Warning Letters

Below are recent warning letter summaries from our e-newsletter FDA Digest.

Multiple GMP faults nets warning letter for Hospira at Clayton, NC facility
Rocky Mount facility also cited for failure to validate heparin lock flush solutions
Hospira, Lake Forest, IL

Hospira’s Clayton, NC, facility received an April 12 warning letter for poor written procedures for production and process controls, and for failure to ensure the responsibilities and procedures applicable to your quality control unit are in writing and are fol-lowed, as well as other violations.

The firm’s Rocky Mount, NC, facility also was cited in the warning letter.

“Your firm failed to assure adequate process design and control of Liposyn, Propofol, and Clevi-prex emulsion products to prevent objectionable particulate contamination (primarily stainless steel). Such controls would include, but are not limited, to appropriate component controls, equipment suitability, equipment maintenance, and filtration,” the warning letter stated.

The letter also noted that this particulate con-tamination problem has been a persistent and serious issue at the firm for many years.
“For example, 16 lots of Propofol and Liposyn manufactured in 2007 contained visible particulate contamination. Your firm did not detect the particu-late problem until November 2009 when you per-formed the second annual retain inspections, which were three to nine months overdue.

“By then, all 16 lots had expired. Further, substandard manufacturing practices led to three re-cent major recalls. These recalls were initiated due to excessive contamination with particulates (primarily stainless steel) and included 78 lots of Propofol, 121 lots of Liposyn, and 24 lots of Cleviprex. These lots were manufactured at your Clayton facility between January 2008 and February 2010.”

FDA deemed Hospira’s response inadequate because it was unclear if the firm had determined the root cause of the problem and resolved it. In addition, Hospira had not designed an interim plan to ensure the quality of drug products that it continued to manufacture and distribute, prior to the completion of its corrective action and validation activities.

Next, FDA stated that the firm’s quality con-trol unit failed to: (1) ensure that the manufacturing processes for Liposyn, Propofol, and Cleviprex drug products were adequately designed, controlled, and monitored; (2) implement adequate corrective and preventive actions related to objectionable particulate contamination in Liposyn, Propofol, and Cleviprex drug products; and (3) complete and approve 178 manufacturing investigations within 30 days and issue NDA Field Alert Reports (FAR) in a timely manner.

“Your March 16, 2010 response describes a number of improvements made to the QCU since the April 2009 inspection, including revising procedures and hiring personnel. However, the most recent in-spection noted serious ongoing violations at this facility despite your efforts to address manufacturing inconsistencies, enhance the monitoring program for particulates, and improve your exception reporting practices,” the agency wrote.

Also, Hospira did not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, or extend investigations to other batches of drug product that may have been associated with the specific failure or discrepancy.

For example, “you failed to conduct adequate investigations that result in your implementation of corrective actions to prevent recurrence of the prob-lems and evaluate other potentially affected lots.

“Specifically, particulates were identified during an inspection of retain samples for two partially distributed lots of Liposyn on January 21, 2010. Sub-sequently, an exception Report (ER) 1685 was opened on January 25, 2010, due to the particulate contamination.

“Although your firm recently experienced multiple serious particulate issues leading to product recalls, you failed to: 1) conduct testing to identify the foreign particulates (which were primarily stainless steel) until February 4, 2010; 2) place the remaining product from the two affected Liposyn lots on distribution hold until February 5, 2010; and 3) inspect retain samples from associated lots until February 10, 2010.”

In addition, Hospira did not establish criteria for the sampling and testing conducted by the quality control unit to assure that the batches of drug prod-ucts meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release.

For example, the firm does not have accep-tance criteria for the five day retain sample inspection of emulsion products. In addition, QAI-0101 does not require the initiation of a manufacturing investigation when any visible particulates are found during the five day retain sample inspection.

“Your March 16, 2010 response states a Parti-culate Analysis Protocol (GP-10-02) was implemented in January 2010, which requires initiating an investigation when particulates are observed during the five day retain sample inspection. However, your response is inadequate because you have not provided the protocol, nor does your response include the acceptance criteria,” FDA added.

