Laboratory Accreditation

 AABB (formerly known as the "American Association of Blood Banks") is a non-profit international association of organizations and individuals who are involved in activities related to transfusion and transplantation medicine.   They were founded in 1947 and are headquartered in Bethesda, Maryland.  Originally an "American" association, the AABB is now international in scope and just calls themselves "AABB". 

AABB offers various types of voluntary accreditation.  Most relevent here is their list of  AABB Accredited Cord Blood Facilities.  Some cord blood banks are not AABB accredited for cord blood, but are instead listed as AABB Accredited Hematopoietic Progenitor Cell (HPC) Facilities.   Technically,  the HPC accreditation is only for adult sources of stem cells, collected from bone marrow or apheresis of peripheral blood, not for cord blood.  

AABB accredited facilites are inspected every two years.   The accreditation process costs the bank $5600 per year.

To some extent, AABB and FACT are competing to be the most prestigious accreditation for cord blood banks.  The private cord blood banks are not eligible for FACT accreditation (see the FACT section) and therefore rely on AABB accreditation as their main quality standard in the United States.

AABB accredited cord blood banks must perform the following medical tests:
family: health history
mother: test for HIV-I&II, Hepatitis B&C, CMV, HTLV-I&II, Syphilis
cord blood: test for ABO, Rh, WBC, CD+34, red cell antibodies, bacterial or fungal contamination

It is very important for parents to understand that AABB accreditation does NOT require a specific procedure for processing cord blood.  The accreditation is like a quality review of the Standard Operating Procedures (SOP): does the bank have clearly defined procedures, do they follow them, do they maintain accurate records?  It does not mandate what those SOP are, and there is a great deal of variation in laboratory practices among accredited banks.

AABB has always required reporting of patient outcomes when products are released from an AABB accredited bank.

As of 1 May 2005,  AABB updated their cord blood accreditation criteria and required all banks to be re-inspected.  The revised standards now require that the cord blood should be stored with "integrally attached segments" for testing purposes.  Some blood bankers believe that the "integrally attached" requirement forces AABB accredited banks to only store in bags, not vials.

The new AABB standards became mandatory in January 2007.  Not coincidentally, those cord blood banks which had been using vial storage had switched to bag systems.  


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The American Association of Tissue Banks (AATB) is a non-profit association of organizations and individuals who are involved in activities related to transplantation of cells and tissues.  They were founded in 1976 and are headquartered in McLean, Virginia.   Like the American Association of Blood Banks, they maintain a voluntary accreditation program.

However, for purely historical reasons, in the United States human blood and human tissue are regulated differently.  The relevent accreditation for cord blood banks is AABB.  The laboratory of a cord blood bank may also hold AATB accreditation if they are also engaged in tissue banking.  For example, sperm banking is considered tissue banking and is eligible for AATB accreditation.

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A cord blood bank must meet these California State requirements if it operates within this state, accepts collections from the state, or releases cord blood units to the state.

Relevant regulation:
California Healthy and Safety Code: Division 2, Chapter 4
Accreditation required: Biologics license

• Initially this license was required for banks that had a permanent location in the state of California. It is now required from out of state banks as well.
• License must be renewed on an annual basis.
• California requires an inspection. However the state will accept accreditation by a private, non-profit accrediting organization approved by the state (i.e. AABB) in lieu of state inspection.
• Bank must meet state specific requirements for personnel.
• Bank must meet quality system requirements.

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The CLIA are US federal laws passed in 1988 which apply to any laboratory that performs any patient testing.  They are not a quality accreditation, they are a basic legal requirement.  They are not specific to cord blood banking at all.

Laboratories which are registered with CLIA do get inspected every two years.  The cost of CLIA validation is paid by the laboratory and the program is managed by the US Centers for Medicare & Medicaid Services (CMS).

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The Foundation for the Accreditation of Cellular Therapy (FACT) is a non-profit organization devoted to voluntary inspection and accreditation in the field of hematopoietic cell therapy.  Their offices are located at the Nebraska Medical Center in Omaha, Nebraska.  The parent agenices of FACT are:

• International Society for Cellular Therapy (ISCT; founder)
• American Society for Blood and Marrow Transplantation (ASBMT; founder)
• International Society for Hematotherapy and Graft Enginerering (ISHAGE; merged with ISCT)
• Netcord international consortium of 14 leading cord blood banks (joined 2004)

In the mid-1990's, FACT coallesced the separate standards of ISCT, ISHAGE, and ASBMT.  In 2004, FACT began cooperating with NETCORD to revise the cord blood accreditation standards.  The NETCORD/FACT cord blood standards were finalized in Spring 2006, and since then cord blood banks are gradually being accredited under the new system.  As of June 2006, only 4 US banks are accredited under the new standards.

There is a FACT website search engine to check the accreditation status of a given facility.

