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1 1. PURPOSE 1.1. The purpose of this procedure is to define the steps to be followed and the responsibility for raising a nonconformance/deviation report where material/product or processes do not comply with organization/regulatory requirements. NOTE: The aim is to segregate product linked with a quality concern, determine the root cause, assign corrective action responsibilities, and whenever possible, actions that lead to prevention Additionally, this procedure provides for a system and instructions for the evaluation, quarantine storage, and disposition of nonconforming products. 2. APPLICATION 2.1. This procedure applies to all personnel who carry out operations with the potential to impact product quality, quality system requirements, safety or the environment This procedure applies to all Products purchased or supplied to CellRight that are intended for incorporation into the finished product (Level 1 Critical Components) Delivery Schedule Performance Deliveries of Level 1 Critical Components and finished product are tracked with respect to their on-time performance. If a supplier of a Level 1 Critical Component or a Finished Product fails to meet their delivery schedule this procedure would be followed to raise a nonconformance report Critical Services (Tissue Recovery, Tissue Distribution, Tissue Processing, Sterilization, Calibration, Transportation and Delivery, and Product Design) In-process products intended for incorporation into the finished product. Individual grafts that are discarded by processing personnel, prior to final packaging, are not considered nonconforming product Products produced by CellRight, distributed under CellRight s name, or produced under contract for a customer Customer returned finished products Manufacturing processes carried out by CellRight Manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor Processing means any activity performed on an HCT/P, other than recovery, donor screening, donor testing, storage, labeling, packaging, or distribution, such as testing for microorganisms, preparation, sterilization, steps to inactivate or remove adventitious agents, preservation for storage, and removal from storage. 1

2 3. POLICY All nonconformance s/deviations concerning Level 1 Critical Components, in-process or released grafts or failure to follow a manufacturing process will be documented by the staff and investigated Errors and Accidents in donor screening or tissue recovery, processing, quarantining, releasing, labeling, storing, and distribution or dispensing, shall be investigated and documented The individual responsible for the quality review shall have the responsibility and authority to approve or reject tissue, as well as discontinue processing and/or release of tissue when deviations from procedures warrant Tissue failing any portion of the review process shall be maintained in quarantine pending resolution, rework, or disposal. Unexplained discrepancies or deviations from specifications shall be fully investigated and documented Each investigation must include a review and evaluation of the nonconformance or deviation, the efforts made to determine the cause, and, when applicable, the implementation of corrective action(s) to address the nonconformance or deviation and prevent recurrence. 4. PROCEDURE 4.1. GENERAL A deviation is a departure from standard procedures or specifications resulting in nonconforming product (allograft tissue) and/or processes, or where there have been unusual or unexplained events which have the potential to impact on product quality, system integrity or personal safety. For compliance and the sake of continuous improvement, these nonconformance s and deviations are recorded on the following forms: QF SUPPLIER - NONCONFORMANCE REPORT QF INTERNAL - NONCONFORMANCE REPORT QF INTERNAL - DEVIATION REPORT A Report should be initiated when there is: A deviation from methods or controls specified in manufacturing documents, material control documents, standard operating procedures for products and confirmed out of specification results In conjunction with the deviation report, deviations in a manufacturing step or product must be documented directly on the processing/production documents at the time of occurrence through a comment Nonconformance/Deviation reports are required to document the nonconformance or deviation regardless of final product disposition. If a product is rejected a report is still required The individual that detects the nonconformance or deviation should initiate the report, perform an initial investigation, write a short description of the facts and notify Quality within one business day to identify the investigation Quality will evaluate the nonconformance/deviation and assess the potential impact to the product quality, validation and regulatory requirement. All nonconformance/deviation reports are to be approved by the quality manager or designee. Final product disposition is the responsibility of quality. 2

