Date:     August 5, 1994 

From:     Director, Center for Biologics Evaluation and Research  
  
Subject:  Use of an FDA Cleared or Approved Sterile Connecting 
          Device (STCD) in Blood Bank Practice
          
To:       All Registered Blood Establishments

  
  

Introduction

     Sterile connecting devices produce sterile welds between two
pieces of compatible tubing.  This procedure permits sterile
connection of a variety of containers.  At the present time, the
only FDA cleared device that can produce sterile welds between
two pieces of compatible tubing is marketed by the Terumo
Corporation.
     
     This memorandum describes recommended practices and
procedures for use of these devices.  This memorandum does not
address the data or information that a manufacturer of a sterile
connecting device must submit to FDA in order to obtain approval
or clearance for marketing.  It is also important to note that
the use of an approved or cleared sterile connecting device for
purposes not authorized in the labeling may cause the device to
be considered adulterated and misbranded under the Federal Food,
Drug and Cosmetic Act.

 
Guidance for Use of STCDs
     
     Manufacturers of blood products who propose to routinely use
an FDA-cleared STCD should incorporate information regarding such
use in standard operating procedure manuals for each blood
product.  These entries should include record keeping, product
tracking, tube weld quality control, lot numbers of software and
disposables (including source(s) of elements to be added). 
Quality control procedures should include a test of the integrity
of each weld.

Applications of the STCD.  The user should be aware that use of
the device may create a new product or significantly modify the
configuration of a regulated product for which safety and
efficacy have not been demonstrated.  For those "new products"
subject to licensure, applications or application supplements
must be submitted to FDA in addition to submission of an SOP.  In
general, pooling or mixing that involves cellular components

represents a change in the product that requires submission and
approval of a license application or application supplement. 
Such applications and application supplements should contain data
and descriptions of manufacturing procedures which demonstrate
that the "new product" is safe and effective for its intended use
throughout the proposed dating period.
     The following comments are provided as guidance on the more
common proposed uses of an FDA cleared or approved STCD:
          
A.  Adding a new or smaller needle to a blood collection set 

     1.   Using the STCD to add a needle prior to the initiation
     of a procedure (whole blood collection, plateletpheresis or
     source plasma collection) is not considered to open a
     functionally closed system.  If a needle is added during a
     procedure, only an STCD approved to weld liquid-filled
     tubing should be used.  If the test of weld integrity is
     satisfactory, the use of an STCD is not considered to open a
     functionally closed system.
          
          Platelets, Pheresis prepared in an open system should
be labeled with a 24 hour outdate and Platelets, Pheresis
products prepared in a functionally closed system should be
labeled with a five day outdate (Revised Guideline for Collection
of Platelets, Pheresis, October 7, 1988).
     
     2.   The source and specifications of added tubing and
     needles should be addressed in the blood center's SOP and
     records.  Using the STCD to add needles does not represent
     an important change in manufacturing for which licensed
     establishments need preapproval.  

B.  Using the STCD to prepare components

     When the STCD is used to attach additional component
preparation bags, records should be properly maintained
identifying the source of the transfer packs and the appropriate
verification of blood unit number and ABO/Rh.  All components
must be appropriately labeled.

     Examples:  Adding a fourth bag to a whole blood collection
     triple-pack for the production of Cryoprecipitated AHF from
     Fresh Frozen Plasma.
               
          Connection of an additive solution to a red blood
     cell unit.

          Addition of an in-line filter that has been FDA cleared
     for use in manufacturing components.

          Addition of a third storage container to a              
     plateletpheresis harness
                             page 2



                                          
     For the above stated uses, SOPs should be developed and
records maintained, but licensees need not have FDA approval in
order to institute the procedures.


C.  Using the STCD to pool blood products
               
     Appropriate use of an STCD to pool Platelets prepared from
whole blood collection may obviate potential contamination from
the spike and port entries commonly used.  Pooling performed
immediately before transfusion is an example of such appropriate
use.  Pooled Platelets should be administered not more than 4
hours after pooling (see 21 CFR 606.122(l)(2)).

     However, pooling and subsequent storage may increase the
risk compared to administration of random donor units - if one
contaminated unit is pooled with others and stored before
administration, the total bacterial inoculum administered may be
increased as a result of replication in the additional volume. 
Accordingly, the proposed use of an STCD to pool and store
platelets for more than 4 hours should be supported by data which
satisfactorily addresses whether such pooling is associated with
increased risk.  Such platelet pooling constitutes manufacture of
a new product.
     
