B.3.1. Quality Management System
Biospecimen collection, processing, management, and distribution should be carried out within a quality management system (QMS) that contains documented quality assurance/quality control (QA/QC) policies and written SOPs. Where feasible, the QMS should be managed by individuals who are not involved in repository operations, although this might not be possible for smaller or less established biospecimen resources. The QMS describes the biospecimen resource’s QA/QC policies and approaches for ensuring that program requirements are met. Each biospecimen resource should either establish a written QMS or adhere to a QMS published by the organization with which the biospecimen resource is associated. There are several common quality management programs available upon which to pattern individual biospecimen resource QMS policies. No particular approach is recommended, but several are mentioned below to help design the appropriate QMS for the biospecimen resource. When a resource is considering a quality management program, and choosing between GLP, CLIA and ISO, there are many considerations such as if the resource has legal obligations to state and federal laws, type of resource, cost, and many other variables. One size quality program does not fit all.
The following Web sites are relevant to the development of a QMS:
- Good Laboratory Practices
- Clinical Laboratory Improvement Amendment
- International Organization for Standardization (ISO9001:2008, 2015)
- U.S. Food and Drug Administration (FDA) Quality System Regulation, 21 CFR 820
B.3.2. Quality Assurance/Quality Control
Formalized QA/QC policies should be developed by biospecimen resources to minimize circumstances that could adversely affect scientific results; to ensure the safety of personnel; to aid in the efficient operation of the resource; and to increase the confidence of users that the quality, quantity, and annotations of the biospecimens are as purported. QA/QC policies should be customized for the intended and potential uses of the biospecimens in a given biospecimen resource. QA/QC implementation should ensure that accurate data accompany biospecimens that are to be analyzed for diagnostic as well as research purposes. The following are key issues for QA/QC implementation and auditing:
- Staff proficiency
- Staff organization and responsibilities.
- Training and competency programs for personnel as appropriate; e.g., training in human subjects protections and privacy regulations such as the Health Insurance Portability and Accountability Act (HIPAA) training, safety training, or bloodborne pathogen training.
- Competency assessment as documentation of training.
- Documentation of staff compliance with policies and procedures.
- Risk mitigation, disaster response, and emergency preparedness.
- Facility infrastructure
- Equipment validation and change control, calibration, maintenance, repair procedures, and environmental monitoring; e.g., temperature monitoring of freezers.
- Supplier management program, including inspection and validation of reagents and other supplies.
- Biospecimen control and documentation
- Control of biospecimen collection, processing, and tracking.
- Documentation of biospecimen collection, processing, and tracking, with detailed annotation of pre-analytical parameters (see Section B.6, Biospecimen Resource Informatics).
- Measurement and analysis of key process indicators to drive quality improvement.
- System security.
- Recordkeeping and document control
- Employment of a data quality management, assessment, and reporting system.
- Clinical data records.
- Accessibility of policies and procedures.
- Documentation records, including audit reports, deviation reports, and corrective action/preventive action reports.
- External document monitoring to ensure that the facility remains up to date with relevant laws, standards, and best practice publications.
- Staff training records, including record of staff adherence to training schedules.
- Data quality management (source documentation and electronic records), assessment of reporting system.
- Supply records.
- Internal audit of program and its policies, scheduled and unscheduled
- Audit for accuracy of all annotation data; e.g., the biospecimen is where it is purported to be, in the purported volume, with the appropriate labels/identifiers.
- Audit for accuracy of patient data associated with biospecimens; e.g., age, gender, diagnosis, etc.
- Audit of compliance of biospecimen resource with institution policies; e.g., human subjects and privacy and confidentiality protections, prioritization of biospecimen use, etc.
- Audit of SOPs for all activities and processes.
- Each biospecimen resource ensures that SOPs are written, reviewed, and appropriately approved.
- Process exists for review and updating at designated time intervals.
B.3.3. Standard Operating Procedures Manual
Each biospecimen resource should develop SOPs that state policies and describe relevant processes in detail. Additionally, a document control program and policies for governing, modifying, or revising SOPs should be at each biospecimen resource. All SOPs should be reviewed on a periodic basis or whenever significant changes in practices, procedures, technology, law, or regulation necessitate an update. The SOPs should be well structured and undergo a rigorous approval process. Upon implementation, all SOPs should be followed as written. Current copies of SOPs (SOPs manual) should be stored in designated locations and available to personnel at all times. Personnel should review new and revised SOPs prior to implementation; reviews and associated trainings should be recorded. Generally, especially for larger biospecimen resources which have the personnel to support a more comprehensive QMS, an electronic document control system should be implemented. One example is MasterControlTM , which is described on their web site :
“The MasterControl™ GxP process management suite consists of configurable, easy-to-use, and connected applications for automating, streamlining, and effectively managing GxP processes throughout the entire product development process from conception to commercialization. Hundreds of companies worldwide rely on MasterControl to facilitate compliance with FDA, and other worldwide regulatory bodies (e.g., GxPs, 21 CFR Parts 11, 210-211, 820, 606), and ISO quality standards (e.g., ISO 9000, ISO 13485, ISO 14000, ISO/TS16949) to improve product quality and safety — and to ensure compliance.”
