Inspections, Compliance, Enforcement, and Criminal Investigations
Cispharma Inc. 7/2/13
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Waterview Corporate Center
10 Waterview Blvd. 3rd Floor
Parsippany, New Jersey 07054
Telephone: (973) 331-4900
FAX: (973) 331-4969
July 2, 2013
VIA UNITED PARCEL SERVICE
Dr. Ravi Annamaneni, Chairman
1212 Cranbury S. River Road
Cranbury, New Jersey 08512
Dear Dr. Annamaneni:
During our March 12 through April 23, 2012 inspection of your pharmaceutical manufacturing facility, located at 1212 Cranbury S. River Road, Cranbury, New Jersey, 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 product(s) to be adulterated within the meaning of Section 501(a)(2)(B) ofthe 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 conducted a detailed review of your firm's response, and it appears that you have not implemented a robust quality system at your firm. Several of the CGMP deficiencies that our investigators observed during this inspection were also observed during our inspection in January 2011, and your current response lacks sufficient corrective actions. We recommend that you implement a comprehensive quality system at your firm to encompass all manufacturing operations.
Our investigators observed specific violations during th e inspection, including, but not limited to, the following:
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
This is a repeat observation from the January 2011 inspection.
a. Your investigation into a complaint of 200mg Phenazopyridine HCI tablets comingled into (b)(4) lots of 100mg Phenazopyridine HCI tablets (lot 009008 and 012006) was inadequate. You concluded the mix-up was probably a pharmacy error without having investigated other possible root causes. Because the production schedule indicates that the 200mg lot had been manufactured just before the (b)(4) 100mg lots subject of the complaint, the possibility of a mix-up in the filling and packaging area should have been investigated.
In your response, you state that you have updated your complaint handling SOP to assign the investigation to the "heads of the functional areas" with final responsibility being assigned to QA. Your response is inadequate because you failed to address how QA will ensure complaint investigations are appropriately completed in the future.
b. Your investigation into the employee accident that occurred during compression of Acetaminophen tablets, lot 112011 was inadequate because you failed to document the specific nature of the event and the product impact.
In your response, you state that you have revised the investigation into the accident. In addition, you state that several extensive cleanings were performed and that all product that was opened during the incident was discarded. Your response is inadequate in that you failed to describe how you ensured there was no blood or tissue remaining after extensive cleaning was completed.
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/or purity they purport or are represented to possess (21 CFR 211.100(a)).
This is a repeat observation from the January 2011 inspection.
For example, the coating processes for three of your products: Salsalate tablets, Acetaminophen White Film Coated Caplets, and A spirin Enteric Coated tablets, are not adequately validated, e.g., you have not demonstrated that a uniform, quality coating is consistently achieved. Specifically,
a. Your Salsalate tablets validation study did not identify the equipment parameters and coating solution characteristics that impact coating quality and assure they are properly controlled. Surface erosion was noted in validation lot 103003 during a QA check but it was not investigated. The lot was released. Your customer rejected the lot after performing their own sampling and inspection in April 2011. Chipped, peeling, and broken tablets were found. You informed our investigators that you subsequently performed a (b)(4) visual inspection of the (b)(4) tablet lot and culled out (b)(4) poor quality tablets. (Note: You did not have any records of this inspection or disposition records of the rejected tablets which you reported were destroyed.) The remaining (b)(4) tablets were packaged and shipped to a different customer. During the inspection your retain samples of lot 103003 and Salsalate lot 103004 were both observed to have surface erosion and faded imprints.
b. Acetaminophen White Film Coat lot 201004 exhibited coating and hardness problems during manufacturing. According to you quality assurance manager the lot was inspected to (b)(4) resulting in approximately (b)(4) of rejected tablets. There was no record of the inspection, no investigation into the discarded tablets and no record of the destruction.
c. During the inspection, our investigators examined retained samples (b)(4) from (b)(4) lots of Aspirin Enteric Coated 81mg tablets, including lot 102010, and (b)(4) lots of Aspirin Enteric Coated 325mg tablets. Colored specks were observed on the surface of the tablets. Aspirin Enteric Coated 81mg tablets, lot 103013, exhibited sticking tablets in addition to having gray and red specks on the surface of the tablets. Your firm failed to investigate these quality issues which could reasonably be related to the coating process. Also, during production of Aspirin Enteric Coated 81mg. tablets, lot 102010, greater than (b)(4) tablets were rejected during compression and coating; however, the batch record does not indicate any cause for the rejected tablets. No investigation was performed by your quality unit.
