Inspections, Compliance, Enforcement, and Criminal Investigations
Nephron Pharmaceuticals Corp 28-Sep-05
Department of Health and Human Services
Public Health Service
Florida District Office
RETURN RECEIPT REOUESTED
September 28, 2005
Mr. William P. Kennedy
President and COO
Nephron Pharmaceuticals Corp.
4121 SW 34th Street
Orlando, FL 32811-6475
Dear Mr. Kennedy:
The Food and Drug Administration (FDA) inspected your drug manufacturing facility located at the above address on March 21-28, 2005.
Our inspection found significant deviations from the Postmarketing Adverse Drug Experience (PADE) reporting requirements, within the meaning of 21 U.S.C. §355(k) [Sections 505(k) of the Federal Food, Drug, and Cosmetic Act ("the Act")]. See also Title 21, Code of Federal Regulations (C.F.R.) Part 314 (21 C.F.R. §314). Based on our review of the establishment inspection report, we conclude that your firm violated Section 301(e) of the Act because you failed to comply with 21 C.F.R. § 314 and Section 505(k) of the Act.
Our inspection also found deviations from the current good manufacturing practice (CGMP) requirements for drug products, within the meaning of 21 U.S.C. §351 (a)(2)(B) [Section 501(a)(2)(B) of the Act]. See 21 C.F.R. Parts 210 and 211 (21 C.F.R. §§ 210-211). The CGMP deviations cause your products, Albuterol Sulfate Inhalation Solution, Ipratropium Bromide Inhalation Solution, Racepinephrine Inhalation Solution and Sodium Chloride Inhalation Solution, to be adulterated within the meaning of 21 U.S.C. § 351 (a)(2)(B) [Section 501(a)(2)(B) of the Act], in that the methods used in, or the facilities or controls used for, the manufacturing, processing, packing, storage or holding of the drug products are not operated or administered in conformity with CGMP. See 21 C.F.R. §§ 210-211.
Please note that we subdivided the warning letter to separately address the PADE deficiencies and the CGMP deficiencies.
A. Deviations from the PADE regulations include, but are not limited to the following:
1. Failure to develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA [21 C.F.R § 314.80(b)].
We recommend that you establish written procedures for the prompt review and identification of all adverse drug experience information obtained or otherwise received from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigation, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers.
2. Failure to report adverse drug experience information to FDA [21 C.F.R. § 314.80(c)].
For example, the following adverse drug experiences were not reported to FDA:
Complaint #A96 which documents the user of your firm's drug product Albuterol Sulfate Inhalation Solution 0.083% (2.5mg/3mL), Lot A3026A, experiencing burning of the throat. The user went to the Emergency Room for treatment.
Complaint #A105 which documents a husband and wife using your firm's drug product Albuterol Sulfate Inhalation Solution 0.083% (2.5mg/3mL), Lot A3088B, experiencing shortness of breath, tingling of the arms and legs, numbness in the face, high blood pressure, and rapid pulse. The husband and wife both went to the Emergency Room for treatment where the attending physician informed them the Albuterol caused their problems.
Complaint #A106 which documents the user of your firm's drug product Albuterol Sulfate Inhalation Solution 0.083% (2.5mg/3mL), Lot A328 1E, experiencing mouth sores/ulcers.
3. Periodic adverse drug experience reports have not been submitted quarterly for one product which was approved less than three years ago and annually for three products that were approved three or more years ago [21 C.F.R. § 314.80(c)(2)].
For example, your firm has not reported, on a quarterly and /or annual basis, to the Food and Drug Administration, adverse drug experiences for the following:
Albuterol Sulfate Inhalation Solution, 0.042% (1.25mg/3mL), application approval date 06/28/2004.
Albuterol Sulfate Inhalation Solution, 0.083% (2.5mg/mL), application approval date 09/17/1997.
Albuterol Sulfate Inhalation Solution 0.5% (2.5mg/0.5mL) application approval date 06/26/2001;
With respect to the PADE regulation deviations, we received your response letter dated May 25, 2005, and have completed our review of your corrective actions. Your revised Standard Operating Procedures (SOPs) appear to address most of the deficiencies observed during this inspection. However, we do have several concerns in regard to your responses. In your SOP, 7.1 .8 on page 2, B., c. and again on your Adverse Drug Experience Determination Sheet, Addendum 3, 1.0, you use the term "reasonably suggests" for determining whether your product caused an adverse drug experience. You should be following the definition of an Adverse Drug Experience, as set forth in 21 C.F.R. 314.80(a), and listed in your SOP 7.1.9, 4.0, Definitions; the definition states that an ADE is any event associated with the use of a drug in humans, whether or not considered drug related. Causality in any form is not a prerequisite for the submission of ADEs to the FDA. You must submit all ADEs you receive to the FDA.
