References to Computer and Software in FDA s CGTPs (Final Rule and Draft Guidance) for HCT/Ps Preamble to the CGTP Final Rule

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1 Preamble to the CGTP Final Rule Pages Computers Proposed (e) would require establishments to validate computer software used as part of manufacturing or tracking or for maintaining data relating to those activities. (Comment 52) One comment asserted that it is reasonable to require that computer systems used in manufacturing and data maintenance be tested to confirm that they perform as intended, and that the testing and results be documented. This comment asked us to confirm that we are distinguishing between this limited requirement and the term validation as it has been applied to computer systems identified as medical devices. (Response) We agree with this comment. Therefore, we revised the requirement in (d) to permit verification or validation of the computer software for its intended use. (Comment 53) Several comments opposed the proposed requirement on computer software validation. One comment asserted that software validation can be a financial burden and stated that the requirement should be implemented to the extent validation will minimize the risk of disease transmission during the manufacturing process. The comment further noted that there was no exemption in this provision for general-purpose software (e.g., spreadsheet, database, and word processing software) intended for broad general use, which are currently exempt from most of the general controls under the act. Two comments suggested limiting the scope of the requirement to the most necessary areas, to encourage the use of software programs in lieu of manual recordkeeping. Another comment asked that we amend the provision to reflect that software must be validated only if it is relied upon as the sole data source for the decisionmaking processes of the quality system. (Response) We do not intend that the requirements for computer validation be unduly burdensome. As a result of these comments, we are modifying the requirements in (d). This section now applies only to software that you rely upon to comply with core CGTP requirements. You must validate the performance of software for its intended use only if the software is custom software or commercially available software that has been customized or programmed (including software programmed to perform a userdefined calculation or table) to perform a function related to core CGTP requirements. If you rely on commercially distributed, noncustom, software to perform a function related to core CGTP requirements, then you are only required to verify the performance of that software for its intended use. With these changes, we have limited the scope of this provision so that it applies to computer software that directly affects communicable disease transmission risks. If such software is inappropriately designed, implemented, or used, the software may increase the risk of communicable disease transmission, perhaps by authorizing the release of HCT/Ps from an infectious donor, or by recording screening test results inaccurately. However, we recognize that commercially distributed general use software has undergone more rigorous testing before it is distributed. When such general use software is used without modification Page 1 of 8

2 to comply with core GTP requirements, it is adequate for the establishment only to verify the performance of the software for its intended use, rather than undertaking more onerous validation. For example, an eye bank that uses commercially distributed software (e.g., spreadsheet, database, word processing) to comply with a core CGTP requirement such as control of storage areas ( (a)), but not for makin decisions or determinations, must verify that this general purpose software can be used reliably in such a way, but would not have to validate the software. Verification in a situation such as this is not intended to be onerous. However, if the eye bank decided to modify and use commercially available computer software for determining donor eligibility, the modifications would increase the risk of problems and the eye bank would then be required to validate the software for this intended use. (Comment 54) One comment noted that eye banks do not use computers as decisionmaking instruments, but only for information storage and retrieval, word processing, and form printing. This comment asserted that appropriate validation in this instance should entail: (1) Routine backup of computer system, (2) physical check of computer printout against paper chart, and (3) signoff by final supervisor before tissue release. (Response) The examples provided are not core CGTP requirements and so the requirements of (d) would not apply. F. Economic Impacts Page (Comment 188) One comment suggested that the impact of the software validation requirements on small tissue facilities would be beyond the means of many and could force them out of business. The comment suggested that (e) be amended to require software validation only if it is relied upon as the sole source of data for quality-related decisionmaking. (Response) With respect to computer software validation FDA assumed: (1) None of the affected entities currently validate custom software, (2) 10 percent of all facilities in each sector have developed custom software requiring validation, and (3) validation of custom software will require 60 hours of laboratory supervisor time ($36 per hour, total cost = $2,160 per affected entity). We have modified (e) to indicate that either validation or verification can be performed, whichever is appropriate. Verification is less burdensome. 2. Estimated Impact on Eye Banks, Conventional Tissue Banks and Hematopoietic Stem/Progenitor Cell Establishments Page c. Section establishment and maintenance of a quality program. Page 2 of 8

