Signature Biologics, LLC — FDA Warning Letter Findings

Laboratory controls do not include the establishment of scientifically sound and appropriate specifications designed to assure that the drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example, at the time of the inspection, your finished product testing was limited to sterility testing as a measurement of product attributes.

Failure to have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)]. For example, at the time of the inspection, you had not validated your process for cleaning and disinfecting the Biological Safety Cabinets (BSCs) and supporting cleanrooms where your product was manufactured.

Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)]. Your firm has not established an adequate system for environmental monitoring in the aseptic processing areas where your products are manufactured. For example: a. You have not performed microbiological monitoring of viable air in the ISO 7 supporting cleanrooms in association with each production run. b. Your environmental monitoring procedure describes the following as acceptable results for microbiological monitoring: (b)(4) colony forming units (CFUs) for surfaces within the ISO 7 supporting cleanrooms, (b)(4) CFUs for settling plate samples within the ISO 7 supporting cleanrooms, (b)(4) CFUs for personnel glove samples within the ISO 7 supporting cleanrooms, and (b)(4) CFUs for personnel garment samples within the ISO 7 supporting cleanrooms. Your allowance for such high numbers of microorganisms could contribute to product contamination and pose a potentially significant safety concern.

Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR 211.113(b)]. Your firm failed to adequately validate the aseptic processes used to manufacture your Signature Cord™ product in that the media fill batches used for your validation studies did not represent the maximum commercial batch size. For example, your validation studies entitled “Aseptic Processing Validation Report—Signature Cord” utilized a maximum of (b)(4) vials per batch. However, from November 2018 through February 2020, your firm manufactured (b)(4) commercial batches of Signature Cord™ with (b)(4) vials.

Failure to establish a written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. Specifically, you assigned a two-year expiration date to your product without supporting data. FDA received your written responses dated January 10, 2022, March 1, 2022, April 1, 2022, May 24, 2022, June 30, 2022, August 31, 2022, and…

Failure to establish written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)]. For example, the manufacturing process for your product has not been validated.

Each of batch of drug product purporting to be pyrogen-free is not laboratory tested to determine conformance to such requirements [21 CFR 211.167(a)]. For example, your firm failed to perform endotoxin testing as a release criterion on (b)(4) units of Signature Cord™ product manufactured and distributed by your firm since November 2018. By the nature of the route of administration, your product is purported to be pyrogen-free and is expected to be pyrogen-free.