21 CFR Part 1271

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21 CFR Part 1271

21 CFR Part 1271

Human Cells,

Tissues and

Cellular & Tissuebased

Products

[HCT/Ps]


Components

• A – General Provisions

• B – Registration & Listing

• C – Donor Eligibility

• D – Current Good Tissue Practices

• E – Additional Requirements

• F – Inspection & Enforcement


Subpart A

GENERAL


Subpart A – Purpose 1271

• To prevent the introduction,

transmission & spread of

communicable disease

• Registration & listing system for

establishments manufacturing HCT/Ps

• Establish donor eligibility

• Current Good Tissue Practices


Two Classes of Products

• Section 361 Products

• Minimally manipulated

• Homologous use (perform normal function)

• No combinations of cells/tissues

• Product does not have systemic effect

OR

• Systemic effect but is for autologous use, or allogeneic

use in 1 st degree relative or is for reproductive use

• Register with FDA and provide list of products

• Comply with Part 1271 regulations


Section 351 Products

• Manipulated & gene-modified

products (e.g. cultured cells, CTLs,

tumor vaccines

• Covered under an IND

• Must comply with Subparts B, C and

D of 1271 regulations


HCT/Ps - Definition

• Do not include

• Vascularized organs for transplant

• Whole blood & blood components

• Secreted or extracted products

• Minimally manipulated Bone Marrow not

combined with another article

• Ancillary products used in manufacturing

• Animal cells & tissues & in vitro diagnostics


Minimal Manipulation

• Processing that does not alter tissue

characteristics or utility

• Processing that does not alter the

relevant biological characteristics of

cells or tissues


Establishment

Registration

• Compulsory – CAGT is registered

• Includes, name, location, reporting official, listing of all

HCT/Ps recovered, processed, stored, labeled, packaged,

distributed or for which screening or testing is performed

• Sate whether each product is 351 or 361

• List new and discontinued products and any

changes

• Annual update – usually December


Subpart B

DONOR

ELIGIBILITY


Donor Eligibility

• HCT/P must not be used until donor has

been determined to be eligible

• Must have procedures for all steps in

screening and determining eligibility

• All procedures must be reviewed &

approved

• Departures from procedures must be

recorded and justified at the time of

occurrence


Screening not required

• Autologous products

• Must be labeled “FOR AUTOLOGOUS USE

ONLY”

• “NOT EVALUATED FOR INFECTIOUS

SUBSTANCES”

• “WARNING: Advise patient of communicable

disease risks”

• Biohazard label

• If applicable “WARNING: Reactive test for

_______”


Donor Screening

• Screening for risk factors

• Screening for clinical evidence of

infection due to relevant

communicable diseases

• Screening for specific diseases


Timing of Screening

• Collect specimen at time of recovery

of cells/tissue

OR

• Up to 30 days before or after

recovery for PBPC donors only

• Otherwise up to 7 days before or

after


Screening of Repeat Donor

• If complete screen was performed

within 6 months then:-

• Use abbreviated screening procedure

• Must determine & document changes in

medical history that would make donor

ineligible - including social behavior


Screening Tests

• HIV 1 and 2

• Hepatitis B

• Hepatitis C

• HTLV I and II

• Treponema pallidum

• CMV (Must have SOP for release of positive products)

• Use FDA licensed, approved or cleared

tests


Screening Tests - 2

• Disease agent or disease not listed

• For which there is a risk of transmission by

HCT/P either to the recipient or to the people

handling the product

• The disease agent has sufficient incidence to

affect the donor population

• Disease agent may have been released

accidentally (or intentionally) in a manner

that could place potential donors at risk


Eligible Donors

• Free from risk factors

• Free from clinical evidence of

infection

• Negative results for listed

communicable diseases


Use of non-conforming donors

• You must not make available or

distribution any HCP/T from a donor

whose eligibility is determined under

such a departure unless a

responsible person has determined

that the departure does not increase

the risks of communicable disease

through the use of the product


Products from Non-eligible Donors

• May be used for

• Allogeneic use in a first degree or second

degree blood relative

• Documented Urgent Medical Need

• Must be labeled “NOT EVALUATED FOR

INFECTIOUS SUBSTANCES” and “WARNING:

Advise patient of communicable disease risks”

• Non-clinical use and labeled as such +

Biohazard Label


Products from Non-eligible Donors &

Donors Pending Clearance

•Must be kept in quarantine

•Storage or identification to prevent

improper release

•Must be easily distinguishable from

released products

•In a physically separate area clearly

identified for such use or through the

use of other procedures (such as

automated designation)


Urgent Medical Need

• Allows use of products from non-eligible donors

• Must be labeled “NOT EVALUATED FOR

INFECTIOUS SUBSTANCES” and “WARNING:

Advise patient of communicable disease risks”

• Accompanied by test results and list of tests not

performed, documentation of notification of

physician

• Must complete donor eligibility testing & inform

physician of results


Donor Records

• The following must accompany the

HCT/P at all times

• Distinct identification code affixed to

the container – except for autologous

donors this must not include:

• The donor’s name

• Donor’s social security number

• Donor’s medical record number


Donor Record Contents - 1

• Records must contain:

• A statement that the testing was

performed by a laboratory:

• Certified to perform such testing under

CLIA

OR

• That has met equivalent requirements as

determined by the Centers for Medicare &

Medicaid Services


Donor Record Contents - 2

• Records must contain:

• A listing & interpretation of the results of all

communicable disease tests performed

• Name & address of the establishment that

made the donor–eligibility determination

• Must NOT contain the donor’s name or

other personal information that might

identify the donor

• Retain all records for at least 10 years

after product administration


Products from Donors

Pending Clearance

• If shipped

• Must be shipped in quarantine

• Accompanied by records

• Identifying the donor (e.g. by affixed code)

• Stating that eligibility has not been completed

• Stating that product must not be used until

completion of eligibility determination – except in

case of urgent medical need


Subpart C

CURRENT GOOD

TISSUE

PRACTICES


cGTP

• Designed to prevent the

introduction, transmission or spread

of communicable disease (virus,

bacteria, fungi, parasites and

transmissable spongiform

ecephalopathy


cGTP

Core Requirements

• Facilities

• Environmental

control

• Equipment

• Supplies &

reagents

• Recovery

• Processing &

Process control

• Labeling controls

• Storage

• Receipt , predistribution

shipment &

distribution


cGTP

Quality Program

• Addresses communicable disease

risks

• Appropriate for types of products

manufactured

• Addresses cGTP core requirements


Quality Program

Functions

• Establish & maintain procedures related

to core cGTP requirements (review,

approval and revision)

• Receive, investigate, evaluate &

document information relating to core

requirements ( e.g. complaints,

contamination etc.)


Staffing

• Sufficient in number

• Competent to perform functions

(education, experience, training)

and only perform functions for which

they are qualified and authorized.

• Must be trained to perform assigned

duties


Procedures

• Establish and maintain procedures

appropriate to meet core requirements

• Reviewed & approved before

implementation

• Readily available

• If from elsewhere must verify that they

meet requirements and are appropriate


Facilities

• Suitable size, construction & location to

prevent contamination and mix-ups

• Good repair

• Provide lighting, ventilation, plumbing,

drainage and access to sinks & toilets to

prevent contamination & crosscontamination


Facility Cleaning

• Maintain in clean, orderly sanitary

manner

• Dispose of sewage, trash and refuse in

timely safe and sanitary manner

• Must have SOPs

• Assign responsibility for cleaning

• Describe cleaning methods

• Describe schedule

• Document and maintain cleaning records for

at least 3 years


Facility Operations

• Divide into separate defined areas of

adequate size for each operation.

• Systems to prevent

• improper labeling

• mix-ups

• contamination

• cross-contamination

• accidental exposure to contaminants.


Environmental

Control

• Control environment to prevent contamination

and cross-contamination

• Controls may include

• Temperature and humidity

• Ventilation & air filtration

• Cleaning & disinfection of rooms

• Maintenance of equipment used to control conditions

• Inspect control systems regularly

• Monitor as appropriate

• Maintain records of control & monitoring


Equipment

• Appropriate design & location to facilitate cleaning &

operation

• Capable of producing valid results

• Cleaned, sanitized and maintained according to established

schedules (SOPs)

