Guidance for Industry


1 Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations U.S. Department of Heal th and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluati on and Research (CBER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) September 2006 Pharmaceutical CGMPs

2 Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations Additional copies are available from: Office of Training and Communication Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 or Office of Communication, Training and Manufacturers Assistance, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 (Tel) 800-835-4709 or 301-827-1800 or Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 301-827-3800 U.S. Department of Heal th and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluati on and Research (CBER) Center for Veterinary Medicine (CVM) Office of Regulatory Affairs (ORA) September 2006 Pharmaceutical CGMP Regulations

3 Contains Nonbinding Recommendations TABLE OF CONTENTS ... 1 I. INTRODUCTION ... 1 II. BACKGROUND AND PURPOSE ... 1 Background A. Goal of the Guidance ... B. 2 ... 3 C. Scope of the Guidance Organization of this Guidance 4 D. ... MODERN QUALITY SYSTEMS ... 4 III. CGMPS AND THE CONCEPTS OF Quality ... 4 A. B. ... 4 Quality by Design and Product Development Quality Risk Management 5 C. ... CAPA (Corrective and Preventive Action) 5 D. ... ... 5 E. Change Control The Quality Unit ... 5 F. G. ... 6 Six-system Inspection Model ... 8 IV. THE QUALITY SYSTEMS MODEL Management Responsibilities ... A. 8 1. Provide Leadership ... 8 2. Structure the Organization ... 9 3. ... 9 Build Your Quality System to Meet Requirements Establish Policies, Objectives, and Plans 10 4. ... Review the System 10 5. ... ... ... 12 B. Resources General Arrangements ... 12 1. 2. ... 13 Personnel Development ... 13 3. Facilities and Equipment Control Outsourced Operations ... 4. 14 C. Manufacturing ... 15 1. Design, Develop, and Document Product and Processes ... 15 2. ... 16 Examine Inputs ... 17 3. Perform and Monitor Operations Address Nonconformities ... 4. 19 D. Evaluation Activities ... 21 1. Analyze Data for Trends ... 21 2. Conduct Internal Audits ... 21 3. Quality Risk Management ... 22 4. Corrective Action ... 22

4 Contains Nonbinding Recommendations 5. Preventive Actions ... 23 Promote Improvement ... 23 6. V. CONCLUSION ... 24 ... 25 USEFUL REFERENCE MATERIALS GLOSSARY ... 27

5 Contains Nonbinding Recommendations 1 Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations on's (FDA's) current thinking on this topic. It This guidance represents the Food and Drug Administrati does not create or confer any rights for or on any pe rson and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes iscuss an alternativ e approach, contact the FDA staff responsible for and regulations. If you want to d implementing this guidance. If you cannot identify th e appropriate FDA staff, call the appropriate number listed on the title page of this guidance. I. INTRODUCTION lp manufacturers implementing mode rn quality systems and risk This guidance is intended to he approaches to m eet the requireme nts of the Agency's current good manufacturing management s 210 and 211). The guidance describes a practice (CGMP) regulations (2l CFR part systems (QS) model, highlighting the model's consistency with the CGMP comprehensive quality regulatory requirements for manufacturing human and veterinary drugs, including biological drug products. The guidance also explains how manufacturers implem enting such quality systems can be in full compliance with parts 210 and 211. This guidance is not intended to place new expectations on manufacturers, nor to replac e the CGMP requirements. Readers are advised to always refer to parts 210 and 211 to ensu re full compliance with the regulations. FDA's guidance documents, including this guida nce, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinki ng on a topic and should be viewed only as recommendations, unless spec ific regulatory or stat utory requireme nts are cited. The use of the word in Agency guidances means that something is suggested or should recommended, but not required. II. BACKGROUND AND PURPOSE A. Background st In August 2002, the FDA announced the Pharmaceutical CGMPs for the 21 Century Initiative. In that announcement, the FDA explaine d the Agency’s intent to integrate quality systems and risk management approaches into its existing programs with the goal of encouraging industry to adopt modern and innovative manufacturing technologies. The CGMP initia tive was spurred by the fact that since 1978, when the last major revision of the CGMP regulations was published, 1 This guidance was developed by the Office of Compliance in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for Veterinary Medicine (CVM), and the Office of Regulatory Affairs (ORA). 1

