Inspections, Compliance, Enforcement, and Criminal Investigations
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Waterview Corporate Center|
10 Waterview Blvd., 3rd Floor
Parsippany, NJ 07054
Telephone (973) 331-4904
June 21, 2010
RETURN RECEIPT REQUESTED
Mr. Christopher J. Worrell, CEO
215 Wood Avenue
Middlesex, New Jersey 08846
Dear Mr. Worrell:
During our November 24, 2009 to January 20, 2010 inspection of your pharmaceutical manufacturing facility, CorePharma, LLC, located at 215 Wood Avenue, Middlesex, New Jersey, investigator(s) 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.
We have reviewed your firm's response of February 3, 2010, 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 reject drug products that did not meet established standards or specifications [21 C.F.R § 211.165(f)].
For example, your Quality Control Unit (QCU) released a batch of Benzphetamine HCI 50mg tablets (lot CPK841) after it failed to meet the established Acceptable Quality Limits (AQL) for coating defects. Your justification for releasing the batch was based on a determination that this defect was unlikely to be noticed by consumers.
In your response, you state that this product is no longer manufactured and that such practices do not represent your company's current CGMP compliance standards. You have committed to have all current and future investigations reviewed and signed by the Vice President of Quality Operations. However, you did not review your records to ensure that other products that failed to meet AQLs were not distributed. In addition, your response does not include training of the QCU to ensure that they are capable of identifying and ensuring appropriate corrections of these types of discrepancies in the future.
2. Your firm has not thoroughly investigated the failure of a batch or any of its components, nor have you extended such investigations to other batches of the same drug product. Your firm has also failed to include conclusions and follow up [21 C.F.R § 211.192]. For example,
a) Your investigation is inadequate regarding Out-of-Specification (OOS) result for thickness in Pilocarpine HCI 5mg tablets. Despite your inability to determine a definitive root cause, you released the batch and based that release on a minimal inspection of 0.02% of the finished lot. In addition, you failed to extend the investigation to other batches manufactured by the same operator even though you determined the probable root cause was due to operator error (i.e., reintroduction of start-up material into the process).
In your response, you state that you have dedicated red bins for the collection of start-up material to prevent this event from recurring. Your response is inadequate because you do not describe the steps you have taken to ensure thorough investigations of discrepancies in the future.
b) You failed to thoroughly evaluate "small black spots" observed in 28 of 100 Pyridostigmine Bromide tablets during a random inspection by your operator. Your investigation of the black spots only included an AQL inspection of the
batch to determine whether the defects were within the AQL limits for "small specks." The investigation did not determine a root cause or evaluate the impact on product quality.
In your response, you state that you will reopen the investigation to evaluate whether prior lots contain similar "small black spots." Your response is inadequate because you fail to address the possible cause of the black spots, the potential impact on product quality, or the implementation of adequate corrective actions to prevent recurrence of this deviation.
c). Your investigation (MER 09-06-003) failed to address the discrepancy between the number of defects noted during your AQL inspection after coating of Ropinirole HCI tablets and the number of defects noted by Quality Assurance (QA) and packaging personnel prior to packaging. In addition, your investigation did not extend to other batches of product using the same coating process even though your root cause analysis noted the need for numerous improvements to the coating process.
During your routine AQL in-process inspection, 19 defects for small specks were identified. Prior to packaging, QA and packaging personnel noted additional (approximately 8%) tablets with defective coating. Conducted as part of the investigation, a secondary inspection identified 47 tablets with defective coating.
In your response, you state that you have developed a comprehensive plan to improve coating operations. However, you did not adequately address the discrepancy between the defects identified during the initial in-process inspection and the secondary inspection.
d) You failed to implement timely corrective actions after identifying increasing trends of crushed/broken tablets even though you identified the rayon insertion process as one cause of the defect. Protocol 09-07-005-00 was executed in August 2009 to investigate the cause of the increasing trend. The protocol identified the rayon insertion process as one cause of the crushed/broken tablets. You state in your response that actions to remove the rayon were to be taken after a shipping study was completed. However, the shipping study protocol was not executed until January 2010 and you continued to manufacture and release the product.
This is a repeat observation from the 2007 and 2008 inspections of your facility.
3. Your quality control unit has failed to follow applicable written procedures [21 C.F.R § 211.22(d)].
For example, your QCU failed to follow your draft Standard Operating Procedure (SOP), 10-008.00, for ensuring Problem Analysis and Corrective Action Reports (PACARS) were assigned a target completion date. Your SOP requires a target completion date to be assigned when corrective actions require more than (b)(4) days to complete. Sixty percent (33 of 55) PACARS (documenting corrective and preventive actions) generated between January and October 2009, were incomplete at the time of our inspection. One PACAR was open for 11 months without an assigned target completion date.