• Appropriately calibrated

• Inspected for cleanliness, sanitation and calibration

• Document all maintenance, cleaning and calibration

• Display results on or near each piece of equipment or

make readily available

• Record each HPT/P manufactured with that equipment


Supplies & Reagents

• Not used until verified to meet

specifications by facility or vendor

• Must be sterile where appropriate

• Validate and/or verify method for

production of in-house reagents

• Maintain records of reagents & supplies


Supply records

• Receipt – type, quantity, manufacturer,

lot number, receipt date and expiration

date

• Verification of each supply or reagent

• Test results

• Certificate of Analysis from vendor

• Records of the lot of each agent used in

the manufacture of each HCT/P


Processing &

Process Controls

• Methods must not cause contamination & crosscontamination

• Cells from 2 or more donors must not be pooled

during manufacturing

• In process controls must be met

• Each in-process HCT/P is controlled until

required inspection/testing has been completed

• Sampling of material must be representative


Process Changes

• Changes to processes verified or

validated not to create an adverse

impact elsewhere

• Timely communication of approved

changes to appropriate personnel


Process Validation

• When processing results cannot be fully verified

by subsequent inspection & test it must be

validated

• Written evidence that processing methods

reduce risk of contamination (e.g. sterility or

pathogen inactivation) must be based on a fully

verified or validated process

• Changes to a validated process must be

reviewed, evaluated and revalidation performed

where appropriate


Labeling Controls

• System to prevent misidentification and

mix-ups

• Must include verification of label

accuracy, legibility & integrity

• Must meet all requirements

• Product must be accompanied by

documentation of donor eligibility

determination


Storage

• Storage areas controlled to prevent mix-ups,

contamination, cross-contamination and

improper distribution of products

• Storage must be at appropriate temperature

• Where appropriate an expiration date must be

assigned based on product

• Type

• Processing

• Storage conditions

• Packaging


Storage – 2

• Take and document corrective actions

whenever storage conditions not met

• Establish acceptable storage temperature

limits at each step of manufacturing to

inhibit growth of infectious agents

• Maintain and record storage temperatures

• Periodically review recorded temperature

to ensure within acceptable limits


Receipt, Pre-distribution,

Shipment & Distribution

• Evaluate incoming HCT/for presence &

significance of microorganisms, damage

and contamination. Determine whether to

accept, quarantine or reject.

• Pre-distribution.

• Determine if eligibility & test criteria met.

• Ship in quarantine if appropriate.


Distribution - 1

• Must review manufacturing, tracking

records before distribution

• Verify & document release criteria met

• Responsible person documents & dates

determination that product is available


Distribution – 2

• Do not make available for distribution

• Products in quarantine

• Contaminated products

• Product recovered from an ineligible donor

• Donor pending full eligibility testing

• If does not meet criteria designed to prevent

disease transmission

• Products manufactured under a deviation that

risks contamination - unless a responsible

person determines that there is no such risk –

must be recorded and justified


Packaging

& Shipping

• Designed to protect product from contamination

• Establish appropriate shipping conditions during

transit

• Maintain documentation that includes

• Identification of HCT/P & manufacturer

• Activities performed and dates of activities

• Quantity of product subject to the activity

• Disposition of product I.e. identity of consignee


Return to Inventory

• Establish & maintain procedures to

determine if product returned is

suitable to be placed back into

inventory


Records

• Concurrent with each step

• Accurate, indelible and legible

• Identify person performing work

• Dated

• Detailed enough to provide product

history


Records Management

• Must allow review of product history before distribution

and for follow-up purposes

• Must be system to promptly identify, locate and retrieve

records stored in multiple locations

• Records may be electronic, hard copy or copies but must

be equipment to make records readily available

• Retain for at least 10 years after product administration or

distribution (whichever is longer)

• Maintain list of all establishments performing a

manufacturing step (name, address & responsibilities)


Tracking

• Establish & maintain system to track:

• Product from donor to consignee or final disposition and vice

versa

• If you perform some of the manufacturing you may

participate in tracking system of other manufacturer as

long as it complies with cGTP

• Each HCT/P must have & be labeled with a distinct

identification code to facilitate tracking – must not identify

the donor (unless autologous)

• Must inform consignees in writing of tracking requirements


Complaints Files

• Establish & maintain procedures for

review, evaluation and documentation of

complaints

• Maintain a record of complaints

• Includes information required for evaluation

and review

• Identification code of HCT/P

• Determination if isolated or represents a trend


Complaints Review

• Must review & evaluate each complaint &

determine if related to:

• HCT/P deviation

• Adverse reaction

• Determine if a Deviation Report is

required

• Investigate all core GTP complaints

• Document why no investigation was

performed in applicable cases


Adverse Reaction

Reports - 1

• Must investigate any adverse reaction

involving a communicable disease risk

related to an HCT/P if:

• Fatal

• Life-threatening

• Results in permanent impairment to body

function or damage to body structure

• Necessitates medical or surgical intervention

• Report on FDA Form 3500A


Adverse Reaction

Reports - 2

• Submit report within 15 days of

receipt of information

• Investigate ASAP adverse events

subject to FDA 15-day report

• Submit follow-up within 15 days of

report or as required by FDA


HCT/P Deviations

• Must report all HCT/P deviations for which

you perform manufacturing

• Report any such deviation relating to GTP

core requirements

• Description of deviation

• Information on all follow-up actions that have

or will be taken (e.g. recalls)

• Report within 45 days of discovery


Labeling

• Include

• Distinct identification code

• Description of the type of HCT/P

• Expiration date if any

• Required Warning


Labeling - 2

• To appear on label or accompany

product

• Name & address of releasing facility

• Storage temperature

• Other Warnings as appropriate

• Instructions for use

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