FACT accredited facilites are inspected every three years.   The accreditation process costs $25,000.

FACT or NETCORD/FACT accreditation is oriented towards public cord blood banks which regularly release units for transplant.  Whereas AABB primarily inspects the processing laboratory, FACT inspection is end-to-end from the collection site to the clinical patient management, and the inspection team includes a transplant physician. 

Private cord blood banks are not eligible for FACT accreditation because they do not have control over the collection site.  In private banking, the collection takes place wherever the parent's OB/Gyn delivered the baby.  The only banks which can obtain FACT accreditation are the ones who use dedicated collection teams in a limited number of facilities.

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The FDA regulates cord blood under the category of  "Human Cells, Tissues, and Cellular and Tissue Based-Products " (HCT/ P's).  The division of FDA which regulates HCT/P's is the Center for Biologics Evaluation and Research (CBER).  The section of FDA regulations pertaining to Human Tissue Intended for Transplantation is called 21 CFR Part 1270.

In recent years, the FDA has formulated a Tissue Action Plan which consists of 3 new rules and their implementation.  These three rules comprise 21 CFR Part 1271: 

1. As of 21 Jan 2004, all cord blood banks are required to register with the FDA.  Any cord blood bank which has a laboratory should be on the web page of FDA Registered Establishments.
2. The second rule was published 20 May 2004 and became effective 25 May 2005.  It pertains to donor eligibility.  In the case of cord blood, the donor is the baby.  This rule requires more screening of donors for communicable diseases.  Previous FDA standards only required screening for HIV 1&2 and Hepatitis B&C.  Now cord blood must also be screened for syphilis, CJD, and vCJD,  HTLV, and CMV.
   
3. The final rule establishes FDA standards of current Good Tissue Practice (GTP) for laboratories which process HCT/P's.  This rule was published 19 Nov 2004, became effective 25 May 2005, and is intended to prevent contamination or cross-contamination during the handling of HCT/P's. 
   

The 3 new FDA rules only apply to cord blood processed on or after the effective date of 25 May 2005.  The final rule allows the FDA to inspect cord blood laboratories to determine compliance with the provisions of 21 CFR Part 1271.  A review of FDA inspections of HCT/P facilities was presented at the 10/23/2006 AABB meeting:  It states (p. 5) that a total of 1,960 HCT/P establishments are registered with the FDA, and 603 or 30% of them are devoted to peripheral blood stem cells (PBSC) or cord blood.  Between Oct. 2005 and July 2006, 30 of these establishments were inspected (p.25) and 10 were issued FDA-483 citations.  This is typical of the tissue industry average rate (p.24) of citations, and the most common causes of citations (p.29) are lack of adequate written documentation of procedures.

This finishes the summary of FDA regulations for cord blood which is banked for family use.  When a patient receives cord blood from an unrelated donor, as would be the case with a public cord blood bank, the hospital at which the patient is treated must have a clinical trial registered with  Investigational New Drug status (see the IND section).

Finally, when stem cells from cord blood are manipulated to become part of a drug, they must be processed under GMP regulations, which are summarized below.

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Good Manufacturing Practice (GMP) is an FDA standard that is somewhat more strict than their Good Tissue Practice (GTP).  The latest FDA rules (see the FDA section) regulate cord blood as an HCT/P and require cord blood to follow GTP, but not GMP.  The GMP are usually applied to drugs and medical devices, which must be sterile.  Cord blood which is "minimally manipulated" is not sterile.

However, when cord blood stem cells are separated and "manipulated" they fall under FDA guidelines for drugs and medical devices, and must be handled in a lab which follows cellular GMP, or cGMP.  Two examples are: cord blood whose stem cell count has been expanded prior to infusion, or cord blood stem cells which are used as vectors for gene therapy.

A review of FDA guidelines for cord blood was presented at the 9/23/2006 ISCT meeting.

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A cord blood bank must meet these Illinois State requirements if it operates within this state, accepts collections from the state, or releases cord blood units to the state.

Relevant regulation:
Title 77:  Public Health, Chapter I: Dept Public Health, Subchapter d: Lab & Blood Bank, Part 470: Sperm Bank & Tissue Bank Code
Accreditation required: Ttissue bank registration

• Registration must be renewed on an annual basis.
• Bank must meet state specific infectious disease testing requirements.

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Cord blood transplants from unrelated donors are regulated by the FDA under Investigational New Drug status, and therefore public cord blood banks must file an IND application.

Much of the medical community views the IND status of unrelated cord blood transplants as a hindrance to their widespread use for transplant patients who cannot find a matching adult donor.  In April 2005, the Institute of Medicine released a report from the Committee on Establishing a National Cord Blood Stem Cell Bank Program.  Among the key findings of the IoM Report was Recommendation 4.4:

"The Food and Drug Administration should move promptly to establish a system of licensure of cord blood units intended for clinical transplantation. As an interim measure until a licensure process is established, all banks participating in the National Cord Blood Stem Cell Bank Program should operate under an investigational new drug application."

