How To Prepare For A Systems-Based Inspection Understanding FDA s Risk-Based Inspections Approach

Transcription

1 CLASSIC How To Prepare For A Systems-Based Inspection Understanding FDA s Risk-Based Inspections Approach Jackelyn Rodriguez The FDA wants its regulatory practices to encourage and assist high tech industries. Its espousal of riskbased prioritization in manufacturing inspections should instigate risk-based decision-making on a practical, day-to-day level throughout the manufacturing site. Implementation of the FDA-suggested comprehensive Quality System Model would bring greater understanding of total operations leading to a more robust and modern Quality System that is fully compliant with GMP regulations. INTRODUCTION Quality management methods, especially in high-tech industries, have undergone significant progress since 1978 when the current Good Manufacturing Practice (cgmp) regulations were last updated, and the Food and Drug Administration (FDA) wants to ensure that its regulatory practices encourage similar progress in the pharmaceutical industry. As a result, beginning in the fall of 2004, the FDA began using a risk-based approach for prioritizing domestic manufacturing site inspections for pharmaceutical manufacturers. In order to keep up to speed with the many advances in manufacturing quality management and to enable the FDA to more effectively allocate its limited regulatory resources, the Agency is implementing a risk-based approach as well as a comprehensive quality-systems model to pharmaceutical manufacturing inspections. 1 It all began in August 2002, when the FDA announced a significant new initiative they called Pharmaceutical Current Good Manufacturing Practices for the 21st Century. This initiative was developed to enhance and modernize the regulation of pharmaceutical manufacturing and product quality to bring the pharmaceutical industry in line with what device companies have been doing for the many years since FDA began the Quality System Inspection Technique (QSIT) approach. FDA S GOAL In the new guidance FDA describes a comprehensive quality systems (QS) model, which fully explains the elements of a systems-based approach. If implemented, manufacturers would reach a higher level understanding of their own operations, and in doing so would operate more robust modern quality systems that are fully compliant with the cgmp regulations. The Agency believes flexibility of the cgmp regulations should enable manufacturers to implement quality systems in forms that are appropriate for their specific operations. Therefore, they do not tell manufacturers how to write their procedures in order to comply with the regulations, much as in the quality system regulations for devices. Instead, both device and pharmaceutical manufacturers retain the full responsibility for knowing what they do and documenting their own processes to ensure compliance. 1 This new quality systems approach takes into consideration the interrelationship of the six-major systems, as in QSIT and the International Organization for Standardization (ISO) 9000/2000, and in the latest ISO13485 (2003), which all use the same quality systems approach. FDA believes that as this new approach is used, pharmaceutical manufacturers will be encouraged to the early adoption of new technological advances, thereby facilitating industry application of modern quality management techniques, including implementation of quality 36 Journal of GXP Compliance

2 Jackelyn Rodriguez systems approaches, and encouraging implementation of risk-based approaches that focus attention on critical areas. The FDA completed its assessment of the existing cgmp programs. They have assessed current practices as well as available new tools for enhancing manufacturing science. Their assessment helped to create a new framework for the regulatory oversight of manufacturing quality that is based on quality systems and risk management approaches. 1 The results of the assessment gave way to the Agency s release of the draft guidance for industry on Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations. Once finalized, this guidance is intended to provide recommendations to regulated industry for meeting the requirements of the Agency's cgmp regulations via a comprehensive quality systems approach, which encourages continuous improvement and risk management in the manufacturing of human and veterinary drugs, including human biological products. IMPLEMENTATION OF RISK-BASED MANAGEMENT PLAN The FDA has identified a risk-based approach as one of the driving principles of the cgmp initiative. The following are some examples of how FDA believes the use of risk management principles will enhance the Agency's inspection and enforcement program: The Agency has developed and will be piloting a risk-based model for prioritizing sites for manufacturing inspections and for the amount of FDA oversight needed. This will be related to several factors, including the degree of a manufacturer's product and process understanding and the robustness of the quality system controlling their processes. For example, changes to complex products made with complex manufacturing processes may warrant more regulatory oversight. In other cases, considerations, such as public health impact and the compliance status or compliance history of the manufacturer will continue to influence the intensity of FDA oversight. 