At Rocky Mount, FDA stated that the com-pany did 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.

For example, the mixing processes for the products included in the firm’s mixing tank validation matrix were not adequately validated. It conducted validation activities only for Mannitol and Endrate, which it deemed to be the “worst case” products based on their solubility indexes. However, other products in the validation matrix such as Amidate, Amikacin, and Droperidol had lower solubilities than Mannitol or Endrate.

“You have not provided a scientific rationale to justify that the mixing studies conducted for Mannitol and Endrate are adequate and fully representative of the mixing processes for the other products,” according to FDA documents.

Next, Rocky Mount was cited for failure to adequately validate with a high degree of assurance, and approve according to established procedures, the results of a process that cannot be fully verified by subsequent inspection and test.

The mixing processes for heparin lock flush solutions were not validated. The batch records of the three lots used for Validation Study RC02016 had re-portedly been destroyed. A “worst case” validation approach was used to support the manufacturing process of these solutions in mixing tanks as discussed previously. The “worst case” process validation used to support the validation of heparin lock flush solution was performed heating the solution to Heparin is manufactured at a certain temperature and requires a recirculation step.

The mixing process validation conducted only evaluated the acceptability of mixing time after QS of the product. The validation did not consider mixing time prior to the final QS and did not include a recir-culation step. Different heparin solutions contain dif-ferent chemical ingredients, different excipients and potentially different critical process parameters. The potential critical process parameters like: pH, temperature, mixing time and mixing speed were not identified and evaluated. The “worst case” validation approach utilized did not support the heparin solutions manufacturing processes performed at the facility.

Clinical investigator warned for poor case histories and lack of
informed consent
Robert Deitz, M.D., San Francisco, CA

Clinical investigator Robert Deitz, M.D., re-ceived an April 1 warning letter for failure to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation.

For example, on January 20, 2005, this subject was enrolled in the study and was administered the study drug. The doctor submitted a protocol devia-tion/violation report to the Institutional Review Board (IRB) on May 2, 2005 stating that this subject was enrolled without having signed an Informed Consent Form (ICF).

The subject’s records contained two copies of the ICF. One was signed on May 10, 2005, and another copy was an altered version which reflected a signature date of January 10, 2005. Deitz stated in hisaffidavit obtained by the field investigator during the FDA inspection that he belived that the ICF with a signature date of January 10, 2005 was an altered document. He stated that he did not alter it and did not know who did.

Also, the electronic Case Report Form (eCRF) for the Baseline Visit states that the subject signed the ICF on January 20, 2005. However, according to the Baseline Visit worksheet, the ICF was signed on September 18, 2003. The subject’s records did not contain an ICF dated September 18, 2003 or January 20, 2005.
In addition, the subject’s records contained two copies of the ICF, one copy was signed on May 10, 2005 and the other was altered to indicate it was signed on January 10, 2005. Thus, it appears that the subject signed the ICF on May 10, 2005, which was not accurately recorded in the Baseline Visit eCFR or worksheet, FDA stated.

Regarding informed consent, the warning letter stated that Subject 34002 was enrolled in the study before he obtained the subject’s legally effective informed consent. On January 20, 2005, Subject 34002 was enrolled in the study and was administered the study drug. Deitz submitted a protocol deviation/violation report to the IRB on May 2, 2005 stating that this subject was enrolled without having signed an informed consent form.

The subject’s records contained two copies of the informed consent form. One was signed on May 10, 2005, and another copy was an altered version which reflected a signature date of January 10, 2005.

“You stated in your affidavit obtained by the field investigator during the FDA inspection that you believe that the ICF with a signature date of January 10, 2005 is an altered document.

“You stated that you did not alter the docu-ment and that you do not know who altered it. Thus, available documentation indicates that you did not obtain the subject’s informed consent until May 10, 2005, months after the subject was enrolled in the study.”