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ISO is a very generic quality accreditation which may pertain to any business or organization.  For example, the US National Aeronautics and Space Agency (NASA) has ISO accreditation.  The motto of ISO (yes, they have a motto) is:

• Say what you do,
• Do what you say
• Be able to prove it

Hence, an ISO accreditation indicates that an organization has well-documented procedures and follows those procedures.  Internationally, many cord blood banks have ISO accreditation.

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A cord blood bank must meet these Maryland State requirements if it operates within this state, accepts collections from the state, or releases cord blood units to the state.

Relevant regulation:
Title 10: Dept of Health and Mental Hygiene, Subtitle 50: Tissue Banks
Accreditation required: Tissue bank permit

• Permit must be renewed on an annual basis.
• Maryland requires an inspection. However the state will accept accreditation by a private, non-profit accrediting organization approved by the state (i.e. AABB) in lieu of state inspection.
• Bank must meet state specific requirements for personnel.
• Bank must meet state specific infectious disease testing requirements.

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A cord blood bank must meet these New Jersey State requirements if it operates within this state, accepts collections from the state, or releases cord blood units to the state.

Relevant regulation:
New Jersey State Sanitary Code; Chapter 8; Section 8:8 Collection, Processing, Storage and Distribution of Blood; Subchapter 13: Hematopoietic Progenitor Cells
Accreditation required: Blood bank license

• A separate blood bank license is required for each permanent location of the bank.
• License must be renewed on an annual basis.
• Bank must be made available for state inspection but no mandatory timeline is imposed.
• Bank must meet state specific requirements for personnel.
• Bank must meet state specific testing requirements (infectious disease testing and sample quality testing).
• Bank must meet quality system requirements.

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A cord blood bank must meet these New York State requirements if it operates within this state, accepts collections from the state, or releases cord blood units to the state.

Relevant regulation:
New York State Health Regulations NYCCR Title 10, Volume A-1, Part 58 Clinical Labs & Blood Banks, Subpart 58-5 Hematopoietic Progenitor Cell Banks
Accreditation required: Tissue bank license

• Initially a provisional license is issued.
  
• License must be renewed every 4 years (or more frequent for provisional license).
• Bank must be made available for state inspection but no mandatory timeline is imposed. Note that an inspection usually occurs during the provisional status, and the permanent license is only granted after successful inspection.
• The state may also change the bank’s status to provisional at any time, usually in response to deficiencies noted during an inspection. Permanent status is then granted after deficiencies are corrected.
• Bank must meet state specific requirements for personnel.
• Bank must meet state specific testing requirements (infectious disease testing and sample quality testing).
• Bank must meet quality system requirements.
• The New York licensing requirements are very rigorous and the permanent license is one of the most difficult state accreditations to earn.
  

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A PharmaStem license is NOT a medical accreditation; it pertains to Patent Law.  It has no bearing whatsoever on the quality of the medical procedures performed by a cord blood bank. 

The possession of a PharmaStem license, or lack thereof, indirectly effects the operations of a cord blood bank through its financial impact:  Those banks which hold a PharmaStem license must pay royalites to PharmaStem, and those banks which do not hold the license must spend money on attorneys to fight PharmaStem. 

A brief history of PharmaStem: The stem cell researchers who were involved in the first successful cord blood transplant, as well as some investors, founded a company named Biocyte in 1985. Through this company, the scientists filed patent applications in 1987 and 1988. The company started commercial cord blood banking in 1993 and stopped in 1995. In 1999 they changed their name to PharmaStem. Then, on 11 April 2001, the US PTO reissued patent no. 5,004,681, after it had been held up nearly 7 years for re-examination. Based on this patent and patent no. 5,192,553, the investors backing PharmaStem began approaching private cord blood banks to collect royalties. The sole employee of PharmaStem is Nicholas Didier.

25 February 2002: PharmaStem Therapeutics Inc. files a lawsuit for patent infringement against eight private cord blood banking companies: ViaCell, Cryo-Cell, CorCell, Cord Blood Registry, StemCyte, NuStem, Bio-Cell, and Birthcells.

7 April 2003: The European Patent Office has revoked PharmaStem's European patent  on cord blood preservation. (EPO release is in German; a report in English is here) The EPO ruled that the methodology claimed in the PharmaStem patents had previously been discovered by others who had published their results; therefore, the PharmaStem patents should never have been issued in the first place. The opposition to PharmaStem was led by the international consortium of public cord blood banks Netcord and the private corporation Thermogenesis. The decision of the EPO is final and applies throughout Europe.

