Understanding GTPs

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18 July 2008

Understanding

and ImplementingGood Tissue

Practices (GTPs)By Darin J. Weber, PhD



Regulatory Focus 19

Many of the requirements of the GoodTissue Practice (GTP) regulation willbe familiar to those who work underGood Manufacturing Practice (GMP)

or Quality Systems Regulations (QSRs). However,it is important to recognize that GTPs do havesome unique requirements not found within

existing GMP/QSR regulations. Thus, to ensurecompliance with GTPs, a systematic assessment of current quality systems is essential to identify andfill any gaps. This article provides an overview of GTPs and offers considerations for assessing thestate of compliance with GTP requirements.

Wh are gtPs?GTPs are a comprehensive set of regulationsenacted by the US Food and Drug Administration(FDA) to cover human cells, tissues or cellularor tissue-based products (HCT/Ps) intended for

implantation, transplantation, infusion or transferinto a human recipient. These regulations governthe methods used in, and the facilities and con-trols used for, the manufacture of HCT/Ps. Theprimary intent of GTPs is to ensure that HCT/Psare manufactured in a manner designed to preventthe introduction, transmission and spread of com-municable disease. In some cases, an HCT/P may be subject only to GTP requirements. In othercases, e.g., when an HCT/P is the starting materialfor creating novel cell- and tissue-based products,GTPs and additional regulatory requirements,such as GMPs, biological product standards and/

or the medical device QSR, will be applicable. Thecriteria governing the specific level of regulatory oversight are described in 21 CFR 1271.10 andhave been reviewed elsewhere.1 Figure 1 depictshow GTPs apply to different regulatory pathwaysfor an HCT/P.

Cre gtPs nd he Quliy PrrmHow does one begin to implement GTPs orperform an assessment of compliance relativeto GMPs and/or QSRs? Fortunately, FDA hasidentified a number of “core” GTP requirements.

These requirements place specific emphasis onprocedures and practices to recover, process,store, label, package and distribute human cellsin a manner designed to prevent the introduc-tion, transmission and spread of communicabledisease. Figure 2 identifies both core items andother GTP requirements.

Quality Program A quality program is the linchpin of GTPs. Itshould be an organization’s comprehensive sys-

tem for manufacturing and tracking HCT/Ps inaccordance with current GTP (cGTP) require-ments. It is specifically intended to prevent,detect and correct deficiencies that may lead to anincreased risk of communicable disease transmis-sion. The quality program must be appropriatefor the specific HCT/Ps and their manufacturing

steps. It must address all core GTP requirements(see Figure 2). A major quality program func-tion is ensuring that procedures for complying

with each core GTP requirement are establishedand maintained. However, the quality programmust also address a number of non-core require-ments such as personnel training, procedures forinvestigation and documentation of complaintsand manufacturing deviations, corrective andpreventative actions (CAPA), information sharingregarding potential communicable disease trans-mission and auditing.

The quality program prescribed by GTPshas more in common with QSRs and is muchmore specific than a GMP-prescribed quality control unit. A summary of each core GTPrequirement follows.

Donor Eligibility Given their emphasis on preventing transmissionof communicable diseases, it should not be sur-prising that GTPs incorporate by reference donoreligibility requirements that dictate that a donor’smedical records must be reviewed for relevant risk factors and clinical evidence of communicable dis-

ease agents. This review includes a donor physicalexam for signs or symptoms of relevant communi-cable diseases. In addition, donors must be testedusing FDA cleared or approved test kits for specificrelevant communicable disease agents or diseases(RCDAD). FDA has issued an excellent guidancedocument that describes current expectations fordonor eligibility determination.2 As additional rel-evant communicable diseases emerge, such as WestNile Virus and Vaccinia, the list of expected donorscreening and/or donor testing will continue togrow.3 There are several exceptions to the need to

perform donor eligibility, e.g., autologous HCT/Ps and directed donations of specific cell or tissuetypes. These are discussed in the aforementionedFDA guidance document.

The detailed donor eligibility requirementsare unique to GTPs.

Recovery Methods used to procure a specific HCT/P mustnot cause contamination or cross-contamination,or otherwise increase the risk of communicable

GxPs



20 July 2008

disease through the use of the HCT/P.This requirement also is unique to GTPs.