There is another concern regarding the Adverse Drug Experience Determination Sheet (SOP 7.1 .8, Addendum 3, 1 .0 & 2 .0). Following the directions on this sheet, it appears that the only "reportable" events would be those which are serious and unexpected (i.e. 15-day reports). MedWatch reports need to be completed for all ADEs you receive, including those that are serious and labeled and all non-serious reports.
Furthermore, in several sections of these SOPs you use both the terms Life-threatening Adverse Drug Experience and Serious Adverse Drug Experience in describing the reporting of ADEs. Please be advised that a life-threatening ADE falls under the definition of a serious adverse drug experience. As you know, the regulation governing the reporting of adverse drug experiences for which an approved application is in effect is 21 C.F.R. § 314.80. If you market any prescription drugs that are not the subject of new drug applications or abbreviated new drug applications, the regulation for adverse drug experience reporting is 21 C.F.R. § 310.305.
B. Deviations from the CGMP regulations
The current inspection documented the following deviations from the current good manufacturing practice (CGMP) regulations [i.e., 21 C.F.R. §§ 210-211]:
1. Written procedures describing the handling of all written and oral complaints do not include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the FDA. Written records for the investigation of a drug complaint do not include the findings of the investigation and the follow-up [21 C.F.R. § 211.198(a) and § 211 .198(b)];
2. There is a failure to investigate any unexplained discrepancy or the 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 C.F.R. § 211.192];
3 . There is a failure to have process control procedures designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.100(a)];
4. Deviations from written specifications, standards, and laboratory mechanisms are not justified [21 C.F.R. § 211.160(a)];
5. Records of the calibration checks and inspections of automatic, mechanical or electrical equipment, including computers or related systems are not maintained [21 C.F.R. § 211.68(a)];
With respect to the CGMP deviations, we received your response letter dated May 25, 2005, and have completed our review of your corrective actions. While your response appears to be adequate, we are concerned that your firm may not fully understand the role of the quality control unit in your overall manufacturing process (See 21 C.F.R. § 211.22 - Responsibilities of the quality control unit).
The failure of your firm's quality control unit to assure overall compliance with the CGMP regulations (e.g., review production records, internal procedures and specifications) likely contributed to the reported product complaints (e.g., release of empty vials, incorrect vial count, plastic in vials, product mix-up). Additionally, the problems (i.e., occurring during the past two inspections), observed in your firm's complaint handling practices seem to indicate an incomplete understanding of the importance of the quality system in your manufacturing process.
The quality control unit should be designed to assure overall compliance with the CGMP regulations, internal manufacturing procedures, and product specifications. As part of an overall quality system, your firm must assure that the quality control unit adequately performs all of its review and approval duties (e.g., change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.). This includes all product defect evaluations, returned and salvaged drug products evaluations, and product complaints reviews.
Please advise the Agency regarding your corrective action plan to address the problems described above with respect to the quality control unit.
Neither the above list of deviations nor the Form FDA 483 "Inspection Observations" which was presented to you at the completion of this inspection are intended to be an all-inclusive list of deficiencies at your firm. It is your responsibility to ensure adherence to each requirement of the Act and its regulations. The FDA requires drug manufacturers to establish written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA. FDA expects these procedures to assure that all adverse drug experiences are recorded, evaluated, and submitted to the FDA within established timeframes as required by 21 CFR 314.80.
You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action by FDA without further notice. These actions include, but are not limited to, seizure and/or injunction. Federal Agencies are advised of the issuance of all warning letters about drugs and devices so that they may take this information into account when considering the award of
We request that you notify this office in writing, within fifteen (15) working days of receipt of this letter, of the specific steps you have taken to correct the noted deviations and to prevent their recurrence. Your response should address the comments listed above and include examples of documentation showing that corrections have been achieved. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which corrections will be completed.
Your reply should be directed to the Food and Drug Administration, Attention: Virginia L. Meeks, Compliance Officer, 555 Winderley Place, Suite 200, Maitland, FL 35271. If you have questions regarding any issue in this letter, please contact Ms. Meeks at (407) 475-4731.
Emma R. Singleton
Director, Florida District