21CFR11 Compliance and Automated Manufacturing

Transcription

1 Presented at the World Batch Forum North American Conference Woodcliff Lake, NJ April 7-10, S. Southgate Drive Chandler, Arizona Fax CFR11 Compliance and Automated Manufacturing presented at the World Batch Forum 2002 North American Conference Kathleen Waters Manager - Automation IT Genentech, Inc. 1 DNA Way MS 30 South San Francisco, CA Tel: (650) Fax: (650) waters@gene.com KEY WORDS 21CFR11, Hybrid System, e-record, e-signature ABSTRACT 21CFR11 took effect in August 1997 with little observed regulatory activity. However, that has changed and increasing numbers of FDA warning letters are being generated for software used for GMP, GCP, or GLP (GxP) purposes. This presentation addresses the impact of 21CFR11 on automated manufacturing systems and processes. Included is an overview of 21CFR11, a discussion of the processes needed to reach compliance including 21CFR11 interpretation, assessment and remediation activities, and some issues for legacy automated manufacturing systems. It will speak to the compliance issues for hybrid systems where there is a multiplicity of options between totally paper based and totally electronic systems. Copyright 2002 World Batch Forum. All rights reserved. Page 1 of 7

2 Introduction One of the top concerns for most pharmaceutical manufacturers today is complying with the FDA regulation for the use of Electronic Records and Electronic Signatures known as 21CFR Part 11 (21CFR11 or Part 11). 21CFR11 defines how pharmaceutical companies must capture and retain electronic signatures, paperless records and reporting procedures related to the manufacture of their products. These records are vital to the day-to-day operation of every pharmaceutical company manufacturing or marketing drugs in the United States and are necessary for establishing an audit trail for literally every pill, capsule and liquid produced. 21CFR11 Overview 21CFR11 regulations set forth the criteria under which the Food and Drug Administration (FDA) considers electronic records and electronic signatures to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures to be executed on paper. Part 11 applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations. The Compliance Policy Guide Enforcement Policy: 21 CFR Part 11 Electronic Records; Electronic Signatures; Final Rule" describes FDA s expectation that firms assess systems for compliance to Part 11 and formulate plans for remediation. In August 1997 when 21CFR11 was signed into law, its scope was sorely misunderstood. Part 11's initial premise was to maintain proper identifiers for electronic data relevant to product safety, purity and efficacy. Just as printed documents provided a paper trail through the product life cycle, computer records needed to create a similar electronic trail, identifying users, approvals and progressions that lead back to the original data. Conceptually there was nothing new about 21CFR11. In essence, it was a response to advances in the tools and equipment being used in the development, production and distribution of a pharmaceutical product. But the tracking of electronic records and signatures was an unknown entity that a majority of manufacturers found intimidating and overwhelming. Even now, five years later, it is still intimidating and overwhelming. Part 11 defines an electronic record as any combination of text, graphics, data, audio, pictorial, or other information in a digital format that is created, modified, maintained, archived or transmitted under any agency records requirement. The easiest way to clarify whether or not an electronic record falls under Part 11 is to evaluate its relevance in terms of a hard or printed copy and if it is retrievable. If the printed record falls under any regulation, the electronic record will most likely need to be Part 11 compliant. Merely maintaining paper copies of those electronic records is not sufficient to achieve Part 11 compliance. The electronic signatures, defined as a computer data compilation of any symbol or series of symbols executed, adopted or authorized by an individual to be the legally binding equivalent of the handwritten signature must also be identified. Furthering the previous example, any identification on the printed record, such as author name, time and date of Copyright 2002 World Batch Forum. All rights reserved. Page 2 of 7