Note that the mention of any particular product such as MasterControl does not comprise an endorsement by the NCI.
Specifically, the SOPs manual and/or electronic document control system as described above should minimally include the following information:
- Informed Consent. Each biospecimen resource should have documentation of the informed consent status for each biospecimen. In addition, procedures for obtaining informed consent and protecting the privacy of identifiable human research participants and confidentiality of data should be clearly described, as should procedures to follow in the case of withdrawal of consent.
- Equipment Monitoring, Calibration, Maintenance, and Repair. Each biospecimen resource should have procedures to routinely monitor devices that are used for biospecimen storage or preparation. This includes ensuring that equipment is accurately calibrated, that operational settings are routinely recorded, and that scheduled maintenance and repairs are documented. Equipment SOPs and records should also cover associated backup and emergency notification systems.
- Control of Biospecimen Collection Supplies (Disposables and Reagents). Each biospecimen resource should have procedures to ensure that consumable supplies and reagents used for collection, processing, and storage conform to required standards. This includes ensuring purchased supplies are approved, are acquired from approved vendors, meet defined material specifications, and are in good condition for use.
- Biospecimen Identification and Labeling Conventions. Each biospecimen resource should define policies and procedures for labeling (coding) biospecimens and linking biospecimens to other data sets and patient informed consent.
- Biospecimen Collection and Processing Methods. Each biospecimen resource should define, in sufficient detail to allow replication, the procedures associated with biospecimen collection, handling, processing, and preservation for each biospecimen type. This includes detailed descriptions of supplies, equipment, methods, and processing for division of a biospecimen into multiple aliquots. Biospecimen collection and processing should always include the recording of personnel names, dates, and times to accurately record these potential sources of pre-analytic variation.
- Storage and Retrieval. Each biospecimen resource should define procedures for the storage and retrieval of biospecimens from a biorepository, including processes for adding new biospecimens, withdrawing biospecimens, responding to and filling requests, and final disposition of biospecimens.
- Shipping and Receiving. Each biospecimen resource should have defined procedures and policies for the packaging and transport of ambient temperature and frozen biospecimens to ensure biospecimen integrity and safety. This includes packaging specifications to maintain appropriate temperature conditions; wet ice, dry ice, and liquid nitrogen handling; shipment temperature monitoring; shipment regulations for hazardous materials; shipment logs; delivery notifications; confirmation of delivery; shipment feedback mechanisms; and MTAs or other appropriate agreements to cover transfers (see Section B.2.8, Shipping Samples).
- Laboratory Tests Performed In-House Including Biospecimen Quality Control Testing. Each biospecimen resource should have SOPs governing standardized in-house testing procedures and should document the results in associated quality records. This includes tests to assess and control biospecimen quality, such as confirmation of histopathology diagnosis, nucleic acid integrity, or biomarker expression.
- Biospecimen Data Collection and Management (Informatics). Each biospecimen resource should have policies for managing records and procedures defining data access, data collection methods, reporting, data QC, and standardized medical terminology (see Standardized Systems for Clinical and Pathology Data, and Section B.6, Biospecimen Resource Informatics).
- Biosafety. Each biospecimen resource should have policies and procedures covering biosafety, including reporting staff injuries, as well as standard precautions for bloodborne pathogens, personal protection equipment, hazardous material handling, and disposal of medical waste and other biohazardous materials (see Section B.4, Biosafety).
- Training. Each biospecimen resource should have policies and procedures for training of all staff members. Such training should be documented and include policies and procedures to manage corrective actions; to resolve inventory and shipment discrepancies; to monitor all sample storage; and to manage power outages, emergencies, and natural disasters.
- Security. Each biospecimen resource should have procedures for administrative, technical, and physical security, including procedures for information systems security . Security SOPs and policies should include information on points of contact and designated backup personnel, including names and emergency contact numbers.
The biospecimen resource director and/or the individual responsible for the QA/QC program should review and approve all SOPs and associated process validation studies prior to implementation. Upon implementation, all SOPs should be followed as written, and any deviations from written SOPs should be clearly noted. Effectiveness of QA/QC measures should be evaluated on a routine basis.