3 NONCONFORMNANCE /DEVIATION LOG QF NONCONFORMANCE/DEVIATION LOG is utilized to track nonconformance/deviation reports Quality assigns the Nonconformance Report # (NCR#) utilizing the following format: YY-####, where YY is the last two numbers of the current year, and ####, represents the sequential number, beginning with 0001 assigned An NCR# is assigned to and used to track Supplier Nonconformance s, Internal Nonconformance s, and Deviation Reports When a nonconformance/deviation is logged it is assigned an NCR #. The responsible individual indicates if the report is a Supplier Nonconformance, Internal Nonconformance and/or a Deviation by checking the space(s) that apply The date reported is documented along with a brief description of the nonconformance or deviation If the nonconformance/deviation is associated with a complaint or the event is elevated to a CAPA the associated Complaint # and/or CAPA number is documented The initials of the individual responsible for investigating the event are documented Once completed, the completion date is documented to indicate the event is closed IDENTIFICATION AND DOCUMENTATION Process operators and personnel performing Level 1 Critical Component, in process and final product inspections and testing are responsible for identifying nonconformance s in the course of their process monitoring and inspection activities. In addition, all other personnel, regardless of their other responsibilities, are encouraged to watch for and identify nonconformances. All personnel are responsible for identifying process deviations in the course for performing tasks When a nonconformity or process deviation is identified, it is documented on the appropriate Nonconformance/Deviation Report: For in-process grafts and components this is done on QF INTERNAL NONCONFORMANCE REPORT, and For purchased product this is done on QF SUPPLIER - NONCONFORMANCE REPORT UNPROCESSED DONOR TISSUE Upon receipt, unprocessed donor tissue or test specimens may be deemed nonconforming due to packaging, labeling or shipping issues. The recovery agency will be notified of the nonconformance and CRT may make the necessary corrections. Corrective actions are documented on QF UNPROCESSED DONOR INSPECTION AND RECEIVING FORM. It may be necessary to contact the recovery agency for clarification. A noticeable trend in a specific nonconformance will trigger initiation of a Corrective and Preventative Action request with the recovery agency After receipt, unprocessed donor tissue may be deemed unsuitable for transplant. The tissue may be dispositioned as For Non-Clinical Use Only or it may be discarded based 3

4 on the reason for nonconformance, the legal next of kin s wishes, and the need for research/education tissue During review of donor records errors or omissions may be discovered. It is not necessary to classify these errors or omissions in documentation as nonconformances unless they result in the donor being deemed unsuitable Quality will notify the recovery agency of the errors or omissions and request corrections. The corrections will become part of the donor record and will be evaluated Donor suitability will be evaluated and documented on QF CERTIFICATE OF DONOR ELIGIBILITY. If a donor is deemed unsuitable for transplant the reason for deferral is noted on QF and its disposition is noted in the donor file. It is not necessary to raise a nonconformance report unless the recovery agency made an error. Example, failed to send appropriate infectious disease samples to the testing laboratory, failed to request appropriate infectious disease testes, failed to obtain appropriate authorization, failed to place the appropriate amount of wet ice in the shipping container, failed to review available medical records prior to recovery, etc If a nonconformance cannot be corrected immediately, the nonconforming product is identified by one of two methods after the Nonconformance Report is initiated The NCR# is marked on a REJECTED sticker or tag associated with the product, or A copy of the Nonconformance Report is attached to the nonconforming product and the nonconforming product is segregated to prevent use or release Exception It is not necessary to document the NCR# on unsuitable donors. Unsuitable donors are discarded or wrapped in colored outer bag and labeled For Non-Clinical Use Only NONCONFORMITY REVIEW AND DISPOSITION Nonconforming products may be: Accepted as-is (may require customer authorization); Reworked/Repaired to meet the specified requirements; Re-graded for alternative, Nonclinical applications; Returned (applies to purchased products); or Scrapped/Discarded The disposition decision is made by quality with input from the appropriate department head and the CEO AND VERIFICATION OF REWORK OPERATIONS All rework operations are documented in written rework instructions. The instructions explain rework operations and/or processes, and determine how the reworked products will be inspected or tested to verify that they comply with specified requirements. 4

