Standard No. Page 1
Clinical Establishment Act Standard for Stem Cell Laboratory (Peripheral Blood Stem Cells and Umbilical Cord Cells) Standard No. Page 2
Introduction In 2010 Clinical Establishments (Registration and Regulation) Act, 2010 has been enacted by the Central Government to provide for registration and regulation of all clinical establishments in the country with a view to prescribe the minimum standards of facilities and services provided by them. The Ministry has notified the National Council for Clinical Establishments and The Clinical Establishments (Central Government) Rules, 2012 under this Act vide Gazette. This Act is applicable to all kinds of clinical establishments from the public and private sectors, of all recognized systems of medicine including single doctor clinics. The only exception will be establishments run by the Armed forces. Page 3
Table of Contents Sr. No. Particulars 1. Definition Page No. 2. Scope 3. Infrastructure 4. Equipments 5. Human Resource 6. Legal/Statutory Requirements 7. Record Maintenance and Reporting 8. Others 9. Annexure 1 10. Annexure 2 11. Annexure 3 12. References 13. 14. 15. Page 4
Introduction: Stem Cell Processing and Storage Facility Stem Cell processing and storage include all cells derived from the below sources: a) Umbilical cord blood b) Bone marrow and mobilized peripheral blood c) Others including Adipose tissue, etc. The major objective for Cellular Therapy Product/ stem cell processing, storage and distribution is to promote quality medical and laboratory practice in hematopoietic progenitor cell transplantation and other therapies using cellular products. These Standards apply to all processing, storage, and distribution activities performed in the Processing Facility on cellular therapy products obtained from living donors. These Standards apply to hematopoietic stem cell progenitor cells, defined as selfrenewing and/or multi-potent stem cells capable of maturation into any of the hematopoietic lineages, lineage-restricted pluri-potent progenitor stem cells, and committed progenitor stem cells, regardless of tissue source (bone marrow, umbilical cord blood, peripheral blood, or other tissue source). These Standards include Therapeutic Cells, defined as nucleated cells from any tissue source (marrow, peripheral blood, umbilical cord, and placental blood) collected for therapeutic use other than as hematopoietic progenitor cells. Also, these Standards apply to all phases of processing, storage and release of these cells that have been derived from marrow or peripheral blood, including various manipulations such as removal or enrichment of various cell populations, expansion of hematopoietic cell populations, and cryopreservation. 1. Definition Stem Cell Processing and Storage Facility: Means a place or organization or unit or institution or other arrangements made by such organization, unit or institution for processing and storage of stem cells derived from umbilical cord blood, bone marrow, mobilized peripheral blood etc. Stem Cell processing and storage facility may be a standalone facility or be a part of the hospital services. 2. Scope The Scope of Stem cell processing and storage facility includes collection, processing, testing, cryopreservation and distribution of stem cells derived from Page 5
umbilical cord blood, bone marrow, mobilized peripheral blood, and others for hematopoietic and non-hematopoietic transplantation. The Stem cell Processing Facility shall establish and maintain policies and procedures, addressing critical aspects of operations and management. These documents shall include all elements required and shall address at a minimum 2.1. Donor and recipient confidentiality. 2.2. Transportation and shipping, including methods and conditions within the Processing Facility and to and from external facilities. 2.3. Stem cell processing and process control. 2.4. Labeling and prevention of mix-ups and cross-contamination of samples. 2.5. Red cell compatibility testing and processing of ABO-incompatible products to include a description of the indication for and processing methods to be used for red cell and plasma depletion. 2.6. Cryopreservation and thawing. 2.7. Release and exceptional release. 2.8. Cell therapy product disposal 2.9. Reagent and supply management. 2.10. Equipment operation, maintenance, and monitoring, to include corrective actions in the event of failure. 2.11. Facility management and Environmental control to include a description of environmental monitoring plan. 2.12. Infection control, biosafety, and chemical and radiological safety. 2.13. Decontamination and disposal of medical and biohazard waste to include Processing Facility-specific requirements where these differ from institutional requirements. 2.14. The Quality Management Plan shall include, or summarize and reference, policies and procedures for documentation and review of cellular therapy product efficacy, and/or outcome analysis, as appropriate, including at least. Page 6