In your response, you state you will revise your CAPA tracking process to include such items as the assignment of an owner responsible for executing the CAPA, assignment of due dates, tracking each CAPA to conclusion and verification of completion by the quality unit, and a management process for monitoring the monthly progress of CAPAs. However, this is a repeat observation from the 2007 inspection of your facility. We note that during the regulatory meeting held on June 25, 2009 the New Jersey District Office stated that the "numerous GMP deficiencies observed are related to the firm's Quality Unit."
4. Your firm has failed to establish written procedures to monitor the output and to validate the performance of your manufacturing processes [21 C.F.R. § 211.110(a)], and your quality control unit failed to reject in-process material that did not conform to its specification [21 C.F.R. § 211.110(c)]. For example,
a) Your Ursodiol 300 mg capsule manufacturing process is not capable of consistently achieving the specified capsule fill weights. Also, out of specification dissolution results have been obtained intermittently over the last two years with no assignable cause.
Changes have been made to your equipment and procedures as corrective actions for variability in fill weight and dissolution results (e.g., changing dosator spring gauges and lowering bed height) without appropriate evaluation of the changes. Inconsistent capsule fill weight and intermittent out of specification results for dissolution persisted after these changes.
We acknowledge that you ceased manufacturing Ursodiol in November 2009. We agree with the proposed actions described in your February 3, 2010 response to the FDA483, e.g., to implement statistical process control, conduct dissolution studies and equipment qualification, and perform a complete product performance assessment. However, this course of action was unjustifiably delayed. It should have been initiated far earlier than during this most recent inspection.
b) There is no assurance that the coating process for Ropinirole HCI tablets can reproducibly meet the finished product specifications for appearance. Partial lot rejections have been documented for seven lots that failed to meet the in-process AQL for such defects as rough coating and white specks. For example, 43% of Ropinirole HCI 2mg tablets, lot CPI874, from coating pan (b)(4) were found to contain coating defects.
The practice of releasing partial batches (after sorting and rejecting tablets with identified coating defects) without a thorough understanding of the cause of the defect is not acceptable. You must identify the root cause and validate
and implement corrective actions (e.g., process or components). In your response, you state that you have a "project" in place to address coating deficiencies. However, your response is inadequate because you did not commit to discontinue this practice or sorting defective batches while you complete the corrections.
5. Your firm has failed to follow your written testing program designed to assess the stability characteristics of drug products [21 C.F.R. § 211.166(a)].
For example, you failed to comply with SOP 25-031-04, Stability Testing Program for Marketed Drug Products. Approximately 90 of 375 commercial stability samples collected between July to December 2009, were tested after the (b)(4) day requirement. Your SOP states that stability samples for the (b)(4) month stability test intervals should be tested within (b)(4) days of the scheduled test date.
Your response appears adequate; however, you had previously failed to test over 20% of your stability samples as required by your SOP.
6. Your firm failed to provide exhaust systems or other adequate systems to control contaminants during production [21 C.F.R. § 211.46(C)].
For example, our investigators observed the manufacturing of Skelaxin 800mg tablets, Potassium Citrate 10mEq tablets, and Glyburide 1.25mg tablets in a room adjacent to ongoing construction. The construction area was open to the exterior of the building with a temporary plastic curtain separating the construction area from the commercial manufacturing rooms. Your QCU did not evaluate the ingress of dust or possible contamination entering your production rooms.
In your response, you state that a new SOP for temporary isolation barriers is being developed that will require approval by your Quality Operations and manufacturing group prior to construction. Your response is inadequate because you have not evaluated the impact on product manufactured during the observed construction.
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 or 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 of distribute any of the drug products manufactured at this facility, and provide the date(s) and reason(s) you ceased production.
Repeat observations and discussions during the June 2009 regulatory meeting indicate that your quality control unit is either not exercising its responsibilities, or may not have the appropriate authority to carry out its responsibilities. For example, it appears that as part of your batch release criteria you rely on a practice of sorting and rejecting tablets with quality defects as a quality control measure. It is our expectation that firms take a systematic approach to correcting and complying with CGMP to ensure the identity, strength, quality, and purity of their drug products.
Your reply should be sent to the following address: U.S. Food and Drug Administration, 10 Waterview Boulevard, 3rd Floor, Parsippany New Jersey 07054, Attn: Andrew Ciaccia, Compliance Officer.
New Jersey District