     Pooling or mixing that involves platelets is considered the
manufacture of a new product that requires submission and
approval of a license application or application supplement if
the storage period is to exceed four hours.

D.  Using the STCD to prepare an aliquot for pediatric use and
divided units 

     Pediatric units and divided units for Whole Blood, Red Blood
Cells and Fresh Frozen Plasma prepared using an STCD will not be
considered a new product for which a PLA supplement is required
providing the following conditions are met:

     1.  The manufacturer should have an approved product license
     or license supplement, for the original (i.e., undivided)
     product, including approval for each anticoagulant used.

     2.  Labels should be submitted for review and approval
     before distribution.  A notation should be made under the
     comments section of FDA Form 2567, Transmittal of Labels and
     Circulars.

     3.  Final product containers approved for storage of the
     component being prepared should be used.

                                
                             page 3

     Platelets manufactured under licensure must contain at least
5.5 X 1010 platelets [21 CFR 640.24 (c)].  Platelets, Pheresis
manufactured under licensure should contain at least 3.0 X 1011
platelets [Revised Guideline for the Collection of Platelets,
Pheresis, October 7, 1988].

     SOPs to be followed regarding the use of an STCD to prepare
divided products from whole blood collections and from plasma and
platelets prepared by automated hemapheresis procedures should
include descriptions of:  1)  How the apheresis harness or
collection container will be modified with an FDA-cleared STCD; 
2) the minimum volume of the split plasma or whole blood
products; 3) the volume and platelet concentration of the split
plateletpheresis products; 4) storage time of the product should
be in an approved container and should be consistent with the
storage time on the label of such container; 5) method(s) to be
used to label and track divided products in the blood center's
records.

NOTE:  Procedures for labeling the aliquots should be clearly    
stated in the SOP.  Record keeping should be adequate to permit
tracking and recall of all components, if necessary. 

E.  Using an STCD to connect additional saline or anticoagulant
lines during an automated plasmapheresis procedure

     SOPs for such procedures should be developed and records
maintained consistent with the instrument manufacturer's
directions for use, but licensees need not have FDA approval in
order to institute the procedures.

F.  Using the STCD to attach processing solutions

     When using an STCD to attach containers with processing
solutions to washed or frozen red blood cell products, the dating
period for the resulting products is 24 hours, unless data are
provided in the form of license applications or application
supplements to CBER to support a longer dating period (21 CFR
610.53(c)).  Exemptions or modifications must be approved in
writing from the Director, CBER (21 CFR 610.53(d)).

G.  Using an STCD to add an FDA-cleared leukocyte reduction
filter

     Some leuko-reduction filters are not integrally attached to
the whole blood collection systems.  SOPs for use of an STCD for
pre-storage filtration should be consistent with filter
manufacturers' directions for use.

                                
                             page 4



     Leukocyte reduction prior to issue constitutes a major
manufacturing change.  Therefore, for new leukocyte-reduced
products prepared using an STCD, manufacturers must submit
product license applications or application supplements to FDA
and await approval.
 
H.  Using an STCD to remove samples from blood product containers
for testing (e.g., using an STCD to obtain a sample of platelets
from a container of Platelets or Platelets, Pheresis for cross
matching).

     If the volume and/or cell count of the product after sample
withdrawal differ from what is stated on the original label or in
the circular of information, the label on the product should be
modified to reflect the new volume and/or cell count.  For
example, samples may not be removed that reduce the platelet
count of a unit of Platelets to less than >5.5 X 1010 platelets
(21 CFR 640.24(c)).

Additional comments 

     SOPs should include special instructions for product
disposition if subsequent inspection of the weld reveals signs of
leakage or air bubbles.  

     The preparation of non-standard blood components using an
STCD is limited to research settings only, and should be
conducted only under an investigational new drug exemption.

Additional Information
     
     An appendix has been included with the currently approved
dating periods for blood components and source plasma [21 CFR
610.53) and currently recommended dating periods for automated
plateletpheresis products (see Revised Guideline for Collection
of Platelets, Pheresis, issued October 7, 1988).

     This memorandum has presented general guidance as well as
specific information and examples concerning specifications for
submission of applications and application supplements to the FDA
addressing use of an STCD.  If further questions arise concerning
appropriate use of an STCD, concerns should be directed to the
Center for Biologics Evaluation and Research in writing.  
     