Receipt Each incoming HCT/P must be evaluated forthe presence and significance of microorganismsand inspected for damage and contamination.

Acceptance, rejection or quarantine of a HCT/Pmust be based upon pre-established criteria. It

is important to note that certain HCT/Ps may contain an inherent bioburden level and, in suchcases, e.g., family-related uses, rejection of theHCT/P for medical uses may not be warranted.

Unlike GMPs or QSRs, GTPs require spe-cific evaluation of incoming HCT/Ps with respectto the presence of microorganisms, damage and

contamination.

Supplies and Reagents Acceptance of incoming supplies and reagentsused for HCT/P manufacturing must be basedupon verification of established specifications.Thus, for each material there should be an asso-ciated materials specification form stating therequired acceptance criteria. For the purposesof GTPs, these specifications would be relatedto preventing transmission of communicabledisease. For example, if an incoming material

should be sterile, verification of sterility basedupon the vendor’s certificate of analysis wouldbe the minimum requirement. Records shouldbe maintained for all materials to provide trace-ability to a specific HCT/P.

Facilities GTP facility requirements are very similar tothose for carrying out aseptic manufacturingoperations under GMPs, since aseptic operationsare necessary for many HCT/Ps. An HCT/Pmanufacturing facility should be of appropriatedesign and layout to segregate operations or have

other means to prevent mix-ups, contamination,mislabeling and exposure of HCT/Ps to commu-nicable disease agents. Similarly, the facility mustbe appropriately designed to allow efficient clean-ing and disinfection of surfaces and equipment.

Environmental Control and Monitoring A key consideration HCT/P manufacturing facil-ity design is the extent of environmental controlrequired given the nature of the HCT/P and thedegree of openness of the manufacturing processto the surrounding environment. Environmental

control and monitoring requirements are moreextensive for HCT/Ps that cannot be terminally sterilized, and therefore must be manufacturedunder aseptic processing conditions, than for thoseconsisting of nonviable tissue that can be renderedsterile by gamma irradiation or other methods.GTPs stipulate that, where appropriate, the follow-ing activities or systems must be controlled:

temperature and humidity •

ventilation and air filtration•

room and equipment cleaning and•

Fiure 1.

Relinship f gtP Requiremens nd HCt/P Reulry Phwy

Fiure 2.

Cncepul View f gtPs

HCT/Ps that meet specific requirements outlined in 21 CFR 1271.10 are not subject

to premarket approval. Such HCT/Ps must only comply with GTP requirements. For

HCT/Ps that must undergo premarket approval to establish safety and efficacy, there

are additional quality system requirements, such as GMPs for biological HCT/Ps orQSRs for medical device HCT/Ps.

Core GTP requirements are shown near the center of the figure. These core require-

ments are surrounded by other GTP requirements, which also must be effectively

implemented and directly support the implementation of core GTPs.

No Premarket

Approval

Premarket

Approval Required



Regulatory Focus 21

disinfecting to ensure aseptic process-ing operationsmaintenance of equipment used to•

control conditions necessary for asepticprocessing operations

Additionally, environmental conditions must be

monitored if they could reasonably be expectedto cause contamination or cross-contamination of HCT/Ps or equipment, or accidental exposure tocommunicable disease agents. Finally, where appro-priate, an HCT/P establishment must provide envi-ronmental monitoring for microorganisms.

There has been much discussion regardingfacility environmental control and monitor-ing requirements for HCT/Ps subject only toregulation under GTPs. For example, it is gener-ally accepted that “open” manufacturing stepsshould be performed in biological safety cabinets

providing a class 100 (ISO 5) environment toprevent introduction of communicable diseaseagents or potential environmental microbes intothe HCT/P. However, for other manufacturingoperations utilizing closed or functionally closedprocessing systems (i.e., bags), some believe it is

unnecessary to provide a high degree of environ-mental control or even to perform environmentalmonitoring during manufacturing operations.