6 Contains Nonbinding Recommendations g science and in our understanding of quality there have been many advances in manufacturin systems. In addition, many pharmaceutical manufacturers are already implementing com prehensive, modern quality systems and risk management approaches. This guidance is intended to help manufacturers implementing modern quality systems and risk management approaches to meet the requirements of the Agen cy's CGMP regulations. The Agency also saw a ith other non-U.S. pharmaceutical regulatory systems and with need to harmonize the CGMPs w ons. This guidance supports these goals. It FDA’s own medical device quality systems regulati also supports the objectives of the Critical Path Initiative, which intends to make the development of innovative medical products more efficient so that safe and effective therapies can reach patients sooner. The CGMPs for the 21st Century Initiative steering committee created a Quality System Guidance Development working group (QS work ing group) to compare the current CGMP regulations, which call for some specific quality management elements, to other existing quality management systems. The QS working group mapped the relationship between CGMP 2 regulations (parts 210 and 211 and the 1978 Preamble to the CGMP regulations ) and various quality system models, such as the Drug Manufact uring Inspections Program (i.e., systems-based 3 the Environmental Protection Agency's Guidance for Developing inspectional program), Quality Systems for Environmental Programs, ISO Quality Standards, other quality publications, and experience from regulatory cases. The QS working group determined that, although the CGMP regulations do provide great flexibility, they do not incorporate explicitly all of the elements that today constitute most quality management systems. The CGMP regulations and other quality management systems differ somewhat in organization and in certain constituent elements; however, they are very similar and share underlying principles. For example, the CGMP regulations More recently developed stress quality control. , and the use of risk management quality systems stress quality management, quality assurance tools, in addition to quality contro l. The QS working group decided that it would be very useful to examine exactly how the CGMP regulations and the elements of a modern, comprehensive ing world. This guidance is the result of that quality system fit together in today's manufactur examination. B. Goal of the Guidance This guidance describes a compre hensive quality systems model, which, if im plemented, will allow manufacturers to support and sustain robust, modern quality systems that are consistent onstrates how and where the elements of this with CGMP regulations. The guidance dem comprehensive model can fit within the requireme nts of the CGMP regulations. The inherent flexibility of the CGMP regulations should enab le manufacturers to implement a quality system in a form that is appropriate for their specific operations. The overarching philosophy articulated in both the CGMP regulations and in robust modern quality syste ms is: 2 See Reference #1. 3 See Reference #2. 2

7 Contains Nonbinding Recommendations Quality should be built into the product, and testing alone cannot be relied on to ensure product quality . This guidance is intended to se rve as a bridge between the 19 78 regulations and our current being part of the FDA's CGMP initiative, this understanding of quality systems. In addition to for a number of reasons: guidance is being issued • ate sectors’ mutual goal of providing a high- A quality system addresses the public and priv quality drug product to patients and prescriber system should reduce s. A well-built quality the number of (or prevent) recalls, returned or salvaged products, and defective products entering the marketplace. It is important that the CGMP regulations are ha rmonized to the extent possible with other widely • used quality management systems, incl uding ISO 9000, non-U.S. pharmaceutical quality management requirements, and FDA’s own medical device quality system regulations. This guidance serves as a first step to highlight common elements be tween the CGMP regulations and Quality Management Systems. With the globa lization of pharmaceutical manufacturing and the increasing prevalence of drug- and biologic-de vice combination products, the convergence of product types is very quality management principles across different regions and among various desirable. ems, when coupled with manufacturing process The FDA has concluded that modern quality syst • and product knowledge and the use of effective risk management practices, can handle many need for prior approval types of changes to facilities, equipment, and processes without the regulatory submissions. Manufactur ers with a robust quality system and appropriate process knowledge can implement many types of improvements . In addition, an effective quality system, by lowering the risk of manufacturing problem s, may result in shorter and fewer FDA inspections. 4 A quality system can provide the necessary framework quality by design for implementing • (building in quality from the development phase and throughout a product’s life cycle), continual improvement, and risk management in the drug ma nufacturing process. A quality system adopted by a manufacturer can be tailored to fit the specific environment, taking into account factors such as scope of operations, complexity of processes, and appropriate use of finite resources. C. Scope of the Guidance This guidance applies to manufacturers of dr ug products (finished pharmaceuticals), including for Biologics Evaluation and Res earch (CBER), the Center for products regulated by the Center ry Medicine (CVM). It may Drug Evaluation and Research (CDER), and the Center for Veterina also be useful to manufacturers of components (including active pharmaceutical ingredients) used in the manufacture of these products. This document is not intended to create new requirements for pharmaceutical manufacturing that go beyond those established in the current regulati ons, nor is the guidance intended to be a guide for the conduct of FDA inspections. Rath er, the document explains how implementing comprehensive quality systems can help manufacturers achieve compliance with 21 CFR parts 4 See ICH Q8 Pharmaceutical Development. 3