3 November 2003: PharmaStem Therapeutics Inc. wins their USA lawsuit for patent infringement against the four private cord blood banks CBR, CorCell, Cryo-Cell, Viacell. The suit was originally filed 25 Feb 2002 against eight companies, some of whom went out of business or settled. The verdict requires the banks to pay PharmaStem 6.125% of future revenues and about $7 million in past damages. All four banks appealed. 

12 February 2004: PharmaStem Therapeutics Inc. files for patent infringement against all the private cord blood banks not named in their original lawsuit.

2 July 2004: Having filed for patent infringement against all the for-profit cord blood banks in the USA, PharmaStem  now tries to collect royalties from non-profit cord blood banks which collect donations to serve the public good. This prompts both Thermogenesis (see June 1 press release), a manufacturer of cryogenic freezers, and NETCORD (17June press release), an international consortium of public cord blood banks, to request that the United States Patent and Trademark Office (PTO) re-examine the PharmaStem patents.

PharmaStem has also released a threatening letter to OB/Gyn's across the USA and to the legal departments of many hospitals, alleging that obstetricians are breaking patent law if they collect cord blood for companies that are not licensed by PharmaStem. On 2 July, Judge Sleet of Del. District Court issued a restraining order prohibiting PharmaStem from distributing false statements to OB/Gyn's. PharmaStem responded by offering OB/Gyn's an Amnesty Agreement.

7 September 2004: The United States Patent and Trademark Office (U.S. PTO) has agreed to re-examine the patents issued to PharmaStem (numbers 5,004,681 and 5,192,553). The re-examination will consider whether the patents' claims are distinct over "prior art": any medical publications describing similar techniques which predated the filing date of the original patents might constitute prior art.

15 September 2004: The Delaware District Court has overturned a jury verdict of infringement on PharmStem's US Patent No. 5,004,681.  The Court finds that the jury verdict was "against the great weight of the evidence" , and a new trial is awarded to the co-defendants (links to press releases): Viacell, Cryo-Cell, CorCell, and CBR.

In addition, the Court has ruled that private cord blood banks are not liable for contributory infringement of PharmaStem's US Patent No. 5,192,553 because they merely offer a preservation service, and are not in the business of selling cord blood. 
 
Similarly, OB/Gyn's are not liable for contributory infringement of the '553 patent.

For an alternate spin on this news, read the  PharmaStem press release 20Sep04

14 Dec 2004: The four private cord blood banks who fought PharmaStem have won in Delaware District Court. The four are CBR, CorCell, Cryo-Cell and Viacell. On 14 Sept., Judge Sleet ruled they had not infringed on patent '553 and granted a new trial to determine damages for infringement of the '681 patent. Now, the Judge has ruled that there is no infringement of '681 either.  Although the PTO is re-examining patents '553 and '681 (see 7 Sept 2004), at  present both patents are still valid.   So long as the patents are valid, those banks who signed licensing agreements with PharmaStem must pay royalties according to the terms of their contracts (patent '681 expires in 2008 and patent '553 expires in 2010). As of 30Sept2004, PharmaStem has received $1.5 million in royalites from banks which signed licensing agreements.

11 January 2005:
PharmaStem files a new round of preliminary injunctions based on patents 6,461,645 and 6,569,427, which have not been asserted in any of the previous legal proceedings. PharmaStem is now filing in the home states of the cord blood banks. A panel of judges must rule by 31Mar2005 on whether to consolidate the "multi-district litigation" and move them all to Delaware District Court.

16 February 2005: Judicial panel on Multi-District Litigation rules to consolidate all PharmaStem lawsuits to Delaware District Court regarding patents '645 and '427 under Judge Sleet.  Stembanc is named under PharmaStem as a third-party defendant. Also pending in Delaware is an "unfair competition" action against PharmaStem by Viacell.

1 March 2005: U.S. Patent and Trademark Office has rejected PharmaStem patent '553.

 27 April 2006:
Upon re-examination, the US Patent and Trademark Office (PTO) issued two new office actions rejecting all of the claims of PharmaStem Therapeutics Inc.'s U.S. Patent No. 5,192,553 and U.S. Patent No. 6,569,427 as being unpatentable over prior art.

Previously, the PTO issued initial office actions rejecting all the claims of PharmaStem Patent Nos. 5,004,681 and 6,461,645.

The PTO office actions are not final rulings.  PharmaStem has the right to appeal the validity of the patents, and this appeals process may continue for a long time.

There are four private cord blood banks who are fighting PharmaStem in court over the enforcement of these patents:  CBR, Corcell, Cryo-Cell, and Viacord.  All of these lawsuits have been stayed pending the outcome of the appeals over whether the patents are valid.

Meanwhile, the remaining cord blood banks which purchased PharmaStem licensing agreements will continue to pay royalties until PharmaStem has exhausted all appeals.

Press releases regarding latest ruling:  Viacell,  Thermogenesis


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