For manufacturers of non-reproductive human cells, tissues, and cellular and tissue-based products (HCT/Ps), FDA released draft guidance on Wednesday outlining the most frequently reported HCT/P deviations reported to the Center for Biologics Evaluation and Research (CBER).

Under FDA’s authority, a manufacturer of non-reproductive HCT/Ps must investigate and report to the agency all HCT/P deviations related to a distributed product for which the establishment performed a manufacturing step.

The reports have to come within 45 days of the discovery of the event.

The look into which deviations are most frequently reported, as well as examples of which deviations are reportable and non-reportable, comes in addition to FDA’s descriptive scenarios illustrating who must report, what must be reported, and when such reports must be submitted.

FDA has seen a rising number inspections of HCT/P manufacturers over the last decade, and has publically disclosed an untitled letter and a warning letter to such companies in recent years, as well as additional guidance in 2014 and an update on adverse event reporting requirements from earlier this year.

Donor Eligibility

The first HCT/P deviation examples look at companies which distributed an HCT/P and then discovered that it was obtained from an ineligible donor:

• A donor tested positive for a relevant communicable disease and this information was provided by the testing laboratory and recorded in the relevant medical records.
• A donor engaged in high risk behavior (e.g., sex in exchange for drugs) in the preceding five years.
• A donor’s final autopsy report documented that death was due to sepsis and the donor’s medical records documented a medical diagnosis of sepsis.

As far as examples of non-reportable findings related to donor eligibility, FDA points to:

• A donor had a localized infection or positive blood culture, but no documented clinical evidence or diagnosis of sepsis.
• A donor had a history of a disease not considered a relevant communicable disease or disease agent (e.g., Chagas, malaria, Lyme disease, or lymphoma).
• The autopsy report stated that the cause of death was unknown or undetermined.

Donor Screening

The following are reportable deviations for donor screening:

• Donor screening for evidence of relevant communicable disease agents or diseases was not performed or documented, or the screening was incomplete. Relevant medical records were not reviewed.
• During an audit (or review) of the electronically recorded donor medical/social history interview, you discover that responses to questions related to a relevant communicable disease risk factor were incorrectly reflected on the written donor medical/social history questionnaire.
• New information was discovered during a quality audit of the relevant medical records, and a re-evaluation indicated there was a relevant communicable disease risk associated with human transmissible spongiform encephalopathy (TSE).

 As far as examples of non-reportable findings related to donor screening, FDA says:

• Donor medical/social history questionnaire was missing responses or had discrepant responses (e.g., yes and no) to questions that were not related to the prevention or spread of communicable disease transmission or HCT/P contamination (e.g., donor had history of heart disease).
• Donor screening was not performed for an autologous HCT/P donor which was required by your establishment’s standard operating procedures (SOPs) but not required by FDA.

Donor Testing

Examples of companies testing a donor specimen for evidence of infection due to communicable disease agents and finding deviations include:

• Donor testing was not performed for all required communicable disease agents.
• Required communicable disease testing was not performed in accordance with the manufacturer’s test kit instructions.
• Testing for a communicable disease was performed with an unacceptable donor specimen, in that the specimen was collected 10 days before the recovery of musculoskeletal HCT/Ps. (See the complete list of current FDA-licensed donor screening tests for HIV, HBV, HCV, and HTLV here)
• A donor specimen was incorrectly filtered or collected in an expired sample collection tube (containing anticoagulant).
• A donor of viable, leukocyte-rich HCT/Ps was not tested for HTLV or cytomegalovirus.
• A donor specimen was tested using a diagnostic test kit instead of an FDA-licensed, approved, or cleared donor screening test.
• A donor was not evaluated, incorrectly evaluated, or the evaluation was not documented for plasma dilution.

Examples of non-reportable findings related to donor testing include:

• Required donor testing was performed by a facility that was not registered with FDA, but was CLIA certified, and licensed test kits were used for testing.
• Donor testing was incorrectly performed on a specimen from an autologous donor.
• Although the donor testing sample was collected within the required timeframe, an incorrect sample collection time was documented on an infectious disease testing result report.

Processing and Process Controls

For companies processing each HCT/P in ways that do not cause contamination or cross-contamination, examples of deviations include:

• An HCT/P was distributed before a positive bacterial or fungal test result was obtained from a post-processing culture.
• HCT/Ps from two or more donors of musculoskeletal tissue were pooled during manufacturing.
• In-process control procedures were not followed.
• During in-process testing, the HCT/P was cultured for microorganisms; however the sample was not representative of the material being evaluated.

Examples of non-reportable findings related to processing and process controls include:

• During cornea recovery, the contact lens was not removed.
• During a processing step of freezing an HCT/P, a different concentration of dimethyl sulfoxide was used than was specified in the HCT/P establishment’s SOP.
• Processing steps were performed according to the HCT/P establishment’s SOP but were not documented concurrently with performance of each step.

Distribution

And finally, as far as examples of reportable HCT/P deviations related to receipt, pre-distribution, shipment and distribution, FDA says:

• A responsible person did not review and verify tracking records, and did not document that the release criteria had been met for an HCT/P that was distributed.  
• A quarantined HCT/P that was not available for distribution because it was recovered from an ineligible donor was distributed.
• An HCT/P with a positive bacterial or fungal culture result was distributed.

Examples of non-reportable findings for such products include:

• An incorrect HCT/P (e.g., the establishment distributed a properly labeled bone instead of tendon, which was ordered) was distributed, but the HCT/P had met all the release criteria and was acceptable for distribution.
• A summary of records is missing the date and time of the release of the HCT/P.

Draft Guidance on Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products