3 The final rule requires that establishments establish and maintain a quality program. The quality program must include: Procedures relating to core CGTP requirements, procedures for exchanging information with other establishments known to have recovered cells or tissue from the same donor, appropriate corrective actions related to core CGTP requirements, proper training and education of personnel involved in activities related to core CGTP requirements, appropriate monitoring systems, investigation and documentation of HCT/P deviations related to core CGTP requirements, audits, computer software validation or verification, and other procedures specific to the quality program. Several of these functions are further specified in subsequent provisions of the rule, and the impact is estimated in the context of those provisions. (appears later in the same section:) Page A number of establishments will also need to institute other requirements of the quality program, including periodic audits, computer software validation or verification, and procedures specific to the quality program. Audits are part of the industry standards published by the AATB, EBAA, FACT, and AABB. However, some establishments following these standards may need to do some additional recordkeeping, and establishments not following standards will need to begin to conduct audits. Referring to table 4 of this document, FDA assumes that up to 95 percent of eye banks will increase their audit efforts, including additional lab director time to prepare for and perform the periodic audit. An estimated 23 percent of conventional tissue banks will allocate additional resources for audits, with a higher allocation of hours at larger establishments, to prepare for, and to conduct, the audit. For hemapoietic stem/progenitor cell establishments, FDA estimates that there will be no additional auditing required at establishments following FACT or AABB standards, but an estimated 80 percent of establishments not following industry standards will need to spend additional time to prepare for and to conduct periodic audits. Section of the CGTP final rule further stipulates that establishments must validate or verify, as appropriate, the computer software used in their operations when it is used in the performance of core (good tissue practice (GTP) functions. Validation would be required for custom software used in core GTP functions. However, for off the shelf commercial software packages (e.g., for data storage and retrieval, recordkeeping, etc.) used as intended by the software manufacturer, it would be adequate for the establishment, when using such products in the performance of core GTP functions, to verify the product s performance. Such products are already validated or verified by the software vendor. FDA assumes that none of the affected establishments currently validate or verify their custom software and that approximately 10 percent of eye banks, conventional tissue banks and hematopoietic stem/progenitor cell establishments have developed custom software that will require full validation or verification under this final rule. Because we received no specific comments regarding these assumptions in response to the proposed rule, we have retained them here. Although the scope of such work can vary, FDA estimates that the custom software in use has a limited scope of application, and that an average of 60 hours of work by the laboratory supervisor will be required to validate or verify custom computer software at an establishment. Detailed presentations of these assumptions are provided in section of the background papers (see footnote 1 of this document) by FDA and ERG. Page 3 of 8

4 Page FDA has made a number of revisions to this final rule, many in response to public comments on the proposed CGTP rule, that are expected to reduce the overall compliance burden on affected entities. Provisions under (c) have been revised to require audits periodically rather than annually as stipulated under the CGTP proposed rule. However, the cost estimates presented in this analysis of economic impacts retain the assumption that audits will impose an annual burden so as to generate conservative estimates of overall compliance costs. The provisions proposed under (f), requiring complete validation of custom computer software used for making HCT/P-related decisions or determinations, have been changed to a requirement for validation or verification as appropriate. Verification is a less burdensome alternative that would apply to software not relied upon for making donor eligibility or HCT/P suitability decisions or determinations (e.g., inventory). GTP Final Rule: Page Establishment and maintenance of a quality program. (d) Computers. You must validate the performance of computer software for the intended use, and the performance of any changes to that software for the intended use, if you rely upon the software to comply with core CGTP requirements and if the software either is custom software or is commercially available software that has been customized or programmed (including software programmed to perform a user defined calculation or table) to perform a function related to core CGTP requirements. You must verify the performance of all other software for the intended use if you rely upon it to comply with core CGTP requirements. You must approve and document these activities and results before implementation. As a reference, these are the core CGTPs: (pages ) Current good tissue practice requirements. (a) General. This subpart D and subpart C of this part set forth current good tissue practice (CGTP) requirements. You must follow CGTP requirements to prevent the introduction, transmission, or spread of communicable diseases by HCT/Ps (e.g., by ensuring that the HCT/Ps do not contain communicable disease agents, that they are not contaminated, and that they do not become contaminated during manufacturing). Communicable diseases include, but are not limited to, those transmitted by viruses, bacteria, fungi, parasites, and transmissible spongiform encephalopathy agents. CGTP requirements govern the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps, including but not limited to all steps in recovery, donor screening, donor testing, processing, storage, labeling, packaging, and distribution. The CGTP provisions specifically governing determinations of donor eligibility, including donor screening and testing, are set out separately in subpart C of this part. (b) Core CGTP requirements. The following are core CGTP requirements: Page 4 of 8

