Inspections, Compliance, Enforcement, and Criminal Investigations
Beach Products, Inc. 8/29/11
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Atlanta District Office|
60 Eighth Street N.E.
Atlanta, GA 30309
August 29, 2011
Richard B. Jenkins
Owner/Chief Executive Officer
Beach Products, Inc.
5220 S. Manhattan Avenue
Tampa, FL 33611
Dear Mr. Jenkins:
During our March 7- April 6, 2011 inspection of your pharmaceutical manufacturing facility, Pharmaceutical Associates, Inc., located at 201 Delaware Street, Greenville, South Carolina, investigators from the U.S. 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 dated April 22, 2011, 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 ensure the responsibilities and procedures applicable to your quality control unit are in writing and are followed [21 C.F.R. § 211.22(d)]. For example:
a. Your firm's quality control unit allowed the release of five lots of drug products (i.e., Lactulose Solution, Lot 1B09; Milk of Magnesia, Lot 1B40 and 1B41; Cherry Sore Throat Spray, Lot OK40; and Theophylline Oral Solution, Lot OL83) for distribution even though the Material on Hold forms had not been reviewed/approved by the Release Coordinator as required by your procedure, Standard Operating Procedure (SOP) 0134.00, "Material On Hold Procedure." In addition, we found multiple instances where your quality control unit released batches prior to the closure of investigations of non-conforming product and OOS results.
b. Your quality control unit released two lots (9057 and OF 55) of ibuprofen Suspension that did not have documentation completed for all required manufacturing steps. No deviation was initiated, or notation made in the batch record for these lots, as part of the release by your quality control unit. Customer complaints were received for product from each of these lots for white particulates or clumping, and your complaint investigation records indicate that these batch records were reviewed a second time by your quality control unit, as part of your complaint investigation. There is no mention in the complaint investigation report of the omissions in the batch records, or in the batch record that either review discovered the skipped manufacturing steps.
In your response, your firm states that personnel will be retrained.This response is inadequate because it does not provide a timeline for retraining, nor does it state the nature of the training to be given. It is your responsibility to ensure required quality assurance functions, such as batch record review for release or the completion of investigations.
2. 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 purity they purport or are represented to possess [21 C.F.R. § 211.1 OO(a)]. For example,
a. Your firm has failed to adequately validate the manufacturing process for the following products: 1) Prednisolone Sodium Phosphate Oral Solution (FN0759, FN0773, and F one Bitartrate and Acetaminophen Oral Solution (FN0771- (b)(4) gallon batch size), and; 3) Lorazepam Oral Concentrate, USP (FN0770).
In your response, your firm states that your validation procedure sampling plan for uniformity is sufficient because it requires collection of (b)(4) samples ((b)(4) of the tank) for batches under (b)(4) gallons and (b)(4) samples (b)(4) for batches over (b)(4) gallons. Your response, however, is inadequate because you have not provided a statistically and scientifically sound rationale to support this claim. You claim that additional samples are not needed as your process contains a true solution, and by nature, is homogenous. However, your firm has received complaints for undissolved material in finished product and has documented (b)(4) dissolution issues during validations. Validation, with appropriate sampling, is undertaken to prove that all process variables during mixing are sufficiently controlled to ensure drug product quality. Furthermore, your firm failed to perform a retrospective review of batches or partial batches that were released prior to the implementation of the most recent process changes (from the date the original validation was approved until the recent changes) to ensure that the variability exhibited during batch production did not adversely affect your drug products.
Your response commits to analyzing samples following any flushes that occur for filling/packaging validations, but this evaluation should be performed for all products currently in production to support product being marketed until your new hose studies have been completed and process changes implemented. Your firm should also provide data to support the adequacy of your flush volumes. In addition, your firm should also review your filling/packaging validations for additional deficiencies.
b. Your firm failed to have adequate written procedures to prevent blue plastic particles, originating from component drums, from entering the manufacturing process. You identified a root cause; however, effective and appropriate corrective actions were not implemented for approximately 8 months, during which your firm released multiple lots of Mag-AI Liquid, Mag-AI Plus, and Mag-AI Plus XS. During this period, your firm only performed additional sampling /examinations of the product when the particles were noted by visual inspection of several bulk batches. However, this practice is not adequate due to the thick, opaque characteristics of the liquid, which may allow for the particles to go undetected.
You identified (b)(4) lots of Mag AI Liquid, Mag-AI XS, and Mag-AI Plus that might have been affected by the plastic particles. For these lots, your firm has failed to provide a plan for further action.
3. Your firm failed to reject drug products failing to meet established standards or specifications and any other relevant quality control criteria [21 C.F.R. § 211.165(f)].
For example, your firm released partial lots of products with associated out-of-specification (OOS) (b)(4) results, including bulk batches of Acetaminophen and Codeine Phosphate Oral Solution and Promethazine HCL and Codeine Phosphate Syrup.
Your response indicates that you plan to continue to release partial batches of products that have OOS (b)(4) results if there is a "clear" delineation of acceptable and unacceptable product. This is not an acceptable practice. Your manufacturing processes should be designed and validated to produce consist product meeting pre-determined specifications.
4. Your firm has not thoroughly investigated any unexplained discrepancy or the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192]. For example:
a. Your firm released a batch of Lactulose Oral Solution (lot #OH31) without an adequate investigation (i.e., considering the possible effect of contamination) when a cloth-like towel was found to have been in the mixing tank during batch processing.