1 Beginning in the fall of 2004, the FDA began using a risk-based approach for prioritizing domestic manufacturing site inspections for certain human pharmaceuticals. The frequency and scope of inspections will be reduced for firms that FDA determines have acquired sufficient process understanding and have succeeded in implementing effective quality systems approaches. The Full Inspection Option The Full Inspection Option is a surveillance or compliance inspection that is meant to provide a broad and deep evaluation of a firm's cgmps. This will be done when little or no information is known about a firm's cgmp compliance (e.g., for new firms), or for situations in which there is doubt concerning cgmp compliance within the firm (e.g., a firm whose history has documented short-lived compliance and recidivism), or as follow-up to previous regulatory actions. Full Inspection may revert to the Abbreviated Inspection Option, with District concurrence. During the course of a Full Inspection, verification of quality system activities may indicate limited coverage in other systems. The Full Inspection Option will normally include an inspection audit of at least four of the systems, one of which must be the quality system - the system that includes responsibility for Annual Product Reviews (APR). The Abbreviated Inspection Option The Abbreviated Inspection Option is a surveillance or compliance inspection that is meant to provide an efficient update evaluation of a firm's cgmps. The abbreviated inspection will also provide documentation for continuing a firm in a satisfactory cgmp compliance status. Typically, this type of firm has a record of satisfactory cgmp compliance with no significant recall, product defect, or alert incidents, or with little shift in the manufacturing profiles of the firm within the previous two years. Selecting Systems for Coverage The selection of the system(s) for coverage will be made by the District Office based on such factors as a given firm's specific operation, history of previous coverage, history of compliance, and other priorities determined by the District Office. Drug Manufacturing Inspection A drug manufacturing inspection is a factory inspection in which evaluation of two or more systems, in- January 2008 Volume 12 Number 2 37

3 CLASSIC Figure 1. The Relationship among the Six Systems: The Quality System and the Five Manufacturing Systems Production System Packaging & Labeling Systems Quality System Facilities & Equipment Systems Materials System Laboratory Controls System cluding the quality system, is done to determine whether manufacturing is occurring in a state of control. Inspection Pilot The Drug Pilot Inspection Program, which was officially implemented as of February 1, 2002, based on inspections completed between January 1, 2001 and June 30, 2001, included more than 150 inspections, from the Philadelphia, Los Angeles, New York, Dallas, San Juan, and Newark Districts using the top-down systems-based approach. This program was used to determine the level of FDA s inspectional requirements and the frequency of FDA audits based on the following: Pilot System Addressed Quality Facilities and Equipment Materials Production Packaging and Labeling Laboratory Control and Operations Pilot System Findings The following is a list of observations or findings that resulted from the study: Failure Investigations Validation Monitoring Record Keeping Stability Specifications Media Fills Training Analytical Methods Cleaning Validation Electronic Issues Facilities and Equipment Vendors Adverse Events IMPORTANCE OF OPERATING UNDER A STATE OF CONTROL Just as with QSIT, when any one system is out of control, this indicates the firm is out of control! Such findings may result in regulatory action and follow up, and that action may include the full inspection option for the next visit, a Warning Letter (WL), seizure, or injunction. Evidence to support significant or a trend of deficiencies within a covered system could demonstrate the failure of a system and should result in consider- 38 Journal of GXP Compliance

