API maker Cambridge revises procedures, conducts training to address FDA observations.

Cambridge Major Laboratories, Germantown, WI, Minneapolis District

FDA investigators Charles Cote, Sandra Hughes and Joel Hustedt inspected two facilities of Cambridge Major Laboratories, an API manufacturer, during July and August 2009, and issued each the Germantown, WI-based plant a 483.

The 483 the company's Edison Drive facility received referenced two observations. The FDA team found the company's system suitability parameters for release testing of USP material (isradipine) did not follow the existing USP requirements for system suitability.

In its written response, Cambridge noted: "In review of the methods reliability with reduced system suitability requirements, CML has an extensive batch history to claim that the system was functioning properly at the time of analyses."

However, the company continued: "In an effort to meet the USP requirements for system suitability, CML has amended its internal test method (TM160) to include full system suitability requirements as defined in the USP for release testing of USP material isradipine. In addition, CML has evaluated its other marketed USP-labeled APIs for similar issues relating to system suitability."

The investigators also observed that siphon pumps for raw materials were not always compatible. The firm used a specific brand of siphon pumps to transfer solvents from drums at the time of use.

"These consist of a hand pump mechanism, a dip (suction) tube and a discharge tube," the 483 reported. "These were noted to be stored in situ (installed into the drum). Specifications for these show construction material as PE [polyethylene.] An information sheet supplied by the firm for compatibility of containers vs. solvents show PE is not compatible with ethyl ether, one of the materials used in production of several products, including dexmedetomidine HCL."

Cambridge explained in its reply that "although ethyl ether is used in the manufacturing of dexmedetomidine HCL" that particular API "is not manufactured at CML's Edison Drive facility but rather at the Washington Drive facility, where compatible stainless steel pumps are utilized."

The company also stated that the polyethylene pump used for ethyl ether at the Edison Drive plant "was immediately removed from use after it was identified by the inspector." A compatible pump is now being used that is rated as acceptable for use with ethyl ether.

"In addition, the ethyl ether drum was immediately removed from cGMP inventory," Cambridge stated. The firm also said it was revising its procedure for equipment and glassware design "to improve the review process for ordering of ancillary equipment (such as hand pumps) before implementation of use. The system will assess the ancillary equipment's compatibility with different solvents."

The Washington Drive facility received a five-time 483 from the FDA team. The report stated that stability packaging did not match bulk packaging of finished product as required in the firm's procedure for its stability program. "Fenoldopam stability is packaged in amber bottles placed in PE bags while the bulk material is only stored in amber bottles. Midodrine stability is packaged in double heat-sealed PE bags while the bulk materials is packaged in two PE bags that are cable-tied."

In its written response to this 483, Cambridge stated that it had "Certificate of Analyses and raw data to support that bulk fenoldopam mesylate API, although not packaged within a PE bag as demonstrated with the stability study, is stable at room temperature storage conditions for up to three years. CML has retested bulk lots of fenoldopam mesylate that have been packaged in only amber glass bottles and proven that the material is stable."

However, the firm agreed that in the future "any bulk fenoldopam mesylate manufactured will be secondarily packaged into a polyethylene bag to mimic the stability packaging." In addition, the company said it would "further package into a polyethylene bag" its existing inventory of the API and revise the labeling "to reflect a one-year test date from the date of manufacturing," which will require that the API be retested before distribution.

Cambridge also noted that it had revised its stability procedure to require "the description of bulk packaging to be included in all stability protocols as a built-in check system to ensure that stability packaging is matching bulk packaging of the finished product."

In regard to midodrine HCI, the company wrote: "CML QA performed a visual inspection of the stability samples currently stored in the stability chamber for long-term storage conditions." The company determined from this inspection that the stability samples for the 2004 validation lots "were packaged according to the Master Production Record final API packaging instructions (i.e., twist-tied poly ethylene bags.) It was discovered that this protocol had an authoring error indicating that the samples were to be in heat-sealed bags but were not packaged accordingly."