8 Contains Nonbinding Recommendations at many of the quality system elements 210 and 211. Although the QS working group found th pliance with do not. The Agency expects com correlate with specific CGMP requirements, some CGMP regulations, and FDA’s inspection program will remain focused on compliance with those regulations. D. Organization of this Guidance To provide a reference familiar to industry, th e quality systems model described in section IV of this guidance is organized — in its major secti ons — according to the structure of in ternational r sections of the model include the following: quality standards. Majo • Management Responsibilities Resources • • Manufacturing Operations • Evaluation Activities Under each of these sections the key elements found in modern quality systems are discussed. When an elem ent correlates with a CGMP regulator y requirement, that correlation is noted. In some cases, a specific CGMP regulation is discusse d in more detail as it relates to a quality system element. At the end of each section, a table is included lis ting the quality system elements of that section and the specific CGMP regulations with which they correlate. A glossary is included at the end of the document. III. CGMPS AND THE CONCEPTS OF MODERN QUALITY SYSTEMS Several key concepts are critical for any discussion of modern quality systems. The following concepts are used throughout this guidance as th ey relate to the manuf acture of pharmaceutical products. A. Quality entity, strength, purity, and other quality Every pharmaceutical product has established id the required levels of safety and effectiv eness. For the characteristics designed to ensure purposes of this guidance document, the phrase achieving quality means achieving these characteristics for a product. B. Quality by Design and Product Development means designing and developing a pr oduct and associated manufacturing Quality by design processes that will be used during product develo pment to ensure that the product consistently 5 e end of the manufacturing process. attains a predefined quality at th Quality by design, in conjunction with a quality system, provides a sound framework for the transfer of product knowledge and process understand ing from drug development to the commercial manufacturing processes and for post-development changes and optimization. The CGMP regulations, when 5 See ICH-Q8 Pharmaceutical Development. 4

9 Contains Nonbinding Recommendations rporate the concept of quality by design. This guidance describes viewed in their entirety, inco how these elements fit together. Quality Risk Management C. 6 Quality risk management is a valuable component of an effective quality systems framework. Quality risk management can, for example, help guide the setting of specifications and process parameters for drug manufacturing, assess and mitigate the risk of changing a process or tions and corrective actions. specification, and determine the ex tent of discrepancy investiga D. CAPA (Corrective and Preventive Action) CAPA is a well-known CGMP regulatory concept that focuses on investigating, understanding, and correcting discrepancies while attemp prevent their recurrence. Quality system ting to models discuss CAPA as three separate concepts, all of whic h are used in this guidance. • Remedial corrections of an identified problem • rrective action to help understa Root cause analysis with co nd the cause of the deviation and potentially prevent recu rrence of a similar problem • Preventive action to avert recurrence of a similar blem potential pro E. Change Control Change control that focuses on managing change to is another well-known CGMP concept prevent unintended consequences. The CGMP regulations provide for change control primarily through the assigned respons anufac turing ibilities of the quality control unit. Certain major m a critical product attribute or bioavailability) changes (e.g., changes that alter specifications, regulatory approval (21 CFR 314.70, 514.8, and 601.12). require regulatory filings and prior Effective change control activities (e.g., quali ty planning and control of revisions to specifications, process parameters, procedures) are key components of any quality system. In change regulatory enviro nment that encourages is discussed in terms of creating a this guidance, means a manufacturer is empowered to make change towards continual improvement. This riability of materials used in manufacturing and changes subject to the regulations based on the va process improvements resulting from knowle dge gained during a product’s lifecycle. The Quality Unit F. Many of the modern quality system concepts described here correlate very closely with the CGMP regulations (refer to the charts later in the document). Current industry practice generally divides the responsibilities of the quality c ontrol unit (QCU), as defined in the CGMP C) and quality assurance (QA) functions. regulations, between quality control (Q • QC usually involves (1) assess ing the suitability of inco ming components, containers, closures, labeling, in-process materials, and the finished products ; (2) evaluating the 6 See ICH Q9 Quality Risk Management. 5