4 Jackelyn Rodriguez ation of the issuance of a WL or other regulatory action by the District. FDA is expecting that these risk-based changes will facilitate continuous improvement in pharmaceutical manufacturing and will improve availability of new drugs while increasing product quality and process efficiency. New Quality Concept So, what is this new concept for modern quality systems? It includes what FDA calls the Six-system Inspection Model as follows: 1. Quality System 2. Facilities and Equipment System 3. Production System 4. Materials System 5. Lab Control System 6. Packaging and Labeling System Much as QSIT has been used as the device systemsbased inspectional approach and how it compares to the pharmaceutical six-system inspections approach, the six-system model requires manufacturers to outline production controls, to maintain compliance for facilities and equipment, and to implement and manage a systems-based approach to internal auditing. The FDA understands that the implementation of a robust quality system can help to ensure compliance with regulations related to product safety, identity, strength, quality, and purity as long as the quality system addresses the minimum requirements of cgmp regulations. It encourages manufacturers to save time and money by planning and focusing on their systems based on the tenet that manufacturers should understand their internal processes well enough to determine where high risk operations exist, therefore, focusing resources based on risk management. This approach should enable manufacturers to develop internal measures to manage risk, and when warranted, implement systems to mitigate high risk levels. 2 TABLE 1 The Quality Systems Model A. The Quality System B. Facilities and Equipment System C. Production System D. Materials System E. Lab Control Systems F. Packaging and Labeling System THE QUALITY SYSTEMS MODEL The quality system provides the foundation for the manufacturing systems that are linked and function within it. Much like QSIT, ISO9000/2000, and ISO13485, which have used the Linked-Process Approach, this new six-system inspection model, includes how the cgmps and the concepts of modern quality systems are linked. Although the new six-system inspection model shows the quality system and the five manufacturing systems (see Table 1), the model is also organized into an additional Four Major Sections, as shown in Table 2. Under the Quality Systems Model, the Agency recommends that senior managers ensure that the quality system they design and implement provides clear organizational guidance and facilitates the systematic evaluation of issues. For example, according to the model, when documenting a quality system, the topics shown in Table 2 should be included. FOUR MAJOR SECTIONS Management Responsibilities Provide Leadership In a robust, modern quality system, management with executive responsibility typically demonstrates commitment to developing and maintaining the quality system. Leadership is demonstrated by aligning quality systems plans with the manufacturer s strategic plans to ensure that the quality systems support the manufacturer s mission and strategies. Senior managers should set implementation priorities and develop action plans. Managers can provide support of the quality system by: Actively participating in system design, implementation, and monitoring, including system review Advocating continual improvement of operations and the quality system Committing the necessary resources Encouraging internal communication on quality issues at all levels in the organization January 2008 Volume 12 Number 2 39

5 CLASSIC TABLE 2 Four Major Sections Management Responsibilities 1. Provide Leadership 2. Structure the Organization 3. Build Your Quality System to Meet Requirements 4. Establish Policies, Objectives, and Plans 5. Review the System Resources 1. Establish General Arrangements 2. Develop Personnel 3. Maintain Facilities and Equipment 4. Control Outsourced Operations Manufacturing Operations 1. Design and Develop Product and Processes 2. Monitor Packaging and Labeling Processes 3. Examine Inputs 4. Perform and Monitor Operations 5. Address Nonconformities Evaluation Activities 1. Analyze Data for Trends 2. Conduct Internal Audits 3. Perform Risk Assessment 4. Determine and Implement Corrective Action 5. Determine and Implement Preventive Action 6. Promote Improvement Note: Under each of these four sections, additional, specific elements of a robust, modern quality systems model are described. This approach is consistent with the cgmp regulations, which require manufacturers to develop and document controls for specifications, plans, and procedures that direct operational and quality system activities that are accurate, appropriately reviewed and approved, and available for use. Many of the quality systems elements correlate closely with the cgmp regulations. 1 It is important to emphasize that the guidance is not recommending new regulatory requirements. A Documented Quality System Another example of leadership according to the model is that when documenting a quality system, the following should be included: The scope of the quality system, including any outsourcing The manufacturer s policies to implement the quality system s criteria, and the supporting objectives. The procedures needed to establish and maintain the quality system The establishment of policies, objectives, and plans to support the system Under a modern quality system, policies, objectives, and plans provide the means by which senior managers articulate their vision of quality to all levels of the organization. This also means that they must make the policy relevant. It must be communicated to, and understood by, personnel and contractors (as applicable), and revised as needed. Quality objectives are typically aligned with the manufacturer s strategic plans. A quality system seeks to ensure that managers support the objectives with necessary resources and have measurable goals that are monitored regularly. 