5 Rework instructions are formally reviewed and approved following the same authorization and approval requirements that were applied to the original instructions for the process that needs to be reworked. Prior to authorization and approval of rework instructions, the rework process is evaluated to determine any adverse effects it may have on the product. The results of this evaluation are documented in the Product History Record (a.k.a DHR for 351 products)/tissue Processing File Before reworked products are used in production or are shipped, they are thoroughly inspected to verify that they conform to the same requirements as originally specified. The manner and scope of inspection are defined, or referenced, in the rework instructions Rework activities and results of reevaluation inspections and tests are recorded in the Product History Record (a.k.a. DHR for 351 products)/tissue Processing File CLOSING OUT THE NONCONFORMANCE REPORT If the disposition decision is Scrap/Discard or Accept as-is, the Nonconformance Report is closed out at that point Rework, Repair and Re-grade dispositions require that reevaluation results be entered into the CLOSE OUT block of the nonconformance report Before closing out the Nonconformance Report, Quality determines whether there is a need for elevating the event to a CAPA Investigation to further evaluate the causes. Additionally quality will determine if the persons or organizations (usually vendors or subcontractors) responsible for supplier nonconformity should be notified. If a CAPA is initiated, the CAPA# is on the report ADVISORY NOTICES 351 MEDICAL DEVICES When nonconforming (351) product is detected after delivery, the customers, users and/or patients are notified, as appropriate, to instruct them on how to mitigate or avoid the effects, or potential effects, of the nonconformity. This process is defined in Operational Procedure QOP-8502, RECALL, ADVERSE REACTIONS, DEVIATION REPORTS, AND ADVISORY NOTICES REPORTABLE ADVERSE REACTIONS When a patient experiences a noxious and unintended response involving a communicable disease for which there is a reasonable possibility that the allograft tissue may have caused the response, the adverse reaction will be reported to CBER as soon as possible and no later than 15 calendar days of the initial report of the information. This process is defined in Operational Procedure QOP-8502, RECALL, ADVERSE REACTIONS, DEVIATION REPORTS, AND ADVISORY NOTICES REPORTABLE PRODUCT DEVIATIONS CRT will investigate all nonconforming product/deviations related to distributed tissue (reference 21 CFR (b)) A product nonconformance/deviation that meets all of the criteria below will be reported to the FDA using FDA-3468A as soon as possible but no later than 45 calendar days of the initial receipt of the information Related to a distributed graft Related to a core GTP (reference 21 CFR (b)) Related to the prevention of communicable disease transmission or tissue contamination. 5

6 4.9. ANALYSIS OF NONCONFORMITY REPORTS AND TRENDS Quality reviews, categorizes, quantifies, and analyzes product nonconformity reports and deviation reports to detect trends and identify the possible need for corrective and preventive actions. These activities are regulated by Procedure QOP-8503, CORRECTIVE AND PREVENTIVE ACTION. 5. REFERENCED DOCUMENT 5.1. Form QF SUPPLIER NONCONFORMANCE REPORT 5.2. Form QF INTERNAL NONCONFORMANCE REPORT 5.3. Form QF INTERNAL DEVIATION REPORT 5.4. Form QF INTERNAL INVESTIGATION WORKSHEET 5.5. Form QF NONCONFORMANCE LOG 5.6. Operational Procedure QOP-8502 RECALL, ADVERSE REACTIONS, DEVIATION REPORTS, AND ADVISORY NOTICES Operational Procedure QOP-8503, CORRECTIVE AND PREVENTIVE ACTION 6. ASSOCIATED RECORDS 6.1. NA THIS SPACE INTENTIONALLY LEFT BLANK 6

7 7. FLOW CHARTS/DECISION TREES Supplier Internal Customer QF INTERNAL NONCONFORMANCE REPORT Report Deviations using FDA Form 3468-A Nonconforming product is identified and segregated QF SUPPLIER NONCONFORMANCE REPORT Documentation is originated to gather information concerning the nature of the nonconformance QF INTERNAL NONCONFORMANCE REPORT REPORTABLE Quality Investigates Nonconformance 1. Distributed Graft, and 2. NC related to core GTP, and 3. NC related to prevention of disease transmission or graft contamination Quality determines if the nonconformance is a reportable deviation to FDA Nonconforming Product is dispositioned Discard Re-Grade Use As Is Rework Non-Clinical Use Only Nonconformance is addressed and only conforming product remains All Nonconformance documents and records are processed to completion, re-verified and the nonconformance closed out. Records stored by Quality Product resumes manufacturing Final Review and Acceptance Distributable Inventory 7