Cleaning validation expected to be complete by year's end, patched screens discontinued. (Human drugs).

Cleaning validation residual studies at active pharmaceutical ingredient (API) manufacturer Bachem California are expected to be completed by the end of the year, the firm said in response to FDA's Jan. 14 warning letter. FDA acknowledged the company's Dec. 12 response to the 483 issued Nov. 27, 2001, but commented that, in several instances, the responses were either inadequate or lacked documentation.

While Los Angeles District Director Alonza Cruse initially called the firm's end-of-2002 completion date "not justified" in his warning letter (Doc. 11367W), the agency changed its tune in a Jan. 31 letter to the firm from District Compliance Officer Dannie Rowland. The FDAer stated the agency had reviewed the firm's warning letter response and found it "adequately" addressed agency concerns.

Bachem VP of Regulatory Affairs and Quality Brian Gregg provided the agency with a 42-item schedule on Jan. 29 listing estimated completion dates for cleaning validation residual studies in response to the warning letter which characterized the firm's cleaning validation to be "limited to only glassware."

"Glassware and equipment that are hardest to clean and are used in the final stages of drug substance manufacturing are the current focus of residual low solubility peptide studies," Gregg wrote FDA. "Sintered glass funnels are expected to be the most difficult to clean, followed by tray lyophilizer screens, lyophilizer temperature probes, lyophilizer trays, and lyophilization flasks."

Bachem's cleaning validation woes began as one part of a 21-observation 483 written up by Investigator Terri Dodds of the Los Angeles District who inspected the firm's Torrance, CA, facility Nov. 13-16 & 27, 2001. According to the 29-page EIR, the inspection was in response to two Establishment Evaluation System requests for Desmopressin Acetate and Calcitonin-Salmon. Dodds noted that only laboratory data for Calcitonin-Salmon was reviewed and "was not covered in total due to the significant GMP observations noted." Dodds added that this application's review was terminated as a result.

In the 483, the investigator continued that the firm had failed to investigate out-of-specification (OOS) outcomes during cleaning validation of lyophilization trays and did not have a cleaning validation "for screens and wire electrodes, which both have product contact during tray lyophilization."

Citing the potential for cross-contamination, FDA took particular interest in the firm's practice of using tape to hold together production trays and screens and that tape residue "was noted on the polypropylene frames" which were also found to be frayed. According to Gregg's Dec. 12, 2001, response to the 483, he noted the "potential for cross-contamination is not expected" and that trays, screens and probes were inspected immediately prior to use. Gregg explained that after Dodds observed the contaminated screens on Nov. 13 that the screens were "immediately isolated by Quality Assurance."

Despite Gregg's explanation and assurances that using tape to secure screens "will be discontinued," Cruse said the executive's response did "not include any timeframes for achieving corrective action" and that the use of tape was "unacceptable in a manufacturing area where product contact is inevitable." Gregg reminded the agency of its promise to discontinue the use of tape and noted it had ceased the practice as of Jan. 25, referring to an attached internal company memo.

Also, Gregg noted that as of the last day of the inspection, Nov. 27, "no bulk drug substance has been lyophilized by tray lyophilization," adding that the firm was looking into a custom-made screen design and was unable to provide a target date for when these screens would be acquired.

Bachem's lab controls also were cited for lack of requirements for high-performance liquid chromatograph (HPLC) column system suitability applicable to the purification process of drug products.

To this Gregg responded that residual low solubility peptide studies for cleaned preparative high-performance liquid chromatography would be completed by the beginning of April.

In a July 19 phone interview, Gregg told VT that he was "not permitted to disclose" information concerning further dealings with FDA.

Bachem California, Inc., Torrance, CA, 11/13-16 & 27/01, Doc. 109188M, $41.50 plus retrieval

The Checklist--Bachem California

[check] cleaning validation

[check] cross-contamination

[check] HPLC requirements

[check] O-O-S results

[check] lypholization