2 Review the System System review is a key component in any healthy quality system to ensure its continuing suitability, adequacy, and effectiveness. Under a quality system, senior managers are expected to conduct reviews of the whole quality system according to a planned schedule. Such a review typically includes both an assessment of the product as well as customer needs. The review should consider at least the following: The appropriateness of the quality policy and its objectives The results of audits and other assessments Customer feedback, including complaints The analysis of data trending results The status of actions to prevent potential problems or their recurrence Any follow-up actions from previous management reviews Any changes in business practices or environment that may affect the quality system (such as the volume or type of operations) Whether product characteristics meet the customer s needs Science-based approaches Typically, successful quality systems share the following characteristics: Decisions based on an understanding of the intended use of a product Proper identification and control of areas of potential process weakness Responsive deviation and investigation systems that lead to timely remediation Sound methods for assessing risk 40 Journal of GXP Compliance

6 Jackelyn Rodriguez Figure 2. Risk Management in the Quality Management System Risk Analysis Risk Management CAPA Occurrence Occurrence Risk Evaluation Risk Control and Monitoring Production and Post-Production Monitoring Occurrence Occurrence Occurrence Risk Assessment Design Development Well-defined processes and products, starting from development and extending throughout the product lifecycle Systems for careful analyses of product quality Supportive management (philosophically and financially) cgmp regulations correlated to specific elements in the quality systems model Resources Resources Under a robust quality system, sufficient allocation of resources for quality systems and operational activities is critical. Additionally, senior management is responsible for providing adequate resources for the following: To supply and maintain the appropriate facilities and equipment to consistently manufacture a quality product To acquire and receive materials that are suitable for their intended purpose For processing the materials to produce the finished drug product For laboratory analysis of the finished drug product, including collection, storage, and examination of in-process, stability, and reserve samples Training and Developing Personnel Continued training is critical to ensure that employees remain proficient in their operational functions and in their understanding of cgmp regulations. Under a quality system (and under the cgmp regulations), training is expected to focus on both the employees specific job functions and the related cgmp regulatory requirements. Managers are expected to establish training programs that include the following: Evaluation of training needs Provision of training to satisfy these needs Evaluation of effectiveness of training Documentation of training and re-training Facilities and Equipment Under a quality system, the technical experts, e.g., engineers, and development scientists, who have an understanding of pharmaceutical science, risk factors, and manufacturing processes related to the product, are responsible for specific facility and equipment requirements. 1 According to the cgmp regulations, equipment must be qualified, calibrated, cleaned, and maintained to prevent contamination and mix-ups. The cgmp reg- January 2008 Volume 12 Number 2 41

7 CLASSIC ulations place as much emphasis on process equipment as on testing equipment, while most quality systems focus only on testing equipment. Control Outsourced Operations When outsourcing to a second party, quality systems call for contracts (quality agreements) that clearly describe the materials or service, quality specifications responsibilities, and communication mechanisms. It is critical to ensure that the contracting manufacturer s officers are familiar with the specific requirements of the contract. Manufacturing Operations Design and Develop Product and Processes There is significant overlap between the elements of a quality system and the cgmp regulation requirements for manufacturing operations. Quality by design means designing and developing manufacturing processes during the product development stage to consistently ensure predefined quality at the end of the manufacturing process. 