10 Contains Nonbinding Recommendations performance of the manufacturing process to ensure adherence to proper specifications bility of each batch for release. and limits; and (3) determining the accepta of all procedures related to production • QA primarily involves (1) review and approval ciated records, and (3) auditing and and maintenance, (2) review of asso performing/evaluating trend analyses. 7 This guidance uses the term quality unit (QU) to reflect modern practice while remaining consistent with the CGMP definition is also in § 210.3(b)(15). The concept of a quality unit ons associated with all consistent with modern quality systems in ensuring that the various operati systems are appropriately planned, approved, conducted, and monitored. The CGMP regulations specifica lly assign the QU the authority to create, monitor, and implement a quality system. Su ch activities do not substitute for, or preclude, the daily acturing personnel to build quality in to the product. The QU should not responsibility of manuf a manufacturer’s organization, such as the take on the responsibilities of other units of 8 responsibilities handled by manufacturing personnel, engineer s, and development scientists. Manufacturing personnel and the QU are both critical in fulfilling the manufacturer’s responsibility to produce quality products. Other CGMP assigned responsibilities of the QU are consistent with modern quality system approaches (§ 211.22): • Ensuring that controls are implemente d and completed satisfactorily during manufacturing operations are appropriate and followed, ecifications • Ensuring that developed procedures and sp including those used by a firm unde r contract to the manufacturer • Approving or rejecting incoming ma terials, in-process ma terials, and drug products ating any unexplained discrepancies • Reviewing production records and investig ent units, Under a quality system, it is normally expected that the product and pro cess developm the manufacturing units, and the QU will remain inde pendent. In very limited circumstances, a single individual can perform both production and quality functions. That person is still menting all th e controls and reviewing the re sults of manufacture to ensure accountable for imple that product quality standards have been met. Under such circumstances, it is recommended that another qualified individual, not ation, conduct an additional, involved in the production oper periodic review of QU activities. G. Six-system Inspection Model The FDA's Drug Manufacturing Inspection Complian ce Program, which contai ns instructions to FDA personnel for conducting inspections, is a syst ems-based approach to inspection and is very 7 quality unit is used in this guidance. However, quality control unit is used when directly Generally, the term quoting parts 210 and 211. 8 See Reference #1, comment 91. 6

11 Contains Nonbinding Recommendations 9 em model presented The diagram below consistent with the robust quality syst in this guidance. e quality system and the five manufacturing shows the relationship among the six systems: th oundation for the manufacturing systems that are systems. The quality system provides the f linked and function within it. The quality system model described in this guidance does not consider the five manufacturing systems as discrete entities, but instead integrates them into appropriate sections of the model. Those familia r with the six-system inspection approach will see organizational differences in r-relationship should be readily this guidance; however, the inte apparent. One of the important themes of the systems based inspection compliance program is that you have the ability to assess whether each of the systems is in a state of control. The quality system model presented in this guidance will also serve to help firms achieve this state of control. 9 See Reference #2; This inspectional approach is currently in use by CDER and by CBER for blood and blood product inspections. CBER and CVM are developing a similar approach for drug product inspections. 7

12 Contains Nonbinding Recommendations THE QUALITY SYSTEMS MODEL IV. The goal of this section is to describe a mode l for use in pharmaceutical manufacturing that can help manufacturers comply with the plementing an CGMP regulations. It should be noted that im effective quality system in a manufacturing organization will require a significant investment of time and resources. However, we believe the long-term benefits of implementing a quality 10 system will outweigh the costs. This section describes a robust quality systems model that, if properly implemented, can provide the controls to consistently ere applicable, the of acceptable quality. Wh produce a product relationship between elements of this model and CG MP regulations is noted. At the end of each section, a table shows how the specific CGMP regulat ions correlate to the elements in the quality systems model. As already explained, many of the quality systems elements correlate closely emphasize that this gui dance is not recommending with the CGMP regulations. It is important to new regulatory requirements. The guidance is intended to provide recommendations to manufacturers who are implementing, or plan to implement, a quality systems model to help them comply with CGMP regulations. FDA re gulatory and inspectional coverage will remain focused on the specific CGMP regulations. The model is described according to four major factors: Management Responsibilities • Resources • Manufacturing Operations • Evaluation Activities • In each of the sections that follow, the specific elements of a robust m odern quality system s model are described. When elements of the qual ity systems model correlate with specific CGMP regulations, this corre lation is noted. A. Management Responsibilities Modern robust quality systems models call for manageme nt to play a key role in the design, implementation, and management of the quality system. For example, management is responsible for establishing the qua lity system structure appropri ate for the specific organization. Management has ultimate responsibility to provide the leadership needed for the successful describes management's role in developing, functioning of a quality system. This section . There is some overlap with the CGMP implementing, and managing a robust quality system regulations in this sect ion (see the table at the end of the section). 1. Provide Leadership management should dem In a robust, modern quality system, senior onstrate commitment to intaining their quality system. Quality system plans should be aligned with a developing and ma manufacturer’s strategic plans to ensure that the system is part of the manufacturer’s mission and quality strategies. For example, quality systems departments normally have equal standing with 10 See Reference #3. 8