     Technical questions should be addressed to

               Division of Hematology, HFM-330
               Office of Blood Research and Review
               Center for Biologics Evaluation and Research
               1401 Rockville Pike
               Rockville, MD 20852
                                
                             page 5
                                


     Application forms and labeling transmittal forms may be
obtained from:

               Division of Blood Applications, HFM-370
               Office of Blood Research and Review
               Center for Biologics Evaluation and Research  
               1401 Rockville Pike
               Rockville, MD 20852
               Phone: (301) 594-2012
               FAX:   (301) 594-1973

    



                              
                              _________________________  
                              Kathryn C. Zoon, Ph.D.
































                                
                             page 6

APPENDIX

USE OF AN APPROVED STERILE CONNECTING DEVICE (STCD) IN BLOOD BANK
PRACTICE

          Currently Approved Dating Periods for Blood
               Components and Source Plasma            
                      21 CFR 610.53

PRODUCT                            DATING PERIOD

Cryoprecipitated AHF               12 months from the date of
                                   collection of source blood,
                                   provided labeling recommends
                                   storage at -18 C or colder
Plasma products:
     Fresh Frozen Plasma           1 year from date of collection
                                   of source blood (-18 C or
                                   colder)

     Liquid Plasma                 a) 26 days from date of
                                   collection of source blood
                                   (between 1 and 6 C).

                                   b)  40 days from the date of
                                   collection of source blood    
                                   only when CPDA-1 solution is  
                                   used as the anticoagulant     
                                   (between 1 and 6 C).  

     Plasma                        5 years from the date of
                                   collection of source blood 
                                   (-18 C or colder).

Platelet Rich Plasma               72 hours from time of
                                   collection of source blood,
                                   provided labeling recommends
                                   storage between 20-24 C or
                                   between 1 and 6 C.  5 days if
                                   certain approved containers
                                   are used (20-24 C).
     
Source Plasma                      10 years (at the recommended
                                   storage temperature stated on
                                   the label).

Platelets                          72 hours from the time of 
                                   collection of source blood,
                                   providing labeling recommends
                                   storage at 20-24 C or between
                                   1-6 C.  5 days if certain 
                                   approved containers are used
                                   (20-24 C).


ACD Red Blood Cells                a) 21 days from the collection
                                   of source blood, providing
                                   labeling recommends storage
                                   between 1 and 6 C and the
                                   hermetic seal is not broken
                                   during processing.

                                   b) 24 hours after plasma
                                   removal, providing labeling
                                   recommends storage between 1
                                   and 6 C and the hermetic seal
                                   is broken during processing.


CPD Red Blood Cells                a) 21 days from the collection
                                   of source blood, providing
                                   labeling recommends storage
                                   between 1 and 6 C and the
                                   hermetic seal is not broken
                                   during processing.

                                   b) 24 hours after plasma
                                   removal, providing labeling
                                   recommends storage between 1
                                   and 6 C and the hermetic seal
                                   is broken during processing.
          
CPDA-1 Red Blood Cells             a) 35 days from the collection
                                   of source blood, providing
                                   labeling recommends storage
                                   between 1 and 6 C and the
                                   hermetic seal is not broken
                                   during processing.

                                   b) 24 hours after plasma
                                   removal, providing labeling
                                   recommends storage between 1
                                   and 6 C and the hermetic seal
                                   is broken during processing.
     
Red Blood Cells                    24 hours after removal form
Deglycerolized                     storage at -65 C or colder,   
                                   provided labeling recommends  
                                   storage between 1 and 6 C.
     
ACD Whole Blood                    21 days from date of
                                   collection, providing labeling
                                   recommends storage between 1
                                   and 6 C.

CPD Whole Blood                    21 days from date of
                                   collection providing labeling
                                   recommends storage between 1
                                   and 6 C.

CPDA-1 Whole Blood                 35 days from date of
                                   collection providing labeling
                                   recommends storage between 1
                                   and 6 C.

Currently approved dating period for automated plateletpheresis
products according to the Revised Guideline for the Collection of
Platelets, Pheresis issued October 7, 1988.

Platelets, Pheresis                24 hours if collected in an
                                   open system.

Platelets, Pheresis                5 days if collected in a
                                   functionally closed system.