2 A quality system provides a sound framework for the transfer of process knowledge from development to the commercial manufacturing processes and for post-development changes and optimization. It is critical to establish responsibility for designing or changing product. Proper documentation of associated processes will ensure that critical variables are identified. This documentation includes: Resources and facilities needed Procedures to carry out the process Identification of the process owner who will maintain and update the process as needed Identification and control of critical variables Quality control measures, necessary data collection, monitoring, and appropriate controls for the product and process Any validation activities, including operating ranges and acceptance criteria Effects on related processes, functions, or personnel The FDA notes that with this information, experts would have an understanding of pharmaceutical science, risk factors, and manufacturing processes as well as how variations in materials and processes can ultimately affect the finished product. Monitor Packaging and Labeling Processes Although, packaging and labeling controls are not specifically addressed in quality systems models, the FDA recommends that, as part of the design process before commercial production, the controls for all processes within the packaging and labeling system be planned and documented in written procedures. Therefore, procedures should outline specifications and controls for the packaging and labeling of materials, which should be included to prevent mislabeling and resulting recalls. 2 Examine Inputs The term input refers to any material that goes into a final product, regardless of whether the material is purchased or produced by the manufacturer. The quality systems model calls for the verification of components and services provided by suppliers and contractors; however, the model offers a method for implementing verification that is different from those in the cgmp regulations. In addition, another essential element of purchasing controls calls for the auditing of suppliers on a periodic basis. During the audit, the manufacturer can observe the testing or examinations conducted by the supplier to help determine the reliability of the supplier s Certification of Analysis (COA). Of course, an audit should also include a systematic examination of the supplier s quality system to ensure that reliability is maintained. Perform and Monitor Operations The main purpose of implementing a quality systems approach is to enable a manufacturer to more efficiently and effectively perform and monitor operations. The goal of establishing, adhering to, measuring, and documenting specifications and process parameters is to objectively assess whether an operation is meeting its design and product performance objectives. The FDA understands that in a modern quality system, a design concept established during product development typically matures into a commercial design after process experimentation and progressive modification. During this period, areas of process weakness should be identified and factors that can influence critical quality attributes should receive increased scrutiny. Sufficient testing data will provide essential information on the performance of the new process, as well as a mechanism for continuous improvement. 42 Journal of GXP Compliance

8 Jackelyn Rodriguez TABLE 3A 21 CFR cgmp Regulations Related to Management Responibilities Quality System Regulatory Citations Element Structure the Organization Build QS to Meet Your Requirements Establish Policies, Objectives, and Plans Review the System Establish Quality Function: (a) (See definition 210.3(b)(15) Notification: (f) QU procedures: (d) Quality Unit (QU) procedures, specifications: (c), with reinforcement in: (a), (a) QU control steps: (a), with reinforcement in : (c), (a), , (c)(1), (c), (b), , (d), QU Quality Assurance; review/investigate: (a), (a-b) (f), , (a) Record control: (a-d), (c), (d), (e), , , , (b) Procedures: (c-d), (a Record review: (e), , (b)(2) Address Nonconformities A key component in any quality system is the handling of nonconformities and deviations. In a quality system, it is critical to develop and document procedures to define responsibilities for halting and resuming operations, recording the nonconformity, investigating the discrepancy, and taking remedial action. The investigation, conclusion, and follow-up should be documented. If the nonconformity is significant, based on consequences to process efficiency, product quality, safety, and availability, it is important to evaluate how to prevent its recurrence. TABLE 3B 21 CFR cgmp Regulations Related to Resources Quality System Regulatory Citations Element Develop Personnel Maintain Facilities and Equipment Control Outsourced Operations Qualifications: (a) Staff number: (c) Staff training: (a-b) Buildings and Facilities: (b), (c), , Equipment: , , (b)(4), Lab Facilities: (b) Consultants: Outsourcing: (a) Evaluation Activities Analyze Data for Trends Quality systems call for continually monitoring trends and improving systems. This can be achieved by monitoring data and information, identifying and resolving problems, and anticipating and preventing problems. Data trending is an excellent way to monitor quality indicators for potential hot spots as well as to monitor the effectiveness of corrective actions and preventive actions. Again, analysis of data can provide indications that controls are losing effectiveness. The information generated will be essential to achieving problem resolution or problem prevention. Data Collection Procedures When implementing data collection procedures, consider the following: Collection methods and their documentation When, during the product lifecycle, data will be collected How and to whom measurement and monitoring activities will be assigned When analysis and evaluation (e.g., trending) of laboratory data should be performed Correlation of cgmp regulations to specific elements in the quality systems model (see Tables 3A through 3D). Trending enables the detection of potential problems at the earliest possible moment to plan corrective and preventive actions. Under a quality systems approach, trends should be continually identified and evaluated. The information from trend analyses can be used to continually monitor quality, identify potential variances before they become problems, and facilitate improvement throughout the product lifecycle. January 2008 Volume 12 Number 2 43

9 CLASSIC TABLE 3C 21 CFR cgmp Regulations Related to Management Operations Quality System Regulatory Citations Element Design and Develop Product Production: (a) and Processes Materials: 210.3(b), , Examine Inputs , , Perform and Monitor Operations Address Nonconformities Production: , , , , QC criteria: (a-c), (b), (a), (d) QC checkpoints: (a), (a), , (c) Discrepancy investigation: (a), , , Recalls: 21 CFR Part 7 Another important concept is the use of trending in process capability assessment. One way of accomplishing this is the use of statistical process control. Process capability assessment can serve as a basis for determining the need for changes that can result in process improvements and efficiency. This use of trending allows the examination of processes as a whole; these trending analyses also can help focus internal audits. Conduct Internal Audit Although this is not included under the current pharmaceutical regulations, most pharmaceutical manufacturers conduct audits to evaluate effective implementation and maintenance of the quality system and to determine whether processes and products meet established parameters and specifications. The quality systems approach recommends that procedures take into account the relative risks of the various quality system activities, the results of previous audits and corrective actions, and the need to audit the entire system, at least annually. Manufacturers should describe auditing procedures, the auditors responsibilities, and how auditors are trained in objective evidence gathering. Audit procedures should also define auditing activities such as the scope and methodology of the audit, selection of auditors, and audit conduct (audit plans, opening meeting, closing meeting, and reports). TABLE 3D 21 CFR cgmp Regulations Related to Evaluation Activities Quality System Element Analyze Data for Trends Conduct Internal Audits Perform Risk Assessment Determine and Implement Corrective Action Determine and Implement Preventive Action Promote Improvement Regulatory Citations Annual Review: (e) Annual Review: (e) Discrepancy investigation: (a), Risk Assessment Risk assessment and risk management have become critical issues in the risk-based approach to compliance. As a result, this new approach to risk management should prompt organizations to determine areas that are the most significant from a product quality, safety, and efficacy perspective. This approach can be used to streamline and focus efforts on areas that are most significant. The concept of risk management is a major focus of the Pharmaceutical cgmps for the 21st Century initiative. Risk management can guide the setting of specifications and process parameters. Risk assessment is also used in determining the need for discrepancy investigations and corrective actions and how to prioritize them. Risk assessment will be implemented more seamlessly within the quality systems framework as manufacturers use it more formally. For example, risk analysis should consist of hazard identification and risk estimation for the consequences of each hazard. Risk evaluation should address the acceptability levels of those risks. Risk control is the process through which decisions are reached and protective measures are implemented to reduce or eliminate unacceptable risks. The monitoring of production information provides the basis for establishing new design (both for a process and a product) safety requirements as well as a baseline for the future risk management of similar products. 44 Journal of GXP Compliance