While GTPs and FDA indicate there is flexibility on this matter, it should be noted that the term“where appropriate” is defined in the regulationsas, “a practice (that) is required unless the estab-

lishment can document justification otherwise.”4 Therefore, each HCT/P establishment

should collect data from its processing environ-ment to ascertain what microorganisms may existin its facilities and design its environmental con-trol and monitoring program accordingly. FDA’s2004 aseptic processing guidance document con-tains helpful information on when and how toperform environmental monitoring.5

Equipment Procedures and records for equipment operation,

maintenance, calibration and cleaning/sanitationshould be established and followed. Files for all equip-ment used should specify maintenance and calibra-tion schedules. For critical equipment, ensure proce-dures are in place for monitoring and notification of out-of-calibration or operating specifications. Logs

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22 July 2008

should document equipment used for processingspecific lots of HCT/Ps. Cleaning validation is notrequired by GTPs. However, procedures should beestablished to verify that cleaning and disinfection/sanitization procedures will prevent the introduc-tion, spread or transmission of communicabledisease agents. For example, establish procedures

that specify the frequency at which disinfectants/sanitizing agents are rotated, and ensure the manu-facturer’s instructions for dilution and contact timeare followed.

Processing and Process Controls In keeping with the intent of GTPs, establish-ments must process HCT/Ps and implementappropriate controls that ensure products arenot contaminated or cross-contaminated duringprocessing and prevent the introduction, trans-mission or spread of communicable disease. Thus,

processing SOPs should be followed and batchrecords or designated forms used to documentprocessing activities. In particular, pooling humancells or tissue from two or more donors duringthe manufacturing process is not permitted, thuspreventing a contaminated HCT/P from onedonor from cross-contaminating HCT/Ps fromother donors. Additionally, establishments mustensure that specified requirements for in-processcontrols are applied and HCT/Ps are controlled,and that in-process sampling is representative of the material to be evaluated.

The prohibition against pooling HCT/Ps

from two or more donors is specific to GTPs.

Labeling Controls Procedures must be established and implement-ed to ensure proper HCT/P identification andprevent mix-ups. This includes verification of label accuracy, legibility and integrity. The infor-mation required to be included on a label willdepend upon the donor type (autologous or allo-geneic), intended recipient if allogeneic (relatedor unrelated), and results of donor screening andtesting. Detailed information is provided in sub-

part E of the human tissue regulations, specifi-cally 21 CFR 1271.370.Unlike GMPs and QSRs, GTPs require that

a distributed HCT/P be accompanied by a sum-mary of records that documents donor eligibility determination as part of its labeling.

Storage HCT/P establishments must control storage areasto prevent mix-ups, contamination and cross-contamination of HCT/Ps, supplies and reagents.

This includes establishing acceptable temperaturelimits for HCT/Ps during manufacturing and stor-age and assigning an expiration date, if necessary.HCT/P storage temperatures must be maintained,recorded and reviewed and corrective action taken

whenever proper storage conditions are not met.

Predistribution Shipment If, as part of the manufacturing process, anHCT/P is shipped from one location to another,e.g., from the tissue procurement site to the siteof tissue processing, and it is not considered suit-able for distribution or clinical use at that time, itmust be shipped in quarantine with documenta-tion that demonstrates it meets pre-establishedcriteria to prevent communicable disease trans-mission at the time of shipment. Such docu-mentation could include, for example, that theHCT/P was appropriately labeled, segregated and

transported under any required temperature and/or time controls.The concept of HCT/P predistribution ship-

ment is unique to GTPs.

Distribution An HCT/P can only be made available for distri-bution for medical use after manufacturing andtracking records have been reviewed by a responsi-ble person to verify that any established release cri-teria have been met. HCT/Ps that were obtainedfrom an ineligible donor, are in quarantine or donot meet release criteria designed to prevent com-

municable disease transmission may not be distrib-uted. There are specific exceptions for autologoususe, family-related use and cases of urgent medicalneed. If an HCT/P that did not meet release cri-teria or was manufactured in a way that departedfrom established procedures is made available fordistribution, a responsible person must justify anddocument the basis for that action. HCT/P pack-aging and shipping containers must be designedand constructed to protect the product from con-tamination. Appropriate shipping conditions to bemaintained during transit must be established for

each HCT/P type.Certain procedures for making an HCT/Pavailable for distribution are unique to GTPs,e.g., the requirements for completing donor eli-gibility determination and for specific design andconstruction of packaging and shipping contain-ers to protect the HCT/P from contamination.

oher gtP Requiremens (Nn-Cre) While not considered “core” GTPs, a number of additional GTP requirements, if not appropriately





28 July 2008

important, albeit non-core, GTP element, withspecific requirements relating product to donor,tracking from original to final disposition andunique codes.