3 development or approval must also be replicated and tracked in its electronic counterpart. Electronic signatures are simply unique identifiers assigned to each individual using or maintaining a system. These are normally user names and passwords, though biometric technology also applies. These electronic identifiers must be tracked within the system, leaving a trail that can be audited should a pharmaceutical product s data or process be called into question. Again, this is similar to the paper process, replacing a filing cabinet full of signed documents with an automated electronic trail. The audit trail must be generated by the system itself, i.e. electronically, to be compliant. This paper is not intended to provide an in depth interpretation of 21CFR Part11. There are several sources to increasing an understanding of the regulation. The process starts with reviewing the regulation and preamble and rapidly becomes a continuous learning process. Several websites provide useful information; a few key URLs are listed below: URL Content NuGenesis resource page and on-line forum Part 11 references and notices Parenteral Drug Association International Society for Pharmecutical Engineering Industry working groups (e.g. GAMP, GERM, PAIR, etc.) make available input from users and consultants and often provide white papers and forums discussing Part 11 issues. Also, guidance dockets have been published and are available on the FDA website ( The applicable dockets are identified in the table below: Docket Number Topic Title of Docket 00D-1538 Validation Electronic Records; Electronic Signatures, Validation 00D-1539 Archiving Electronic Records & Electronic Signatures, Retention of Electronic Records 00D-1540 E-Copies Electronic Records & Electronic Signatures, Electronic Copies of Electronic Records 00D-1541 Audit Trails Electronic Signatures: Audit Trails 00D-1542 Time stamps Electronic Signatures: Time Stamps 00D-1543 Glossary Electronic Signatures: Glossary of Terms To understand the full force and effect of the law for regulated manufacturing systems (e.g. MES, ERP, DCS, SCADA, PLC, etc.), the predicate rules need to be reviewed. The predicate rules are the regulations where any records or signature requirements identified in the Federal Food, Drug and Cosmetic Act, the Public Health Services Act or any FDA regulation. The predicate rules mandate what records need to be maintained, the content of the records, whether signatures are required and the record retention periods for research, production, and control of FDA regulated articles. Most of the GMP predicate rules are contained in Title 21 Code of Federal Regulations (CFR). The principal predicate rules applying to GMP systems used for pharmaceutical manufacturing purposes are summarized below: Copyright 2002 World Batch Forum. All rights reserved. Page 3 of 7

4 21CFR Part 211 cgmps for Finished Pharmaceuticals Subpart C: Buildings and Facilities Automated, Mechanical and Electrical Equipment Subpart J Records and Reports General requirements Equipment cleaning and use log Master production and control records Batch production and control records Production Record Review In addition, many corporations have interpreted the predicate rules and identified additional record or signature requirements in SOPs. These documented procedures must be considered to achieve Part 11 compliance. Compliance Process Part 11 mandates that new systems (e.g. those implemented after August 1997) must be compliant from the start. This requires revising computer system selection and procurement policies to mandate Part 11 requirements. It also requires revision of computer system validation procedures to include Part 11 compliance. For legacy systems and new systems known not to be in compliance, the compliance process begins with a systems assessment plan. An extensive review of 21CFR Part 11 to identify the intent of each section provides the baseline for a comprehensive systems assessment. An inventory of all computer systems used in a GxP or potential GxP process should be generated to identify the Part 11 systems. Each system should be analyzed to determine the risk factors for product safety if a computer error should occur to help organize and prioritize the assessment scheduling. An assessment should be conducted on each system against the corporate interpretation to identify the non-compliance gaps. Master Remediation Plans should be developed to define the tasks required to reach compliance for all systems that are non-compliant. A documented process helps demonstrate an organization s commitment to a comprehensive approach towards Part 11 compliance. A corporate level cross-disciplinary team should be chartered with the task of developing a common interpretation of Part 11. This process begins with an extensive review of all available FDA documentation on Part 11 including warning letters and 483s. It is also helpful to participate in industry seminars and attend training programs. Since the iinterpretation crosses disciplinary boundries, the discussions need to review the business processes in each area. Consultants may be involved in the interpretation process, but the final interpretation must be one that the entire corporation owns and is accountable to. Using the information from the Part 11 interpretation, CFRs and corporate record and signature requirements, assessment templates should be developed for the analysis. The assessment tool should measure systems against consistent criteria for cross-system comparison. For example, a column would identify a Part 11 requirement, such as Security Design Protocols. In that column, specific system functions impacted by that requirement are identified. Observations of the system are noted, along with the corrective actions needed to establish Part 11 compliance. Copyright 2002 World Batch Forum. All rights reserved. Page 4 of 7