10 Jackelyn Rodriguez Corrective and Preventive Action (CAPA) Corrective Action Corrective action is typically a reactive tool for system improvement to ensure that significant problems do not recur. Both quality systems and the cgmp regulations emphasize corrective actions. Quality systems approaches call for procedures to be developed and documented to ensure that the need for action is evaluated relative to its possible consequences, the root cause of the problem is investigated, possible actions are determined, a selected action is taken within a defined timeframe, and the effectiveness of the action taken is evaluated, 2 and confirmed as effective to ensure that the chosen corrective action actually works. Corrective action should include reviews of several quality indicators such as: Inspection and test results and records Scrap and yield data Supplier quality and performance data Equipment calibration Audit results Training issues Corrective and Preventive Action CAPA should focus on investigating and correcting discrepancies and attempting to prevent recurrence. The degree of CAPA taken to eliminate or minimize actual or potential nonconformities must be appropriate to the magnitude of the problem and commensurate with the risks encountered. The quality systems model discusses CAPA as three concepts, all of which are used in the new guidance: Remedial corrections Root cause analysis with corrective action to avert recurrence Preventive action to avoid initial occurrence So what does this mean? It means that the manufacturer must establish CAPA procedures. For example, with devices, FDA will determine whether sources of product and quality information, which may show unfavorable trends, have been identified. Confirm that data from these sources are analyzed to identify potential product and quality problems that may require preventive action. In addition, companies must define the problem and: Identify root cause of problem Remove root cause of problem Prevent recurrence of problem Complete a closed-loop investigation Follow FDA emphasis Allow no more band-aid fixes! In addition, manufacturers should determine whether failure investigation procedures are being followed. Determine whether the degree to which a quality problem or nonconforming product targeted for investigation is commensurate with the significance and risk of the nonconformity. Determine whether failure investigations are conducted to determine root cause. Verify that controls exist for preventing the distribution of nonconforming product. Prevent Recurrence It is also essential to determine the actions needed to prevent problem recurrence by using information from sources such as: Nonconformance reports and rejections Complaints Internal and external audits Data and risk analyses related to operations and quality system processes Management review decisions Preventive Action Acting proactively is an essential tool in quality systems management. Tasks can include succession planning, training, capturing institutional knowledge, and planning for personnel, policy, and process changes. A preventive action program will help ensure that potential problems and root causes are identified, possible consequences assessed, and appropriate actions considered. The selected preventive action should be evaluated and recorded, and the system should be monitored for the effectiveness of the action. Problems can be anticipated and their occurrence prevented by using information from reviews of data and risk analyses associated with operational and quality system processes, and by keeping abreast of changes in scientific and regulatory requirements. Change control focuses on managing change to prevent unintended consequences. The major implementation of change control in the cgmp regulations is through the assigned responsibilities of the quality control unit. In the new guidance, change is discussed in terms of creating a regulatory environment that encourages change towards continuous January 2008 Volume 12 Number 2 45

11 CLASSIC improvement. This means a manufacturer is empowered to make changes based on the variability of materials used in manufacturing and the optimization of the process from learning over time. 2 Promote Improvement The effectiveness and efficiency of the quality system can be improved through the quality activities described in the new FDA guidance. Management may choose to use other improvement activities as appropriate; however, it is critical that senior management be involved in the evaluation of this improvement process. 