Complaint File Each HCT/P establishment must establish and

implement procedures to ensure that all com-plaints relating to core GTPs are appropriately reviewed, evaluated, documented and investi-gated. This information must be maintained ina designated complaint file that can be reviewedand photocopied by FDA during an inspec-tion. Since this file is subject to inspection, it isimportant for the firm to ensure it has carefully evaluated whether there is a need for an investiga-tion and, if so, has carried out the investigationand implemented any necessary corrective andpreventative actions. If it is determined that an

investigation is not needed, this must be docu-mented and justified in the complaint file. If thecomplaint is related to an HCT/P deviation oran adverse event, reporting requirements under21 CFR 1271.350 must be carefully reviewed todetermine whether it is reportable.

Exemptions and Alternatives Because of the diverse nature of HCT/Ps, FDA recognizes the possibility that there may beaspects of GTPs that may not be feasible or for

which alternative means exist to address thepotential for transmission of communicable

disease. As a result, the agency has provideda mechanism for requesting an exemption tospecific GTP requirements and/or identifyingalternative approaches for satisfying the regula-tions. This request must be presented in writing,including supporting documentation such as rel-evant, valid scientific data, to justify the exemp-tion for a specific requirement or describe how the alternative method meets the specific require-ment. Operating under the proposed exemptionor alternative may only begin if the Director of the Center for Biologics Evaluation and Research

grants the exemption or alternative. While GMPs do not contain this type of provision, biological product regulations doinclude a section that addresses alternative meth-ods (21 CFR 610.9), but it is not as specific asthat described in GTPs.

SummryThe current Good Tissue Practice (GTP) regula-tions were broadly written to encompass thosehuman cells and tissues that fall within the

definition of HCT/Ps. The primary focus of GTPs is for establishments to implement effec-tive systems, procedures and practices to ensurethat HCT/Ps are manufactured in a mannerthat prevents the introduction or transmissionof communicable disease while providing cellsor tissues that may have medical utility for

recipients. Some HCT/Ps are only subject to theGTP requirements as described in this article.Others are starting materials for use in the cre-ation of cell and tissue-based products that areregulated as biological products, medical devicesand biologic-device combination products (tis-sue engineering/regenerative medicine) andmust meet additional regulatory requirements.

As highlighted in this article, GTPs have someunique requirements not found in other quality systems. Thus, HCT/P establishments shouldcarefully review their existing quality programs

to identify and fill any existing gaps.

REFERENCES

1. Weber DJ. (2004) “Navigating FDA Regulations for

Human Cells and Tissues,” BioProcessing International .

2(8): 22-26.

2. US Food and Drug Administration (2007) Guidance for

Industry: Eligibility Determination for Donors of Human

Cells, Tissues, and Cellular and Tissue-Based Products

(HCT/Ps). http://www.fda.gov/cber/gdlns/tissdonor.htm

3. US Food and Drug Administration (2008) Guidance

for Industry: Use of Nucleic Acid Tests to Reduce the Risk

of Transmission of West Nile Virus from Donors o f Whole

Blood and Blood Components Intended for Transfusion

and Donors of Human Cells, Tissues, and Cellular and

Tissue-Based Products (HCT/Ps). http://www.fda.gov/cber/gdlns/natwnvhctp.htm

4. Definition of “where appropriate” in Good Tissue

Practice regulations. §1271.150(e)

5. US Food and Drug Administration (2004). Guidance

for Industry: Sterile Drug Products Produced by Aseptic

Processing—Current Good Manufacturing Practice .

http://www.fda.gov/cber/gdlns/steraseptic.htm

AUTHOR

Darin J. Weber, PhD, has more than 11 years’ experience

in regulatory affairs. He is a Senior Consultant with the

Biologics Consulting Group and assists clients with develop-

ing regulatory strategy and product development for cell-

based therapies and engineered tissues. He can be reached at

[email protected].

F

Documents

Understanding GTPs