5 An inventory of the systems that already require validation is a clear starting point for the assessment process. These systems have already been identified as having a direct effect on the safety, purity and efficacy of a product. In addition to systems directly impacting production, computer systems that can affect decisions relating to production should also be included in the inventory. This may have been developed during the Y2K analysis initiatives and could be expanded to include the systems installed since then or be part of a living inventory maintained for computer systems. If systems have been properly validated, defined requirements and functions are documented, and their operational and functional performance has already been qualified, this expedites the Part 11 assessment. To facilitate the assessment process, the automation computer systems could be categorized based on the platform (e.g. PLC, HMI, DCS, packaged, etc.). In addition, this categorization may be further delineated to individual classes within each major category (e.g. HMI category would contain ifix, RSView, Wonderware, etc.) to help elucidate the gap analysis process for different system architectures. The class-based approach may not clearly identify all procedural gaps (i.e. SOPs, department procedures, etc.), but captures all the technological gaps for the individual systems. However, each system should be uniquely identified with specific compliance gaps captured in the assessment process. A high-level data flow for each computer system class helps determine how the application and resultant record(s) are being used in the business processes. The data flow provides a brief overview of the computer system, identifies what records and signatures are being used and where, and identifies outstanding issues that need to be managed during the assessment. If the computer system has applicable electronic record and/or electronic signature requirements, the link to the specific applicable regulation(s) should be captured along with how the system is used in the business process in the assessment tool. The assessment process requires interviewing both the system expert (knowledge of the system) and the system owner (knowledge of the business process). Information from each assessment should be documented in the assessment tool with the compliances gaps s status recorded. Additional information on the individual technology and procedural gaps should also be summarized in the assessment tool. This will facilitate the remediation process in identifying common themes. Comprehensive remediation plans identify remedial solutions for systems while allowing for the development of long-term solutions with vendors. The remediation plans include the major milestones for both types of solutions. Most procedural issues will be found on multiple systems, the remediation plan should identify these common themes (e.g. security, data retention, audit trails, etc.) as a collective effort and provide for an additional focus on the individual system issues independent of this effort. The urgency of system remediation activities should be prioritized based on product impact and data integrity for the individual system. Many new business processes, including new SOPs, will need to be included in the remediation plan. The information captured in the interpretation, assessment and remediation processes help establish a foundation for Part 11 Standard Operating Procedures (SOPs), not only for retrospective validations, but also for new system implementations. The system life Copyright 2002 World Batch Forum. All rights reserved. Page 5 of 7

6 cycle model must include Part 11 considerations in its design, development, testing, implementation, maintenance and retirement phases. Legacy Systems There is no grandfather clause in Part 11, so legacy systems fall under its compliance requirements. These older systems actually pose a more difficult problem than new technology. Legacy systems were often designed to overwrite data, virtually eliminating the electronic trail, and their encryption protocols and user signature capabilities rarely meet suggested guidelines. Legacy systems may have been validated according to standards at that time or may not have been considered regulated and therefore not validated. These systems are often integrated with others, creating a hybrid system housing both cgmp and non-cgmp functions since compliance issues include any hardware or software interacting with cgmp data. Many in the industry chose to avoid 21CFR11 by maintaining their paper systems. The familiarity of that more labor-intensive and error-prone practice, combined with an uncertainty of how to establish and sustain Part 11 compliance, stalls opportunities offered by emerging technology. Fierce competition within the industry has forced a reevaluation of that approach, bringing Part 11 compliance to the forefront. Of course, concerns of FDA inspection and enforcement have also played a part in this trend. Avoidance was never a true option, as long as technology exists within an organization. But until vendors provide technological solutions, hybrid systems utilizing both paper and electronic records/signature components will exist. Many legacy systems out there are being used in "Hybrid Mode", where handwritten signatures are stored against electronic records. The main reason for this is that many inhouse and vendor based software solutions for GxP applications do not fully meet Part 11 requirements on the electronic signature elements. Therefore, a Hybrid is the most acceptable method for using this system. This means using automated systems to create static and dynamic data, but then printing outputs that are signed prior to that data being used. An example of a hybrid system is a master recipe is created on an electronic system and a printout which is then signed prior to release for use. There is a requirement to ensure the printout reflects the recipe accurately and the process is proceduralized rather than automated. A GxP system that includes electronic records but does not include e- signatures support must be run in hybrid mode. This is not a good long-term approach, because hybrids are notoriously difficult to maintain and defend. The main problem is one of synchronicity: An electronic record can be modified seconds, hours, days, months or years after being created, on various occasions. Keeping paper-based signatures of these changes is clearly challenging, and even more so when the handwritten signature only includes the date. No new systems should be implemented in the hybrid mode. The only exception is if there are no equivalent systems that support e-signatures available on the market. In that case, a hybrid should be considered a short- to mid-term solution, with an intention to upgrade to e-signature compliance in the future. Copyright 2002 World Batch Forum. All rights reserved. Page 6 of 7

7 Conclusion 21CFR11 is one of the biggest issues facing pharmaceutical manafactuirng, much large than Y2K. It must become part of the processes supporting GxP system life cycles, beginning with inception and ending with retirement, it will never be complete. The regulation must be interpreted and applied, first to new systems and then to legacy systems to bring them into compliance. Using the interpretation, an assessment of the existing systems provides the magnitude of the gaps. The Master Remediation Plan aligns and prioritizes the activities necessary to reach compliance. Achieving and maintaining Part 11 compliance will be an on-going project; learn it, live it, make it part of the every day business processes supporting your company. Copyright 2002 World Batch Forum. All rights reserved. Page 7 of 7