2 CONCLUSION The quality systems model does not treat the five manufacturing systems as discrete entities, but instead integrates them into appropriate sections of the model. The interrelationships should be quite apparent. One of the important themes of the systems-based inspection compliance program is to be able to assess whether each of the systems is in a state of control. FDA believes that the quality systems model will also serve firms in achieving the desired state of control. FDA s goal is to describe a model for use in pharmaceutical manufacturing that can help achieve compliance with cgmp regulations, and to provide the foundation for the manufacturing systems that are linked and function within it. It should be noted that implementing an effective quality system in a manufacturing organization might require significant costs in time and resources. However, the long-term benefits of implementing a quality system will outweigh the costs. Implementation of the comprehensive quality systems model for pharmaceutical products, including biological products, will facilitate compliance with the Code of Federal Regulations (CFR) 21 parts 210 and 211. The central goals of a quality system are to ensure consistent production of safe and effective products and to ensure that these activities are sustainable. A robust quality system will promote process consistency by integrating effective knowledge-building mechanisms into daily operational decisions. Successful quality systems share the following characteristics: Science-based approaches Decisions based on an understanding of the intended use of a product Proper identification and control of areas of potential process weakness Responsive deviation and investigation systems that lead to timely remediation Sound methods for assessing risk Well-defined processes and products, starting from development and extending throughout the product lifecycle Procedures for the careful analysis of product quality Supportive management 2 Good Business Sense! Quality and productivity improvement share a common element: reduction in variability through process understanding, which implies the application of knowledge throughout the product lifecycle. Reducing variability provides continuous improvement opportunities from both public health and industry perspectives. Both good manufacturing practice and good business practice require a robust quality system. When fully developed and effectively managed, a quality system will lead to consistent, predictable processes ensuring that pharmaceuticals are safe and effective. REFERENCES 1. Pharmaceutical cgmps for the 21st Century - A Risk-Based Approach Final Report - Fall 2004: gmp/gmp2004/gmp_finalreport2004.htm 2. Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations: 3. Title 21--Food and Drugs Subchapter C Drugs: General Part 210 Current Good Manufacturing Practice In Manufacturing, Processing, Packing, or Holding of Drugs General: h.cfm?cfrpart=210&showfr=1 4. Title 21--Food and Drugs Subchapter C - Drugs: General Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals: cfdocs/cfcfr/cfrsearch.cfm?cfrpart=211&showfr=1 5. ANSI/ISO/ASQ Q : Quality Management Systems Fundamentals and Vocabulary, (American Society for Quality, 2000) 6. ANSI/ISO/ASQ Q : Quality Management Systems Requirements (American Society for Quality, 2000) 46 Journal of GXP Compliance

12 Jackelyn Rodriguez 7. Proposed Draft SG3/N15R6: Risk Management as an Integral Part of the Quality Management System: sg3/inventorysg3/sg3_pd_n15-r6.doc GXP ARTICLE ACRONYM LISTING APR Annual Product Review CAPA Corrective and Preventive Action CDRH Center for Devices and Radiological Health CFR Code of Federal Regulations cgmp Current Good Manufacturing Practice COA Certificate of Analysis DHR Device History Record FDA Food and Drug Administration GHTF Global Harmonization Task Force HACCP Hazard Analysis and Critical Control Point ISO International Organization for Standardization QS Quality System QSIT Quality System Inspection Technique QU Quality Unit WL Warning Letter ABOUT THE AUTHOR Ms. Jackelyn Rodriguez has 20 years experience in all facets of Quality Assurance and Regulatory Compliance and is currently the President of Monarch Quality Systems Solutions, a consulting firm in New Jersey. Ms. Rodriguez has published numerous compliance and validation-related articles and has been a global industry speaker and presenter on compliance topics worldwide including FDA workshops. She has worked closely with CDRH s, FDA HACCP team for both promotion of Risk Management and training to over 1000 individuals. Ms. Rodriguez has specialized in International and U.S. regulations, which define all aspects of Quality System Implementation and Auditing (FDA QSR/GMP, ISO 9001/13485, 21 CFR Parts 210 and 211, Part 820 and Part 11, cgmps for the Medical Device and Pharmaceutical Industry). Her extensive knowledge of Compliance Inspections, FDA-483s, Warning Letters, Part 11 Electronic Records and Signature, and Documentation Systems, as well as Lean Manufacturing and Six-sigma initiatives, provide her with a well rounded knowledge base, which she has actualized by implementing such systems at several U.S., Mexican, and South American companies. Ms. Rodriguez may be contacted by phone at (856) , by at Jackelynr@comcast.net, or at her Website: January 2008 Volume 12 Number 2 47