2.15. For HPC products to be used for hematopoietic reconstitution, a process for documentation and review of time to engraftment following cellular therapy product administration. 2.16. For other cellular therapy products, the criteria for product efficacy and/or the clinical outcome shall be determined and should be reviewed at regular time intervals. 3. Infrastructure 3.1 Signage 3.1.1 The centre shall display appropriate signage which shall be in at least two languages. 3.1.2 Registration details of the centre as applicable shall be displayed. 3.1.3 Availability of fee structure of the various services provided (refer to CEA 2010 rules & regulation CG 4 Annexe) shall be displayed as applicable. 3.1.4 Timings of the facility and services shall be displayed. 3.1.5 Safety Hazard and Caution signs, for e.g. hazards from electrical shock, inflammable articles, radiation etc shall be displayed at appropriate places, and as applicable under law. 3.1.6 Appropriate Fire exit signage shall be displayed. 3.1.7 Signage for No Smoking shall be displayed in prominent places. 3.2 Facility Premises 3.2.1 Stem cell processing and storage facility shall be situated and shall have such measures as to avoid risk of contamination from external environment including open sewage, drain, public lavatory or any factory which produces disagreeable or obnoxious odour or fumes, excessive soot, smoke, chemical or biological emissions. 3.2.2 The facility shall be secure to prevent the entrance of unauthorized persons. Page 7
3.2.3 The facility shall be adequately provided with working space to allow orderly and logical placement of equipment, material and movement of personnel so as to maintain safe operations and prevent contamination. 3.2.4 The facility shall be developed to provide, safe, clean and hygienic environment. 3.2.5 The facility should be well illuminated and ventilated. It shall have 24hr provision of potable water for drinking & hand hygiene. It shall also have 24 hrs supply of electricity, either through direct supply or from other sources. 3.2.6 The facility shall be divided into defined areas of adequate size to prevent improper labelling, mix ups, contamination, cross contamination of cellular therapy products. 3.2.7 Provided with defined environmental conditions for temperature, humidity, ventilation, and air filtration. Classifications shall be defined and, if appropriate, monitored. For other minimum infrastructure requirement refer to Annexure 1. 3.3. Furniture 3.3.1 Furniture and fixtures shall be available in accordance with the activities and workload of the facility. They shall be functional and properly maintained. 3.3.2 Furniture shall be placed in aseptic areas which are smooth, washable and made of stainless steel or any other appropriate no-shedding material other than wood. 4. Equipments 4.1 The Stem cell processing and storage facility is equipped for cell processing, isolation, testing, and cryopreservation. 4.2 The facility shall ensure the availability of the accessories, spare-parts and back-up/maintenance/service support for all equipment. An equipment logbook shall be maintained for all the major equipments. For indicative list refer to Annexure 2. 5. Human Resource Page 8
5.1 The centre shall have qualified administrative, scientific, medical, technical and nursing staff to carry out various processes. For details refer Annexure 3. 5.2 All personnel shall undergo medical examination prior to employment and shall be free from infectious and contagious diseases and thereafter they should be medically examined periodically at least once a year and for this purpose records shall be maintained thereof. 5.3 All the new staff will undergo screening of HBV, HIV and TB as a preemployment screening, and offer hepatitis B immunization, and test for postimmunization antibody titer. 5.4 For every staff (including contractual staff), there shall be personal record containing the appointment order, documentary evidence of qualification and/or training (and professional registration where applicable). 5.5 Periodic skill enhancement/updation/refresher training shall be provided for all categories of the staff as relevant to their job profile, as prescribed by professional bodies and as per local law/regulations. 6. Legal/Statutory Requirements 6.1 TheCell Processing Facility shall abide by all applicable laws and regulations. 6.2 For the purpose of collection, processing, testing, storing, banking and release of umbilical cord blood stem cells umbilical cord blood bank Licence from Drug Controller office is essential. 7. Record Maintenance and Reporting 7.1 A records management system shall be established and maintained to facilitate the review of records pertaining to a particular cellular therapy product prior to distribution and for follow-up evaluation or investigation. 7.2 Records shall be maintained in such a way as to ensure their integrity and preservation. If records are maintained in more than one location, there shall be a system to ensure prompt identification, location, and retrieval of all records. 7.3 Records shall be accurate, legible, and indelible. All records and communications between the collection, processing, and transplant facilities, Page 9
and their patients and donors, shall be regarded as privileged and confidential. 7.4 All records pertaining to the processing, testing, storage, or distribution of cellular therapy products shall be maintained for minimum of 10 years or according to applicable laws and regulations or institutional policy, whichever requires the longest maintenance period. 7.5 Safeguards to assure this confidentiality shall be established and followed in compliance with applicable laws and regulations. 7.6 The records management system shall facilitate tracking of the cellular therapy product from the donor to the recipient or final disposition and tracing from the recipient or final disposition to the donor. 7.7 For cellular therapy products that are to be distributed for use at another organization, the receiving organization shall be informed of the tracking system and requirement for tracking the product in writing or electronic format at or before the time of product distribution. 7.8 Records shall be maintained in one or more forms that are available and retrievable. 7.9 The following essential records shall be maintained minimally in the stem cell processing facility a. Stem cell collection and transportation record b. Master record of stored Stem cells. c. HLA matching record d. Cell therapy product distribution record. e. Cryopreservation record. f. Record for adverse events (AEs)/ severe adverse events (SAEs). g. Record for Cell analysis i.e. cell counts (TNCC, MNCC), cell viability, and CD34 + ve enumeration. h. Sterility record of cell therapy product 10 Page