13 Contains Nonbinding Recommendations other departments within an organization. Quality systems staff are effectively integrated into manufacturing activities and are involved in activities such as nonconformance investigations. ans. All levels of Senior managers set implementation priorities and develop action pl ma nagement can provide support of the quality system by: • Actively participating in system design, implementation, and monitoring, including system review (see IV.A.5.) • Advocating continual improvement of operations of the quality system • Committing necessary resources In a robust quality systems environment, all managers should demonstrate strong and visible support for the quality system and ensure its implementation throughout the organization (e.g., across multiple sites). All managers should encourage internal communication on quality issues at all levels in the on organization. Communicati research and development, regulatory should be ongoing among es that affect quality, with management affairs, manufacturing, and QU personnel on issu included whenever appropriate. 2. Structure the Organization management has the responsibility to When designing a robust quality system, the structure organization and ensure that the production, assigned authorities and responsibilities support quality, and management activitie s needed to produce quality products. Senior managers have the responsibility to ensure that the organization’s structure is documented. All managers have the responsibility to comm unicate employee roles, responsibilities, and within the system are defined and understood. and ensure that interactions authorities An organization also has the responsibility to give the individual who is appointed to manage the quality system the authority to detect problems and implement solutions. Usually, a senior anager administers the quality system m and ca n, thus, ensure that the organization receives prompt feedback on quality issues. 3. to Meet Requirements Build Your Quality System Implementing a robust quality system can help ensure compliance with CGMP regulations nder the quality systems model, ted to drug safety, identity, strength, quality, and purity. U rela re that the quality system that is designed and that senior managers ensu the Agency recommends implemented provides clear organizational guidan ce and facilitates systematic evaluation of issues. For example, according to the model, when documenting the implementation of a quality system, the following should be addressed: including any outsourcing (see IV.B.4.) The scope of the quality system, • The quality standard th at will be followed • The manufacturer’s policies to implemen t the quality systems criteria and the • supporting objectives (see IV.A.4.) 9

14 Contains Nonbinding Recommendations The procedures needed to establish • and maintain the quality system pproach that a formal process be established It is recommended under a modern quality systems a to change procedures in a controlled manner It is also recommended that, when operating under . a quality system, manufa cturers develop and docum ent control procedures to complete, secure, operational and quality protect, and archive records, including data, wh ich provide evidence of system activities. This approach is consiste nt with the CGMP regulations, which require manufacturers to establish and follow scientifically sound and a ppropriate written controls for specifications, plans, and procedures that direct operational and quality system activities and to ensure that these directives are accurate, appropr iately reviewed and approved, and available for use (see the CGMPs at § 211.22 (c) and (d)). Establish Policies, Objectives, and Plans 4. Policies, objectives, and plans under a modern qual ity system provide the means by which senior itment to quality to all levels m anagers articulate their vision of and comm of the organization. Under a quality system, senior managem ent should incorporate a strong commitment to quality into the organizational mission. Senior managers should develop an organizational quality is mission; commit to policy that aligns with th nd improving the quality meeting requirements a policy. Under a quality system, to make the system; and propose objectives to fulfill the quality o, and understood by, personne l and contractors (if policy relevant, it must be communicated t applicable) and revised, as needed. Managers operating within a quality system shoul d define the quality obj ectives identified for anageme nt should ensure that the quality objectives implementing the quality policy. Senior m on (and other levels as needed) through a for are created at the top level of the organizati mal quality planning process. Objectives are typi cally aligned with the manufacturer’s strategic plans. A quality system seeks to ensure that managers support the objectives with necessary resources and have measurable go als that are monitored regularly. nagers would use quality planning to identify and allocate Under a quality systems approach, ma resources and define methods to achieve the quality objectives. Quality system plans should be documented and communicated to personnel to ensure awareness of how their operational activities are aligned with st rategic and quality goals. 5. Review the System System review is a key component in any r obust quality system to ensure its continuing , senior managers should suitability, adequacy, and effectiveness. U nder a quality system conduct reviews of the quality system’s performa nce according to a plan ned schedule. Such a review typically includes assessments of the pr ocess, product, and customer needs (in this section, customer is defined as the reci pient of the produc t and the product is the goods or services provided). Under a quality systems a pproach, a review should consider at least the following: • The appropriateness of the quality policy and objectives • The results of audits and other assessments 10

