'Good Tissue Practice' rules may mean CBER team inspections.

FDA's Nov. 18 final rule creating "Good Tissue Practices" (GTPs) draws upon drug and de-vice GMPs in requiring process validation, software and computer validation and prohibitions on pooling tissue to avoid contamination, but also will mean team inspections, similar to "Team Biologics."

The GTP rule is the last of three under the Center for Biologics' overall plan to make human cells and tissues safer. GTP includes the methods, facilities and controls used to manufacture these products. The other two related concerned registration and listing requirements, which became effective Jan. 21, 2004, and a May 25 rule, "Suitability Determination for Donors of Human Cellular and Tissue-Based Products," which focuses on donor screening and testing measures to prevent the unwitting use of contaminated tissues with potential to transmit infectious diseases. It will become effective on May 25, 2005, and applies to all human cells, tissues and cellular and tissue-based products (HCT/Ps), including reproductive cells and tissues. The new GTP rule, which applies to all non-reproductive cells and tissues, also will become effective on May 25, 2005.

The GTP rule--entitled "Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based Establishments; Inspection and Enforcement" (21 CFR part 1270)--requires manufacturers to recover, process, store, label, package and distribute HCT/Ps in a way that prevents the introduction, transmission or spread of communicable diseases.

According to the rules, examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix and semen or other reproductive tissue.

The following articles are not considered HCT/Ps:

(1) Vascularized human organs for transplantation;

(2) Whole blood or blood components or blood derivative products subject to 21 CFR Parts 607 and 207;

(3) Secreted or extracted human products, such as milk, collagen and cell factors; except that semen is considered an HCT/P;

(4) Minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent, does not raise new clinical safety concerns with respect to the bone marrow);

(5) Ancillary products used in the manufacture of HCT/P;

(6) Cells, tissues and organs derived from animals other than humans; and

(7) In vitro diagnostics as defined in 21 CFR Sec. 809.3(a).

Additionally, FDA said human heart valve allografts and human dura mater allografts, currently regulated as medical devices, would be regulated if they meet certain criteria under the new tissue rules [21 CFR Sec.1271.10(a)]. The Jan. 27, 2004, interim rule, under which these products continued to be regulated as medical devices, will be revoked, FDA said. The agency clarified, however, that with two minor exceptions, the regulation is not being finalized with respect to reproductive HCT/Ps, which are presently regulated solely under section 361 of the Public Health Service Act and the regulations in part 1271. The agency said it chose not to address the requirements for reproductive HCT/Ps because it has received few recent reports of transmission of communicable disease associated with them, adding that "we don't know whether this is because such HCT/Ps pose low risk or whether occurrences of disease transmission are overlooked or under-reported." The docket, however, will remain open for comments on communicable disease risks associated with HCT/Ps and appropriate regulation to minimize those risks.

At an audio news briefing, Center for Biologics Director Jesse Goodman, M.D., said reproductive tissues "like sperm and egg are coming un der FDA regulation, but are not registered yet." He said they are subject to donor screening requirements, but not GTPs just yet.

As far as inspections, the rules give the same authority to field investigators as they have for drugs, devices and other biologics. Goodman said FDA will train a special group of auditors to under-stand tissue banking practices and that audits would be conducted with the Office of Regulatory Affairs.

Goodman added that inspectors "will be looking at manufacturing facilities and how they are cleaned and how people prevent contamination from one tissue to another." He also said there will be an expectation of cleaning validation "to prevent contamination. We've been very aggressive on that." Asked if inspections will now change, Goodman said "they will evolve in a positive way." "... we've been working with these other kinds of industries to be aware of what clearly the needs are." Inspections also may be conducted without notice, FDA noted. According to the preamble of the GTP rule, several companies in the tissue business felt donor screening and industry standards, such as guidelines from the American Assn. of Tissue Banks, would suffice and that GMP-like rules were not needed. However, FDA noted that about 23% of tissue banks in the U.S. do not follow AATB guidelines and that the agency cannot enforce a private association standard. The rule also requires manufacturers to re-port certain adverse reactions and HCT/P deviations to have labeling that contains accurate and complete information, and to allow FDA inspections to ensure compliance with regulations. But re-porting of adverse reactions and HCT/P deviations will not be required for reproductive HCT/Ps at this time.

The GTP rule, as well as the suitability de-termination rule, will become fully effective on May 25, 2005. The requirements, however, will apply only to HCT/Ps recovered on or after the effective date.

The GTP rules and related documents are available here: http://www.fda.gov/cber/tissue/docs.htm.