5 (1) Requirements relating to facilities in (a) and (b); (2) Requirements relating to environmental control in (a); (3) Requirements relating to equipment in (a); (4) Requirements relating to supplies and reagents in (a) and (b); (5) Requirements relating to recovery in ; (6) Requirements relating to processing and process controls in ; (7) Requirements relating to labeling controls in (a) and (b); (8) Requirements relating to storage in (a) through (d); (9) Requirements relating to receipt, predistribution shipment, and distribution of an HCT/P in (a) through (d); and (10) Requirements relating to donor eligibility determinations, donor screening, and donor testing in , , , and CGTP Draft Guidance Page 15 L. If the establishment relies on computer software to comply with core CGTP requirements, what activities must be performed before implementing the software? If the computer software is either custom software (designed specifically for you) or commercially available software that has been customized or programmed for you (e.g., to perform a user-defined calculation or create a table), you must validate the software for its intended use. If the computer software used to comply with core CGTP requirements has not been customized, but rather is off-the-shelf software that has not been modified, then you must verify the performance of the software for its intended use. You must approve and document these activities ( (d)). If the software is being used for functions other than those related to core CGTP requirements, there is no requirement to either validate or verify. Validation means confirmation by examination and provision of objective evidence that particular requirements can consistently be fulfilled ( (kk)), (e.g., a process consistently produces an HCT/P that meets its predetermined specifications). Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled ( (ll)). Example 1: An establishment develops its own computer software to store information used to make donor eligibility determinations (a core CGTP requirement). The establishment must validate its software for this intended use ( (d)). Example 2: An establishment uses a computer-generated labeling system, such as bar-coding, developed by a software company for a different intended use, such as labeling blood products. Since labeling controls ( (a) and (b)) are core CGTP requirements, and the establishment is using the software for its own intended use, the establishment must validate the software for this intended use ( (d)). You could refer to FDA s Guidance for Industry and FDA Staff entitled, General Principles of Software Validation (Ref. 5). Example 3. An establishment uses a commercial electronic spreadsheet to record donor testing Page 5 of 8