8. Others i. Record for infectious marker testing (HIV, HBsAg, HCV, CMV, HTLV, Syphilis, malaria) results. j. Stock record of the consumables, reagents and supplies. k. Preventive maintenance record of all the equipments. 8.1 Basic Process 8.1.1 Stem Cell processing and storage facility shall facilitate tracking of the cellular therapy product from the donor to the recipient or final disposition and tracing from the recipient or final disposition to the donor. 8.1.2 Stem cell processing and storage facility shall have appropriate process for collection, processing, testing, cryopreservation and release/issue of cellular products to be used in related or unrelated hematopoietic stem cell transplantation. 8.2 Infection control and safety 8.2.1 All the personnel must operate under the universal precautions for health care workers. 8.2.2 All persons shall wear clean coverings appropriate for their duties before entering the cell Processing Zone and the Change Rooms with adequate facilities shall be provided prior to entry into any specific zone. 8.2.3 The centre shall have measures for cleaning and sanitation, environmental monitoring for microorganisms and inspection of environmental control systems to ensure adequate conditions for proper operations. 8.2.4 Appropriate safety equipments shall be available and functional. 8.3. Waste Disposal 8.3.1 Waste materials awaiting disposal shall be stored safely. 8.3.2 The disposal of sewage and effluents from the facility shall be in conformity with the requirements of the pollution control board. 11 Page
8.3.3 Segregation, collection, transportation, storage and disposal of biomedical waste shall be as per Bio medical waste handling rules, 1998. 12 Page
Annexure 1 Minimum infrastructure requirement shall be as follows: Facility areas:separate dedicated and designated areas specifically designed for the purpose and the workload shall be provided. a) Reception: Reception area with space for transient storage of units and physical examination shall have adequate facilities for registration, data entry and generation of bar-coded labels. b) Cell Processing Areas: The room shall be clean and have an air handling system to provide a Class 10,000 environment. Entry to this area shall be through air lock. The room will house class 100 biological safety cabinets for Umbilical cord blood processing. The temperature of the clean room shall be maintained 20 to 25ºC and with a positive differential pressure of 10-15 Pascal and relative humidity of 50-60%. c) Hematology and Serology Laboratory: The laboratory shall be equipped and utilized for the purpose of independently testing of cell therapy products for ABO grouping and Rh Typing, Total Nucleated Cell count, Progenitor Cell Count and viability test. The room shall be air conditioned. d) Transfusion transmissible Disease Screening Laboratory: The Laboratory shall be equipped and utilized for screening test on maternal blood for infectious diseases viz. HIV I & II; Hepatitis B & C virus, syphilis, malaria, CMV and HTLV 1& 2. The room shall be air conditioned. e) Cryostorage Room: The cryogenic storage room shall have provision for temperature monitoring of storage vessels, liquid nitrogen level in storage vessels and oxygen meter. The service space between each liquid nitrogen storage vessel, supply cylinders and connecting hose should be minimum 1.00 sq. Meters. Separate storage space for other accessories required shall be provided. The room shall be air-conditioned. f) Sterilization-cum-washing: Appropriate facility shall be provided within the premises for proper washing and sterilization. This facility would be optional for laboratories using entirely disposable items. g) HLA Typing Laboratory: The cell processing unit shall have arrangements for HLA typing and genetic disease testing. In-house testing can be done by providing a well demarcated Laboratory from the processing area for evaluating 13 Page
of possible genetic disease and HLA typing. This facility would be optional for laboratories that are out sourcing these services for testing. h) General Storage Area: General storage area shall be provided to store all the consumables, under conditions deemed optimum for storage by manufacturers. i) Record Room: There shall be designated record room permitted only to authorize persons. The room will have adequate protective facilities as the documents and records are to be preserved for long period. Facility Design: The facility is divided into two main work areas. The testing laboratory and processing laboratory which are clean rooms designed for GMP workflow. The clean rooms are interlocked, with 3 interlock ante rooms or change rooms. Once staff entered the clean room, they must exit either through the exit anteroom. Workflow through the anteroom is bidirectional, whereas movement through the waste-out room is unidirectional. Flow of supply is unidirectional. Product flow is restricted to the clean areas of the laboratory. Air handling systems: Air handling systems for sterile areas shall be different from those for other areas. The filter configuration in the air handling system shall be suitably designed to achieve the grade of air as given in the Table 1. Table 1: Maximum permitted number of Non-viable particles/m 3 equal to or above At Rest At Operation Grade Class Size 0.5 Size 5 um Size 0.5 um Size 5 um um A 100 3,500 0 3,500 1 B 100 3,500 0 3,50,000 2000 C 10,000 3,50,000 2000 35,00,000 20,000 D 100,000 35,00,00 0 20,000 Not Defined Not defined The environmental microbiological monitoring of clean areas shall be in accordance to the recommended limits (Table 2). 14 Page
