all of the required warning information described in 21 CFR 341.72(c)(6)(ii) such as, “May cause drowsiness. Sedatives and tranquilizers may increase the drowsiness effect. Do not give this product to children who are taking sedatives or tranquilizers, without first consulting the child’s doctor.”
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. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, until such time as your manufacturing practices are verified to comply with CGMPs, your firm will remain on FDA Import Alert and FDA will continue to refuse admission of all articles manufactured at Selder S.A. de C.V. Fernando Villapando #48, Colonia Guadalupe Inn, 01020, Mexico, D.F., Mexico, into the United States. Because your firm is currently on Import Alert, the articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Program immediately, as you begin your internal discussions, at email@example.com in order to ensure that your action(s) does not adversely affect the public health.
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, in your response, you should state if you no longer manufacture or distribute any specific drug products and for each, provide the product name, date, and reason(s) you stopped producing it. Please identify your response with FEI # 3001362772.
If you have questions or concerns regarding this letter, contact Allison A. Aldridge, Ph.D., Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0483
Fax: (301) 847-8741
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research