Without a thorough investigation to understand the root cause of coating defects (or hardness problems) proper corrective actions to prevent recurrence cannot be implemented. Repeated instances of sorting finished tablet lots to cull out defective tablets is indicative of your failure to assure your manufacturing processes are in a state of control.
Final product inspection for visibly defective product is an acceptable quality control practice but only in conjunction with a well-designed and controlled operation. Reliance on end-product testing alone will not offer adequate assurance that all substandard product is removed and that the portion of the batch releas ed and distributed will meet all product specifications throughout expiry.
3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
a. Test procedure DOC-TP-147-01, for the release testing of Salsalate Film Coated Yellow Tablets, 500mg, and Salsalate Caplets, 750mg, has not been validated.
b. Chromatographic test methods do not have established integration parameters, and analysts are permitted to (b)(4)
In your response, you state that integration parameters and processing methods will be secured so that all data is processed with the same processing method. Your response to this observation will be evaluated at the next routine inspection of your facility; however, it is important to note this is a repeat observation from the January 2011 inspection.
4. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals (21 CFR 211. 84(d)(2)).
This is a repeat observation from the January 2011 inspection.
For example, your firm has failed to perform identity testing on Magnesium Stearate, NF that was used to manufacture Guaifenesin Tablets, lot 202002 in February 2012.
In your response, you do not provide details on what specific identity tests with acceptance criteria will be performed on all incoming materials. You state all active and inactive ingredients will be covered under a comprehensive approval process based on your vendor qualification procedures; however, you acknowledge your vendor qualification program is not adequate and you do not provide details on how you will improve it or when a new program will be implemented.
Although the most recent inspection was completed April 23, 2012, the inadequacy of your 483 response, repeat deficiencies, and your continued marketing of unapproved new drugs, we believe that a Warning Letter is still warranted. The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the caus es of the violations identified above and for preventing their recurrence and the occurrence of other violations.
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.
Also, based on the information your firm submitted to FDA's Drug Registration and Listing System and the information collected during the March-April 2012 inspection, FDA found that your firm is manufacturing the following unapproved prescription drugs:
• Salsalate Tablets, USP, 500mg oral tablets
• Salsalate Tablets, USP, 750mg oral tablets
• Phenazopyridine HCl F/C Tablets, USP, 95mg oral tablets
• Phenazopyridine HCl F/C Tablets, USP, 100mg oral tablets
• Phenazopyridine HCl F/C Tablets, USP, 200mg oral tablets
FDA's guidance entitled "Marketed Unapproved Drugs-Compliance Policy Guide (CPG)," explains FDA's policies aimed at ensuring that all drugs marketed in the U.S. have been shown to be safe and effective. Please see:(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070290.pdf).
The CPG outlines FDA's enforcement policies aimed at efficiently and rationally bringing all drugs requiring approved applications into the approval process without adversely affecting public health, imposing undue burdens on consumers, or unnecessarily disrupting the market. As described in the CPG, all drugs marketed without required applications are subject to enforcement action at any time, without additional notice.
You should contact FDA's unapproved drugs coordinator, Dr. Sally Loewke, at 301-796-0710 for assistance in communicating with the FDA on the application process for your unapproved drugs. Also, please note that if you are no longer marketing these products, you must update the Drug Listing files in accordance with 21 C.F.R. 207.30(a)(2).
If, as a result of receiving this Warning Letter or for other reasons, you are considering a decision that could reduce the 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 so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drugs under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug products at issue, provide the date(s) and reason(s) you ceased production.
Please send your reply to the following address: U.S. Food and Drug Administration, Erin D. McCaffery, Compliance Officer, New Jersey District Office, 10 Waterview Boulevard, 3rd Floor, Parsippany, New Jersey 07054.
New Jersey District