| Public Health Service Food and Drug Administration |
| 555 Winderley Pl., Ste. 200 Maitland, FL 32751 |
Department of Health and Human ServicesCERTIFIED MAIL
RETURN RECEIPT REQUESTED
WARNING LETTER
FLA-10-18
May 12, 2010
Terry E. Yon, President and CEO
Terry Yon & Associates, Inc
dba TYA Pharmaceuticals
2930 Crescent Drive
Tallahassee, FL 32301
Dear Mr. Yon:
During our November 16-18, 2009 inspection of your pharmaceutical manufacturing facility, Terry Yon & Associates, Inc., dba TYA Pharmaceuticals, located at 2930 Crescent Drive, Tallahassee, FL 32301, 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.
We have reviewed your firm's response of December 7, 2009, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited to, the following:
1. Your firm has failed to establish separate or defined areas or such other control systems for your firm's manufacturing and processing operations [21 C.F.R. § 211.42(c)(5)]. Your firm has also failed to perform operations related to the manufacture, processing, and packing of penicillin in facilities separate from those used for other drug products for human use [21 C.F.R. § 211.42(d)).
For example, your firm does not have facilities for repackaging penicillin drug products (e.g., amoxicillin capsules) that are separate from those used for repackaging non-penicillin betalactam products (e.g., cephalexin capsules, a type of cephalosporin drug). Amoxicillin capsules and cephalexin capsules are both repackaged into unit-dose "bingo cards" inside a single hooded cabinet (b)(4) within a single "laminar air-flow room."
In your December 7, 2009 response, you state that you have discontinued repackaging all penicillin products and will only market such products in unopened, original containers in the future. Further, you state that the laminar air-flow room will only be used to repackage cephalosporin drug products. We find your response to be inadequate because your firm has previously made similar assurances, but resumed repackaging penicillin and cephalosporin drug products in December 2008 without having full segregation in place to prevent cross contamination.
This is a repeat observation from the February 2007 inspection.
2. Your firm has failed to test non-penicillin drug products for the presence of penicillin when a reasonable possibility exists that a non-penicillin drug product has been exposed to cross contamination with penicillin [21 C.F.R. § 211.176].
For example, your Firm repackages penicillin drug products (e.g., amoxicillin) with non-penicillin beta-lactam drug products (e.g., cephalexin) within a single laminar air-flow room without testing or providing assurances that the non-penicillin beta-lactam drug products are free from penicillin contamination. Between December 18, 2008 and November 13, 2009, your firm has repacked (b)(4) batches of cephalexin drug products and (b)(4) batches of penicillin drug products in the same laminar air-flow room.
Under regulation 21 C.F.R. § 211.176, you are required to test non-penicillin drug products for the presence of penicillin where a reasonable possibility of exposure to penicillin cross-contamination exists. Your non-penicillin drug products should not be marketed if detectable levels of penicillin are found. Since you repackage penicillin drug products in the same laminar air-flow room as non-penicillin beta-lactam drug products, there is a reasonable possibility of penicillin cross-contamination at your facility. Therefore, all non-penicillin beta-lactam drug products you repackage at your facility must be tested for the presence of penicillin.
In your December 7, 2009 response, you state that you will secure swab samples from the laminar-airflow room and from various other areas in your packaging facility to test for the presence of penicillin. Your response is inadequate in that the referenced environmental testing does not address the issue of testing non-penicillin beta-lactam products for the presence of penicillin.
3. Your firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 C.F.R. § 211.67(a)].
For example, your firm has failed to validate its cleaning procedures for all equipment used in its repacking operations to ensure that drug residues from repackaged drug products are not transferred to other drug products repackaged using the same equipment. Your firm's Standard Operating Procedure (SOP) requires annual testing using either a Glo-Germ Kit test (test for residues of a UV florescent powder) or a swab test (test for Total Organic Carbon (TOC)) on the surfaces of repackaging machines after cleaning to ensure that the cleaning process is adequate. Your SOP also states that all repackaging equipment is to be scrubbed with disinfectant and steam-cleaned annually. However, your cleaning procedures have not been shown to adequately clean multi-product equipment to prevent cross-contamination of drug products. The cleaning process itself must first be validated to ensure that your cleaning procedures (or "cleaning SOP") are adequate to prevent equipment contamination of drug products.
