FDA shifts to collection at Alpha Therapeutic.

Alpha Therapeutic, Seattle, WA, Seattle District.

Two Alpha Therapeutic plasma collection facilities in Seattle were the subject of May and June inspections and a July warning letter, one more round in the company's battles with FDA.

Alpha's experience shows how a company may be subject to extra scrutiny, once the agency's antennae are up.

FDA aimed a consent decree at Alpha's plasma fractionation operations in January 1998 after grueling inspections, triggered by reports of contamination (See August 1998 issue, page 7).

Problems with donor screening and changes to donor status already had elicited a warning letter in September 1995 (Doc. 3337W), issued by the Atlanta District Office.

A second warning letter, issued in August 1997, cited the firm's Del City, OK, facility (Doc. 5675W) for deficiencies in taking informed consent, an investigation into an adverse reaction, inadequate donor-screening records and SOP deviations.

Both the May and June audits, conducted respectively by Lisa Althar and Jessica Moell, focused on donor screening and how Alpha handled unsuitable units. In contrast, the prior FDA visits to both Seattle sites were classified NAI.

During the May visit, Althar cited distribution of source plasma for further manufacture after it was discovered that the plasma was collected from donors who were not screened for high-risk behavior, among other omissions.

Althar did not think the firm's SOP would have communicated this practice accurately to CBER for approval, the records stated. She also questioned the firm's decision to divert unsuitable plasma from use in injectables to in vitro diagnostic (IVD) manufacturing purposes.

In related observations, Althar queried the diversion of units collected from the spouse of a donor who tested reactive for anti-hepatitis C virus (HCV).

ABRA guidance, CBER approval cited

Management argued that American Blood Resources Assn. (ABRA) guidance did not require deferring such individuals, that CBER had approved the practice and that the decision to divert questionable plasma for use in diagnostic reagents was a choice to "err on the side of caution to injectables," the EIR said. Viral marker test results for the units were negative, FDA added.

However, Althar also referred to a donor screening procedure that required a 12-month deferral for donors who had close contact with a person with hepatitis.

In addition, Althar cited an SOP for devia-tions that did not address documenting when and how errors were discovered. For instance, Althar wrote that a donor gave affirmative responses regarding AIDS and unexplained needle marks.

A deviation form directed the alert coordinator to "downgrade" the unit for non-injectable use. There was no record of how the error was discovered and why the corrective action was not requested until seven months later - after the unit had been shipped and could not be downgraded.

Althar also noted a lack of procedures to document the labeling of downgraded plasma.

Second site gets similar citations

In June, Moell cited similar issues at the second Seattle site. According to the 483 and EIR, she objected to the distribution of source plasma units for manufacture after the donors were found unsuitable due to missed screening questions and contact with an intravenous drug user.

Further concerns involved lapses in donor screening and related records, without document-ed retraining, plus a permanently deferred donor with no reject card on file.

During discussion, Alpha said a company task force was evaluating the practice of downgrading units determined to be unsuitable. The task force was set up in response to a previous 483 observation, the EIR stated.

Regulatory Affairs Director Kurt Carlson said Alpha was "unaware that source plasma for in vitro non-injectables had the same qualifications as source plasma for injectables," according to the EIR.

Alpha's responses to the 483s stressed re-training in donor screening and documentation, also noting that its staff already had caught the errors FDA cited.

In addition, Alpha asserted that there was no regulation or guidance requiring deferral of the spouse of an anti-HCV donor or a look-back in such cases.

Not all of the issues cited in the 483s ap-peared in the subsequent warning letter (6846W), which addressed observations at both sites.

Instead, the letter targeted missed donor screening questions and a lack of specificity in the SOP for disposing and labeling source plasma units that were found suitable only for use in manufacturing IVD reagents.

According to the letter, FDA wanted the SOP to specify what types of unsuitable products can be labeled for this purpose.

The warning letter said FDA accepted Alpha's corrective actions addressing retraining and related documentation for screening deficiencies. However, FDA said it was not completely satisfied with the firm's response concerning procedures for downgrading units for IVD use.

Noting that Alpha representatives had participated in a teleconference with officials from the Seattle District Office and CBER, FDA asked for an update on promised SOP revisions. The agency requested a progress report on an audit of product releases at all facilities, since all used the same labeling SOP for plasma destined for reagents.

In addition, the agency wanted to know the disposition of units cited on the 483.

The company's response to the warning letter suggested that management was taking more "global" action than that described in the 483 responses, emphasizing prevention and corporate management's involvement in these areas:

* Retraining staff in screening procedures.

* Distributing a copy of the warning letter to all Alpha regional directors.

* Re-instructing staff to ensure proper screening.

* Establishing a control desk at the Seattle centers to screen all charts before donations.

* Logging and reviewing all screening errors.

* Visits by the regional director and corporate director of donor center QA to perform thorough chart reviews and observe the screening process.

* Apportioning extra time and resources to screening and suitability concerns.

* GMP training emphasizing "concurrent documentation and record keeping."

The company had submitted a revised procedure to CBER for review, explained the dis-position of all units cited in the 483, quarantined all units designated for in vitro use, inventoried all units shipped for in vitro use from September 1997 to July 1998 and verified the reason for the IVD disposition. Two August 1997 shipments were "still being researched," the response stated.

A meeting of Alpha and FDA representa-tives followed in September to provide a progress report, address observations from an August in-spection of the firm's Everett, WA, facility and assure that corrective actions were "on target," according to the proposed agenda.

Subsequent FDA correspondence indicated that it generally approved of Alpha's corrections, requesting only one revision to a draft document, "Source Plasma Unit Decision Matrix."

But the approval did not last long. On Feb. 22, FDA issued yet another warning letter to one Seattle center (Doc. 7376W) tackling different instances where SOPs were either inadequate or not followed.

Among these were: not disconnecting a donor despite three safety system fault detection error alarms; not documenting on donor cards the volume of red blood cell loss; and no SOP describ-ing what actions to take when source plasma was collected in the wrong bottle.

In an interview, Alpha's regulatory compliance director, Michael Dubinsky - a former deputy director of CBER's Office of Compliance - said management was confident that product quality was not compromised and that the firm had submitted its written response.

However, a company spokesperson said in an interview that Alpha had not heard back from FDA and the inspection remained open.

Alpha Therapeutic, Seattle, WA, 5/13-15, 22 & 26, Doc. 108646M, $18, and 6/10-16/98, Doc. 108647M, $13.50. Retrieval extra.