15 Contains Nonbinding Recommendations • Customer feedback, including complaints • The analysis of data trending results • The status of actions to prevent a potential problem or a recurrence • Any follow-up actions from previous management reviews onment that may affect the quality system • Any changes in business practices or envir (such as the volume or type of operations) • Product characteristics meeting the customer’s needs stems, reviews should take place more When developing and implementing new quality sy frequently than when the system has matured. Outside of scheduled reviews, the quality system nda item in general m should typically be included as a standing age anagement meetings. In addition, a periodic review performed by a qualif ied source, external to the organization, may also be useful in assessing the suitab ility and effectiveness of the system. Review outcomes typically include: Improvements to the • quality system and related quality processes • Improvements to manufacturing processes and products • of resources Realignment Under a quality system, the results o f a management review would typically be recorded. Planned actions should be implemented using nd preventive action and effective corrective a change control procedures. The following table shows how the CGMP regulati ons correlate to specific elements in the should always refer to the specific Manuf acturers quality systems model for this section. regulations to make sure they are in compliance. 11

16 Contains Nonbinding Recommendations 21 CFR CGMP Regulations Related to Management Responsibilities Quality System Element Regulatory Citations — 1. Leadership 2. Structure Establish quality function: § 211.22 (a) (see definition § 210.3(b)(15)) Notification: § 211.180(f) 3. Build QS QU procedures: § 211.22(d) QU procedures, specifications: § 211.22(c), with reinforcement in: §§ 211.100(a), 211.160(a) QU control steps: § 211.22(a), with reinforcement in §§ 211.42(c), 211.84(a), 211.87, 211.101(c)(1), 211.110(c), 211.115(b), 211.142, 211.165(d), 211.192 QU quality assurance; review/investigate: §§ 211.22(a), 211.100(a-b) 211.180(f), 211.192, 211.198(a) Record control: §§ 211.180(a-d), 211.180(c), 211.180(d), 211.180(e), 211.186, 211.192, 211.194, 211.198(b) 4. Establish Policies, Objectives and Plans Procedures: §§ 211.22(c-d), 211.100(a) 5. System Review Record review: §§ 211.100, 211.180(e), 211.192, 211.198(b)(2) B. Resources Appropriate allocation of resources is key to cr eating a robust quality syst em and complying with the CGMP regulations. This sec of resources in developing, implementing, tion discusses the role and managing a robust quality system that complies with the CGMP regulations. 1. General Arrangements ces should be allocated for quality system and Under a robust quality system, sufficient resour nior management, or a designee, should be operational activities. Under the model, se responsible for providing adequa te resources for the following: • To supply and maintain the appropriate f acilities and equipmen t to consistently manufacture a quality product • are suitable for their intended purpose To acquire and receive materials that produce the finished drug product For processing the materials to • • For laboratory analysis of the finished drug product, including colle ction, storage, and examination of in-process, stability, and reserve samples 12