While you have agreed to recall this lot, your response does not address the failure of the quality control unit to conduct an appropriate investigation and disposition of this lot.
b. Your firm has not adequately evaluated OOS results for Promethazine CL and Codeine Phosphate Syrup stability samples. For example, your firm documented OOS (b)(4) results at the 12 month room temperature stability time point for Promethazine CL and Codeine Phosphate Syrup (lot 9E46).
Your response states that you are tightening your specification for the (b)(4) in this syrup.
However, we note that assay results reviewed during this inspection showed that (b)(4) results decline as much as (b)(4) in unit dose cups of some products, and the tightened specification will likely result in more stability failures. Please clarify if the tightened specification applies only for release and you plan to create a different (b)(4) specification for stability. Your response also does not address if your firm plans to re-evaluate the current expiration date of 15 months for this product in light of the stability failures at 12 months.
c. Your firm did not extend an investigation regarding blue plastic particles, originating from component drums that were found in a portion of Mag-AI Liquid (lot #OC47) to the first portion of the same batch that was already filled. Although your firm identified a root cause and destroyed the portion of the lot located in the bulk tank, you released the part of the lot that had already been filled without proper justification.
Your response does not indicate any additional actions to address the portion of the lot of MagAI Liquid (lot #OC47) that may contain the plastic particles and is currently on the market, or any other lots produced from the same co-blend.
5. Your firm failed to establish time limits for the completion of each phase of production to assure the quality of the drug product [21 C.F.R. § 211.111].
For example, your firm has not validated your bulk or process hold times assigned for most products (studies have been done for only 5 products out of approximately (b)(4). The assigned (b)(4)-day hold time limits for solutions and (b)(4) day limits for suspensions are largely unsupported. Your firm also lacks data to support the adequacy of your process hold times even though some of your products contain (b)(4) that are known to be absorbed by your hoses.
In your response, your firm states that you will review the historical data of (b)(4) lots for all products to establish hold times. Your response, however, fails to provide a justification for how these lots will be selected. Moreover, maximum hold times should be supported by stability data to ensure that the marketed product will remain within specification throughout their shelf-life. Your firm has provided a completion date of May 1, 2012, to review specific problems relating to hold times (i.e., (b)(4) evaporation prior to and during filling and the hose absorption of (b)(4)). This timeline is not acceptable to address these known problems.
6. Your firm has failed to subject returned drug products that are held, stored or shipped before or during their return under conditions which cast doubt on their safety, identity, strength, quality or purity, to examination, testing or other investigation to prove the drug products do meet all the necessary parameters [21 C.F.R. § 211.204].
For example, your firm has placed thousands of returned products into active inventory or donated them to charities without adequate assurance that they have been appropriately transported and stored.
In your response, your firm fails to include any assurances that the returned products, which are returned to stock for distribution, have been continuously held under proper storage conditions. Your procedure for the handling of returned products indicates that you will conduct a review of the tracking data from the returned product shipments to look for weather extremes, but failed to address transit temperatures can reach extremely high or low temperatures in shipping containers and truck trailers. Further, your procedures do not require that products have any temperature monitoring during transit. In addition, your revised procedure entitled, "Receipt, Storage and Disposition of Returned Goods," states to record the reason for return "if known." If the reason for return is not known, the product should not be returned to active inventory despite any visual or other inspection that may be performed. Products that lack assurances of product safety, identity, strength, quality or purity are considered to be adulterated in accordance with CGMP.
7. Your firm has failed to establish and follow written procedures for evaluating, at least annually, the review of returned or salvaged drug products and investigations conducted for each drug product [21 C.F.R. § 211.180(e)(2)].
For example, your firm failed to include a review of laboratory investigations, variance reports, complaints, recalls, and associated reworks in your Annual Product Reviews (APR) of 2009 and 2010 for Prednisolone Sodium Phosphate Oral Solution (FN0759), Hydrocodone Bitartrate and Acetaminophen Oral Solution (FN0655), Trihexyphenidyl Hydrochloride Elixir (FN0658), Ethosuximide Syrup (FN0670), and Valproic Acid Oral Solution (FN0675). This information is required by your SOP 0150.10 (version 17), "Annual Product Review." The APRs only included a list of the investigations, complaints, etc., without an evaluation to determine trends or the need for changes in drug product specifications or manufacturing/control procedures.
In your response, your firm provides a revised APR procedure, SOP 0150.10 (version 18), "Annual Product Review." Your response, however, is inadequate because it does not include a requirement for the review of production investigation reports. Your response furthers states that multiple SOPs and other documents need revision, or need to be newly created. Since these procedures and documents are not submitted or identified in some cases, they will be evaluated when submitted. In addition, the retraining of Quality Assurance (QA) personnel should be completed immediately and prior to your stated completion date of September 30, 2011, in light of the violations that have been noted during this inspection.
Lastly, your response fails to adequately address the significant problem of quality procedures not being followed, even by senior members of your quality team. The creation of additional or revised procedures will not be effective if they are not followed. It is imperative that your firm's senior management take an active role in ensuring that the quality systems are effectively and consistently implemented to ensure that these critical functions are performed.
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 drug products manufactured at these facilities, and provide the date(s) and reason(s) you ceased production. For discontinued products, you must update the Drug Listing files in accordance with 21 C.F.R. § 207.30 (a)(2).
Your written response should be sent to Marie Mathews, Compliance Officer, at the address noted in the letterhead. If you have any questions about this letter, please contact Ms. Mathews at (404) 253-1279 or email at firstname.lastname@example.org.
John R. Gridley, Director
Ms. Jane Hicks
Pharmaceutical Associates, Inc.
201 Delaware St
Greenville, SC 29605-5823
VIA UNITED PARCEL SERVICE