Any future midodrine HCI will be packaged into heat-sealed PE bags, Cambridge noted.

The FDAers observed: "Trending of stability data is not adequate for the isradipine stability study." Specifically, they noted, data trending was not performed at the end of the accelerated studies.

Cambridge replied that it had evaluated its stability data for this API to determine if any trends were identified. "According to the Stability Protocol, the study was conducted for long-term condition only as this was an annual batch placed on stability. This study did not require accelerated conditions as they were previously conducted on the validation lots. Based on the review of long-term data, no trends were identified."

All other studies related to isradipine were also reviewed and no trends were identified in those, as well, the firm noted.

The company told FDA that it had revised its stability procedure "to include instruction on trending and how it is reported." Future trends analysis "will consist of graphing/ charting of the raw data" and further instructions were added to the procedure "to identify measures to be taken if a trend is identified," including investigation, CAPA and/or generating additional reports.

FDA also faulted the company for trending only for a limited number of time points, the team noted in the 483. Again, Cambridge referenced the stability protocol that required a study only for long-term conditions for midodrine HCI. The corrective and preventive actions noted for the previous observation were applied to this observation as well.

The investigative team observed that CML's supplier qualification was not adequate, noting that "the critical starting material for etonomine (etomidate)--(R)-(+)-alpha-Methylbenzylamine--has not been tested" as required by the firm's subcontractor and vendor qualification procedure.

Cambridge replied that it had evaluated "all of its critical starting materials for all commercially available APIs and determined that the inadequate testing of (R)-(+)-alpha-Methylbenzylamine is an isolated incident and no systemic issue has been identified." The company initiated a deviation report to further investigate the failure to test the raw material, and stated: "Preliminary results from the retesting of one recent retain lot has shown passing results within CML specifications for GC and chiral purity and consistency with the results reported by the vendor."

The FDAers observed improperly labeled or unlabeled product in both cold and room-temperature storage. They noted that one lot of a product was sitting on a quarantine sticker, which was not attached. Other products and materials were found in cold storage with no quarantine or release labels affixed.

Cambridge replied: "Following the citing of the observation, CML immediately affixed all applicable labeling and ensured all labeling was consistent." The company stated it also had conducted a retraining session with all its appropriate staff "to ensure that all materials are properly and consistently labeled and that labels are properly affixed to the containers." The firm also had revised its internal audit schedule "to include more frequent inspections of the cGMP cold and room-temperature storage areas until there is assurance that the issue has been resolved."

The investigation found that Cambridge had not conducted adequate investigations on discrepancies, as required by its CAPA plan. The team specifically noted the inadequacy of one investigation/disposition report. Cambridge replied: "It should be noted that this investigation was performed in 2006 utilizing a now-obsolete SOP."

The following year, the company revised its investigative procedures "to include a more thorough process for performing investigations and determining root cause(s) for discrepancies." The firm also stated that it was expanding its initial investigation in an attempt to identify root causes for earlier discrepancy.

A review of the company's raw material inventory logbooks, which include inventory reconciliation, found that several of the notebooks were "inaccurate with no follow-up or discrepancy report or investigation made."

Cambridge explained that "the raw material use logbooks are implicitly used for lot use trace-ability in the event of an investigation. These logbooks are not used for inventory reconciliation as the receiving logbook is maintained for inventory control." The amounts recorded in these logbooks, the company said, "are approximations as exact amounts cannot always be determined based on the label information provided by the vendors."

The firm stated that it had performed "a cursory review of the 2009 logbooks" and determined that the discrepancies were most often seen "with solvent/water drums in which multiple containers are received."

To ensure that "the correct information is being documented on the form and a clear indication for the purpose of the use logbooks is defined," Cambridge said it was in the process of modifying its procedure for raw material usage through the firm's change control system. It also had held a training session "to address the proper notification of an identified discrepancy to a superior and/or QA in a timely manner in order to ensure further investigation is performed."