17 Contains Nonbinding Recommendations 2. Personnel Development Under a quality system, senior manageme nt should support a problem-solving and rs should encourage communication by creating communicative organizational culture. Manage an environment that values em ns and acts on suggestions for improvement. ployee suggestio groups to share ideas to improve procedures Management should also develop cross-functional and processes. In a quality system, personnel should be qualified to do the operations that are assigned to them in accordance with the n ature of, and potential risk of, their operational activities. Under a anagers should define appropr iate qualifications for each position to help quality system, m signed appropriate responsibilit ensure that individuals are as ies. Personnel should also activities on the product and th understand the effect of their e customer. Although QU personnel should not take on the responsibilities of other units of the organization, these personnel should be selected based on their sc ientific and technical understa nding, product knowledge, process ilities to appropriate ly execute certain quality functions (this knowledge and/or risk assessment ab so found in the CGMP regulations, which identify specific quality systems feature is al qualifications, such as educa tion, training, and experience or any combination thereof (see § 211.25(a) and (b)). Under a quality system, continued training is cr itical to ensure that the employees remain proficient in their operational functions and in their understanding of CGMP regulations. Typical quality systems training should address the policies, processes, procedures, and written activities, the product/se rvice, the quality system, and the instructions related to operational unication, change, behavior). Under a quality desired work culture (e.g., team building, comm ould focus on both the employees’ specific job system (and the CGMP regulations), training sh regulatory requirements. functions and the related CGMP Under a quality system, managers are expected to estab lish 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/or re-training • ent, it is important that managers verify that When operating in a robust quality system environm skills gained plemented in day-to-day performance. from training are im Facilities and Equipment 3. Under a quality system, the technical experts (e.g., engineers, development scientists), who have an understanding of pharmaceutical science, risk f actors, and manufacturing processes related to the product, are responsible for defining specif ic facility and equipment requirements. 13

18 Contains Nonbinding Recommendations Under the CGMP regulations, the quality unit ( QU) has the responsibility of reviewing and approving all initial design criteria and procedures pertaining to facilities and equipment and any subsequent changes (§ 211.22(c)). qualified, calibrated, cleaned, and maintained Under the CGMP regulations, equipment must be Note that the CGMP nd mix-ups (§§ 211.63, 211.67, 211.68). to prevent contamination a regulations require a higher standard fo r calibration and maintenance than most non- pharmaceutical quality system models. The CGMP regulations place as much emphasis on process equipment as on testing equipm ent (§§ 211.160, 211.63, 211.67, and 211.68) while most 11 quality systems focus only on testing equipment. 4. Control Outsourced Operations act to perform the operational processes ond party under a contr Outsourcing involves hiring a sec example, a manufacturer may hire inherent responsibilities. For that are part of a manufacturer’s bel or perform CGMP regulatory another firm to package and la training. Quality systems call for contracts (quality agreements) that clearly describe the materials or service, quality specification responsibilities, a echanisms. nd communication m ract firm is qualified before Under a quality system, the manufacturer should ensure that a cont signing a contract with that firm . The contract firm’s personnel should be adequately trained and monitored for performance according to their quality system, and the contract firm's and not conflict. It is critical in a quality system contracting manufacturer’s quality standards should to ensure that the management of the contractor be familiar with the specific requirements of the contract. However, under the CGMP requirement s, the manufacturer’s QU is responsible for approving or rejecting products or services provided under a contract (§ 211.22(a)). As the following table illustrates, the CGMP regul ations are consistent with the elements of a wever, manufacturers should always refer to the quality system in many areas in this section. Ho ey are complying with all regulations. specific regulations to ensure that th 21 CFR CGMP Regulations Related to Resources 21 CFR CGMP Regulations Related to Resources Quality System Element Regulatory Citation Quality System Element Quality System Element Regulatory Citation Quality System Element Regulatory Citation Regulatory Citation — — — — 1. General Arrangements 1. General Arrangements 2. Develop Personnel Qualifications: § 211.25(a) Qualifications: § 211.25(a) 2. Develop Personnel Staff number: § 211.25(c) Staff number: § 211.25(c) Staff training: § 211.25(a-b) Staff training: § 211.25(a-b) Buildings and facilities: §§ 3. Facilities and Equipment 211.22(b), 211.28(c), Buildings and facilities: §§ 211.22(b), 211.28(c), 3. Facilities and Equipment 173 211.58, 211. 211.42 – 211.42 – 211.58, 211.173 Equipment: §§ 211.63 – 211.72, 211.105, 211.160(b)(4), Equipment: §§ 211.63 – 211.72, 211.105, 211.160(b)(4), 211.182 211.182 Lab facilities: § 211.22(b) Lab facilities: § 211.22(b) 11 See Reference # 4. 14