6 results which are used to make a donor eligibility determination. Since the software has not been modified, you must verify that it performs this activity correctly ( (d)). Page 25 G. What equipment calibration must I perform? Under (c), where appropriate, you must routinely calibrate according to established procedures and schedules all automated, mechanical, electronic, or other equipment used for inspection, measuring, and testing. For example, an instrument used to monitor the temperature of an HCT/P storage unit must be regularly calibrated. Some equipment, such as computers, are not subject to calibration. In order to determine an appropriate calibration schedule, you could consult the Operations Manual or contact the manufacturer of the equipment to determine and establish appropriate intervals for calibrating each piece of equipment. You should also take into consideration the specific use of this equipment within the manufacturing facility to determine if special conditions could warrant more frequent calibration than is recommended by the equipment manufacturer. Calibration accuracy should be traceable to accepted/known standards (e.g., National Institute of Standards and Technology, or the manufacturer s supplied or recommended standard. Pages XVII. STORAGE ( ) A. What storage area activities must I control? Under (a), you must control your storage areas and stock rooms to prevent the following: mix-ups, contamination, and cross-contamination of HCT/Ps, supplies, and reagents; and an HCT/P from being improperly made available for distribution. You should identify and design areas used for storage of HCT/Ps to facilitate monitoring of temperature and locating in-process HCT/Ps, quarantined HCT/Ps, and HCT/Ps that have been made available for distribution. Each storage area should have signs indicating the types of supplies, reagents, and HCT/Ps contained in that area, and should be organized to prevent mixups, cross-contamination, and improper release of HCT/Ps. Before the completion of the donor-eligibility determination, you must keep an HCT/P in quarantine and clearly identify it as in quarantine ( (a) and (b)). The quarantined HCT/P must be easily distinguishable from HCT/Ps that are available for release and distribution ( (b)). Quarantine means the storage or identification of an HCT/P, to prevent improper release, in a physically separate area clearly identified for such use, or through use of other procedures, such as automated designation ( (q)). An example of automated designation is the use of a validated computer system to maintain information on bar-code-labeled HCT/Ps held in a freezer. When you release the HCT/P, the computer system is activated to ensure Page 6 of 8

7 identification and retrieval of the specific HCT/P for the intended recipient. Pages XIX. RECORDS ( ) A. What are the general requirements for records? Under (a), you must maintain records concurrently with the performance of each step required in 21 CFR part 1271, subparts C and D. All required records must be accurate, indelible, and legible. To help ensure the accuracy of records retained, we recommend that establishments that make an HCT/P available for distribution obtain records directly from the creator of such documents whenever possible (e.g., serology/microbiology results should be obtained directly from the testing laboratory; death certificates, if needed to make an adequate donor eligibility determination, should be obtained directly from the state health official). The records must identify the person performing the work and the dates of the various entries, and must be as detailed as necessary to provide a complete history of the work performed and to relate the records to the particular HCT/P involved ( (a)). For specific requirements for retention of donor eligibility records, see (d). B. What kind of records management system must I have? Under (b), you must establish and maintain a records management system relating to core CGTP requirements. Under this system, you must maintain records pertaining to a particular HCT/P in such a way as to facilitate review of the HCT/P s history before making it available for distribution and, if necessary, subsequent to the HCT/P s release as part of a follow-up evaluation or investigation. You must also maintain and organize records pertinent to the manufacture of the HCT/P (e.g., labeling and packaging procedures, and equipment logs) under the records management system. If you maintain records in more than one location, you must design the records management system to ensure prompt identification, location, and retrieval of all records. The regulations do not specify the details of a records management system. You should organize your records in a useful manner in accordance with the requirements in this section. Example: A recovery establishment under contract with a processor sends HCT/Ps to the processor. The recovery establishment should send all relevant records, including donor and cleaning records, to the processor. The recovery establishment must maintain copies of all transferred records and organize them in their records management system. C. What are acceptable methods of record retention? Under (c), you may maintain records electronically, as original paper records, or as true copies such as photocopies, microfiche, or microfilm. Equipment that is necessary to make the records available and legible, such as computer and reader equipment, must be readily available. You must back up records stored in electronic systems. Page 7 of 8

8 Example: You are a processor that receives paper records of the donor s medical history from the recovery establishment. You review the medical history as part of the donor eligibility determination. At a later time, you scan the paper records and save them as a.pdf file on a computer that is backed up. The electronic records are true copies of the paper records. Therefore, you may destroy the paper records. However, if instead of scanning, you were to retype (transfer) the information into the computer, then we cannot be certain that this is a true copy or if errors have been made while re-typing, either intentionally or unintentionally. So in this scenario, you would be required to keep the original paper (hardcopy) records as proof of concurrent recordkeeping. Page 58 XXIV. REFERENCES 5. FDA General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 2002 ( Page 8 of 8