The US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) on Tuesday issued new guidance to provide establishments that manufacture human cells, tissues, and cellular and tissue-based products (HCT/Ps) with recommendations for complying with the requirements for investigating and reporting adverse reactions involving communicable diseases.

CBER notes that examples of HCT/Ps that are subject to adverse reaction reporting and fall within the scope of this guidance, include:

• Amniotic membrane
• Bone
• Cartilage
• Cornea
• Fascia
• Ligament
• Pericardium
• Hematopoietic stem/progenitor cells derived from peripheral blood
• Hematopoietic stem/progenitor cells derived from cord blood
• Sclera
• Skin
• Tendon
• Vascular graft
• Heart valve
• Dura mater

Within 15 calendar days of initial receipt of information about adverse reactions that are fatal, life-threatening, result in permanent damage or necessitates medical or surgical intervention or hospitalization, FDA must be notified, according to the guidance.

Manufacturers also must submit to FDA follow-up reports within 15 calendar days of the receipt of new information or as requested by FDA.

Adverse Event Investigation

As far as what the adverse event report investigation should include, FDA says it should evaluate pertinent information about the recipient’s adverse reaction that might be informative about possible etiologies of the adverse reaction. Pertinent information may include: “The time course, symptoms, and outcome of the reaction; The recipient’s medical and social/behavioral history (including pre-existing medical conditions and travel history); Relevant test results; and History of transfusions, infusions, transplants, implants, and transfers that may have been a source for communicable disease transmission.”

The investigation also should include the review of processing records to determine whether there were any deviations or departures from established procedures that may have resulted in contamination or cross-contamination of the HCT/P.

And FDA says the investigation should specifically include:

• A review of records related to the evaluation of the incoming bioburden, such as the results of recovery or procurement cultures, or findings on inspection of the HCT/P packaging or container for damage and contamination.
• The review of pre- and post-processing culture results, if applicable, and the determination as to whether any microorganisms present on those cultures were also present on recipient cultures.
• The determination as to whether multiple cellular products were collected at different times from the same donor and combined to attain a certain therapeutic dose, and a review of the results of cultures performed on each separate product, if available.
• A verification that the process used for removal or inactivation of microorganisms was validated and performed as established in standard operating procedures.
• The review of records of sterilization and/or disinfection process failures (i.e., positive microbiological testing results following sterilization or disinfection of an HCT/P) within the timeframe spanning an appropriate period before and after the suspect HCT/P was manufactured and a determination as to whether the establishment has experienced sterilization or disinfection process failures involving the same microorganism as identified in the recipient adverse reaction. An appropriate period should be supported by a risk-based analysis that includes the volume of processing cultures performed, but it should be no less than seven days.
• A determination as to whether any HCT/Ps from the donor were discarded during or after processing because they did not meet pre-established acceptance criteria related to communicable diseases (e.g., organism considered unacceptable, sterilization or disinfection process failures, contamination).

FDA also requests information on what environmental control and monitoring information was reviewed in the investigation of an adverse reaction, as well as storage and distribution information and tracking and labeling information.

The agency calls on industry to implement the recommendations in this guidance within the next six months.

Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely under Section 361 of the Public Health Service Act and 21 CFR Part 1271