In your December 7, 2009 response, you stated that you have previously validated the cleaning procedure by conducting a swab test, after cleaning, in three different repackaging machines repacking three different drug products. Since the swab tests were found negative, you considered the cleaning procedure to be validated. However, you provided the results of two swab tests (conducted April 2007) during our inspection that had been performed on an Auto-Med strip filling machine and an (b)(4) machine to detect residues of a single drug product. We find your response referencing your April 2007 results to be inadequate because you failed to test other filling equipment or test for other drug product residues that would fully represent the operations at your firm. As such, we find that you have not validated cleaning procedures.
This is a repeat observation from the February 2007 inspection.
4. Your firm has failed to establish an expiration date determined by appropriate stability testing, described in 21 C.F.R. § 211.166, for your repackaged drug products to assure that they meet applicable standards of identity, strength, quality, and purity at the time of use [21 C.F.R. § 211.137(a)].
For example, your firm is repackaging solid oral dosage products into unit-dose Class A packaging strips and Class A bottles, and declaring a one year expiration date without supporting stability data. Examples of repackaged products using this one year expiration date include lithium carbonate extended-release (ER) 300 mg tablets and trihexyphenidyl 5 mg tablets.
In your December 7, 2009 response, you support the use of a one-year expiration date by referencing the draft revision of the FDA Compliance Policy Guide Section 480.200 "Expiration Dating of Unit Dose Repackaged Drugs - Testing/Examination under CGMPs (CPG 7132.13)," dated May 2005. This draft would revise the Current CPG 480.200 recommended maximum 6-month expiration to a maximum one-year expiration. However, as you also acknowledge in your response, the draft has not been made final and as such, you have now revised your SOP to observe the current FDA recommended maximum expiration dating of 6-months. We will verify this revision during our next inspection.
This is a repeat observation from the February 2007 inspection.
The violations documented during this inspection demonstrate that you have not implemented a robust Quality System at your firm. Several of the CGMP deficiencies observed during this inspection were also observed during our inspection in 2007. We recommend that you implement a comprehensive Quality System at your firm to encompass all repackaging operations.
This Quality System should also include an effective containment control program to prevent cross-contamination of non-beta-lactam repackaged drug products by beta-lactam drug products (such as penicillin products and cephalosporin products). In addition to full segregation of facilities, the containment control program procedures should address procedures for detecting and correcting any flaws or deviations in your containment program. Any beta-lactam contamination on surfaces alerts a firm that contamination is present in the manufacturing environment due to poor containment practices. Major elements of an effective beta-lactam containment control program include: (1) a representative sampling plan to test production areas, including worst-case locations, for undesired beta-lactam residues; (2) containment control procedures to include SOPs that address how to determine, control and correct deficiencies, control the movement of personnel, equipment and materials between beta-lactam and non-betalactam repackaging areas, and investigate the extent and cause of any failures, with proper corrective actions; (3) analytical procedures of proper sensitivity and specificity to detect undesired residues of beta-lactam drugs in the application of surface sampling techniques to assess the effectiveness of your containment control program; and (4) a provision to conduct product testing before release if there is a reasonable possibility of contamination of non-beta lactam products with beta-lactam drugs. The risks presented by the cross-contamination of drug products with non-penicillin beta-lactam drugs (such as the cephalosporins) are similarly serious to those of cross-contamination with the penicillins. Thus, equal care must be given to providing containment control for the repackaging of cephalosporins as for penicillins.
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.
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 repackaged drug products manufactured at this facility, and provide the date(s) and reason(s) you ceased production.
Your response should be sent to: Winston R. Alejo, Compliance Officer, U.S. Food and Drug Administration, 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.
Sincerely,
/S/
Emma R. Singleton
Director, Florida District
No comments:
Post a Comment