Ms. Lou Kennedy
Chief Executive Officer
Nephron Pharmaceuticals Corp.
4121 SW 34th St.
Orlando, FL 32811-6475
Dear Ms. Kennedy:
The U.S. Food and Drug Administration (FDA) inspected your Nephron Pharmaceuticals facility at 4121 SW 34th St., Orlando, Florida, from July 20 to August 14, 2015.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic (FD&C) Act, 21 U.S.C. 351(a)(2)(B).
We reviewed your September 4, 2015, response in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific violations 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)
Our investigators uncovered multiple examples of your firm failing to thoroughly investigate discrepancies and failures in the manufacture of sterile inhalation products used for treating breathing disorders including asthma and chronic obstructive pulmonary disease.
Industrial Lubricant Contamination
Your quality unit did not appropriately evaluate potential patient risk and rejected only a portion of lots due to contamination with industrial grade lubricant. (b)(4) times in April 2014, you investigated black stains on plastic ampules made by your blow-fill (b)(4). You determined that the contamination was caused by excessive industrial lubricant that dripped onto the mold surface as plastic unit dose ampules were formed and filled. You removed the excess lubricant and continued filling the batch. You failed to inspect your other (b)(4) blow-fill (b)(4) machines. Based on visual inspection, your quality unit approved portions of the affected lot. While you rejected (b)(4) pallets after visual inspection, you released more than (b)(4) other pallets produced on machines (b)(4).
You opened investigations but treated the lubricant as a cosmetic defect rather than as a potential safety, purity, or quality defect. Your investigation failed to determine that your lubricant was non-sterile and industrial-grade. Your firm was apparently unaware that it was using industrial-grade lubricant until our investigator noticed this during the inspection. Your investigation did not describe the extent of the contamination, the effect on sterility, nor the potential health effects of inhaling a solution that may have been rendered non-sterile from industrial grease.
Your risk analysis assessed toxicity based on oral and dermal exposure to the lubricant in rats and rabbits, but it did not assess the risk in terms of potential harm to humans via inhalation, the intended route of administration. You have not indicated whether you intend to use a different lubricant. We acknowledge that you recalled products, but you have not adequately investigated the lubricant contamination.
Inadequate Impurities Investigations
Your firm did not adequately investigate impurities.
Your sterile inhalation ampules of ipratropium bromide contained excessive levels of a degradant. This impurity discolored and reduced the clarity of your ipratropium bromide inhalation solution. Your investigation was inadequate because you failed to perform a timely evaluation of affected lots that remained on the market. You also received related customer complaints that warranted investigating whether your product specifications and controls were appropriate.
In addition, one of your drugs contained an unknown impurity, which you initially concluded was ink that leached from product packaging. You developed an improved test method for detecting impurities, but you failed to fully investigate whether the ink was the source of the impurity and, if so, how much of the leachable ink impurity was in distributed batches of inhalation solutions. Upon further investigation, you identified the (b)(4) bags used to store samples as another potential source of the unknown impurity. You also failed to file a field alert report within three working days to notify the FDA of the potential leachable impurity in this product. Your response failed to address whether you have identified a conclusive root cause and whether you continue to use the same ink on product packaging or the same (b)(4) bags for storage.
Unexplained data alterations
You also released drug product lots despite numerous instances of unexplained altered analytical data during quality control testing, some of which included impurity testing data.
Our findings indicate that your firm lacks an adequate corrective action and preventive action program. This program is an essential part of an effective quality system that vigilantly monitors manufacturing and product quality and ensures prompt actions are taken to maintain an ongoing state of control.
2. Your firm failed to follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates. (21 CFR 211.166(a))
Starting in October 2014, several lots of racepinephrine inhalation solution failed both color and clarity specifications, including failure of these attributes at the (b)(4) stability testing interval. In March of 2015, your quality unit determined that the raw material for racepinephrine contained elevated levels of the degradant adrenolone. These levels were linked to your color and clarity failures. You failed to perform a timely evaluation of affected lots that remained on the market. Approximately three months passed from the time you established a root cause to when you recalled affected product from the market.
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at firstname.lastname@example.org
, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) 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.
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Send your reply to:
Andrea Norwood, Compliance Officer
Food & Drug Administration
555 Winderley Place, Suite 200
Maitland, FL 32751
Please identify your response with FEI 1000114235.
Susan M. Turcovski
FDA Florida District Office