Table 2: Maximum limits for microbiological monitoring of clean areas during operation Grade Class air sample cfu/m 3 settle plates (diameter 90mm) cfu/2hrs contact plates (diameter 55mm) cfu/plate Glove points 5 fingers (cfu/glove) A 100 <1 <1 <1 <1 B 100 10 5 5 5 C 10,000 100 50 25 - D 100,000 500 100 50 - These are average, individual settle plates may be exposed for not less than 2 h in grade B, C and D areas, and for not less than 30 min in grade A areas. a) The processing facility shall be divided into defined areas of adequate size to prevent improper labelling, mix-ups, contamination, or cross-contamination of cellular therapy products. b) There shall be a process to control storage areas to prevent mix-ups, contamination and cross-contamination of all products during quarantine and prior to release or distribution. c) The processing facility shall provide adequate lighting, ventilation, access to sink and air quality where applicable to prevent the introduction, transmission, or spread of communicable disease. d) There shall be documentation of facility cleaning and sanitation, environmental monitoring for microorganisms, and inspection of environmental control systems to ensure adequate conditions for proper operations. 15 Page
Annexure 2 Equipments for Stem Cell Processing and Storage Facility Processing and storage of stem cells derived from umbilical cord blood, bone marrow or mobilized peripheral blood. 1. Processing equipment includes a) Bio Safety Cabinet b) B.O.D Incubator c) Weighing Balance d) Plasma Expresser e) Auto Volume Expresser f) Refrigerated Centrifuge g) Sealers ( Tube and Bag) h) Automated cell separator 2. Testing Equipment includes a) Flow Cytometer b) Haematological Cell coulter c) Microscope d) Bact/ALERT e) ELISA Reader f) Centrifuge g) Incubator 3. Cryopreservation Equipment includes a) Controlled Rate Freezer b) Liquid nitrogen Storage Tank c) Deep Freezer (-80 degree) d) Refrigerator e) Liquid nitrogen supply Cylinders 16 Page
Annexure 3 Manpower for Stem Cell Processing And Storage Facility Facility or Laboratory Director: There shall be a designated Facility Director or Laboratory Director with a relevant Doctoral degree in a relevant science (Cell Biology/immunology/ /Microbiology/Medical Sciences), qualified by training or experience for the scope of activities carried out in the processing facility. The Processing Facility/ Laboratory Director shall be responsible for all procedures, administrative operations, and the Quality Management Program of the Processing Facility, including compliance with these Standards and other applicable laws and regulations. The Processing Facility Director or designee shall have authority over and responsibility for ensuring that the Quality Management Plan is effectively established and maintained. Medical Director:The Facility shall have a Medical Director who is a licensed Physician with post-graduate degree i.e. MD in Pathology/Transfusion Medicine/Microbiology and qualified by training and/ or experience and relevant continuing education in activities performed by the facility. The Medical Director shall have responsibility and authority for all medical aspects of the specific facility that are related to the provision of the cellular therapy products and related services. Technical Supervisor: The technical supervisor shall have a degree in life science, Microbiology/ Biochemistry / Medical lab technology with minimum of three years of experience in the preparation of blood components and / or experience and training in stem cell processing and cryogenic storage. This person he shall be qualified by training and/ or experience and relevant continuing education in activities performed by the facility. Quality Supervisor: The quality supervisor shall have a Post graduate degree in life science (Microbiology/Biochemistry/Pharmacy) with minimum of three years of experience / training in stem cell processing facility. The quality supervisor for the processing facility is approved by the processing facility/laboratory director to establish and maintain systems to review, modify, and approve all policies and procedures intended to monitor compliance with these standard and /all the performance of the processing facility. Laboratory Technologist: The laboratory technologist shall have a degree in life science or Microbiology or Biochemistry or Medical Laboratory Technology with six months experience and / or training in stem cell processing and cryogenic storage or 17 Page
Diploma in Medical laboratory Technology (MLT) with one year experience and / or training in stem cell processing and cryogenic storage. References a) Standards for Cellular Therapy product services, American Association for Blood banks (AABB), 3 rd edition. b) International Standards for Cellular Therapy Product, collection, processing, and administration. Foundation for the accreditation of Cellular Therapy (FACT) and Joint accreditation committee (JACIE), 5 th edition. 18 Page