19 Contains Nonbinding Recommendations Consultants: § 211.34 4. Control Outsourced Operations Outsourcing: § 211.22(a) Manufacturing C. Significant overlap exists between the elements of a quality system and the CGMP regulation requirements for manufacturing ope emphasize again that FDA’s rations. It is important to remain based on the CGMP regulations. When enforcement programs and inspectional coverage e CGMP regulations, the guidance quality system elements in this section do not correlate to th makes recommendations to help facilitate compliance with the CGMP regulations. The language in this section has been tailored to th e pharmaceutical manufacturing environment. Design, Develop, and Document Product and Processes 1. In a modern quality systems manufacturing enviro nment, the significant characteristics of the product being manufactured should livery, and control should be be defined from design to de exercised over all changes. d manufacturing processes and procedures — In addition, quality an and changes to them — must be defined, approved, and controlled (§ 211.100). It is important to establish responsibility for designing or changing products. Documenting processes, associated sure that sources of variability are identified. controls, and changes to these processes will help en Documentation includes: • Resources and facilities used Resources and facilities used • Procedures to carry out the process • Identification of the process owner who will maintain and update the process as needed • Identification and control of important 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 process, functions, or personnel As discussed under section IV.A., above, the mode l calls for managers to ensure that product ined by the appropriate technical experts (e.g., specifications and process parameters are determ engineers, development scientists). In the pharmaceutical environment, experts would have an understanding of pharmaceutical science, equipmen ess types and of how t, facilities, and proc variations in materials and processes can ultimately aff ect the finished product. Packaging and labeling controls, critical stages in the pharmaceu tical manufacturing process, are not specifically addressed in quality systems models. However, the Agency recommends that manufacturers always refer to th e packaging and labeling control re gulations at § 211 Subpart G. In addition — and this is consistent with modern quality systems — FDA recommends that, as 15

20 Contains Nonbinding Recommendations production, the controls fo r all processes within part of the design process, before commercial and documented in written procedures. The the packaging and labeling system be planned procedures should outline quality control activities and the responsible positions. Specifications and controls for the packaging and labeling ma terials should also be determined before commercial production. Distinct labe ls with discriminating features for different products, such as a product marketed with different strengths, should be included to prevent mislabeling and resulting recalls. 2. Examine Inputs In a modern quality systems model, the term input includes any ma terial th at goes into a final product, no matter whether the material is purc hased by the manufacturer or produced by the manufacturer for the purpose of processing. can include item s such as components Materials (e.g., ingredients, process water, and gas), containe rs, and closures. A robust quality system will ess are reliable because quality controls will have ensure that all inputs to the manufacturing proc tion, storage, and use of all inputs. been established for the receipt, produc The CGMP regulations require eith er testing or use of a certificat e of analysis (COA) plus an ing. In the preamble to the nufactur identity analysis (§ 211.84) for th e release of materials for ma 12 CGMP regulations, these requirements were explicitly interpreted. The preamble states that reliability can be validated by conducting tests or examinations and comparing the results to the supplier’s COA. Sufficient initial tests should be done to establis h reliability and to determine a ssential element of purchasing controls, it is schedule for periodic reassessment. As an e recommended that data trends for acceptance and rejection of materials be analyzed for 13 information on supplier performance. The quality systems approach also calls for periodic auditing of suppliers based on risk can observe the testing or examinations conducted assessment. During the audit, a manufacturer of the supplier’s COA. An audit shou by the supplier to help determine the reliability ld also quality system to ensure that reliability is include a systematic examination of the supplier’s maintained. It is recommended that a combination approach be used (i.e., verify the suppliers' and audits of the supplier). Under a quality systems approach, if full COA through analysis cover the supplier’s analysis (i.e., a specific analytical testing is not done, the audit should identity test is still re quired under § 211.84(d)(2)). ocedures should be established to verify that materials are Under a quality systems approach, pr from qualified sources (for appli cation and licensed products, certain sources are specified in the submissions). Procedures should also be estab lished to encompass the acceptance, use, or the rejection and disposition of materials produced by the facility (e.g., purified water). Systems that produce these in-house materials should be desi gned, maintained, qualified, and validated where the mate rials meet their acceptance criteria. appropriate to ensure that 12 See Reference #1, comment 239. 13 The Agency recommends that manufacturers have a measure of the variability of materials that could affect their process controls. For example, certain changes in physical properties may aff ect the process, which may affect a finished product’s dissolution characteristics. 16

21 Contains Nonbinding Recommendations In addition, it is recommended that changes to materials (e.g., specification, supplier, or nge control system (certain changes require materials handling) be implemented through a cha review and approval by the QU (§ 211.100(a)). It is also important to have a system in place to respond to changes in materials from suppliers so that necessary adjustm ents to the process can be made and unintended consequences avoided. 3. Perform and Monitor Operations An important purpose of implementing a quality syst ems approach is to enable a manufacturer to rform, and monitor operations (§ 211.100(a)) and more efficiently and effectively validate, pe te. The goal of establishing, ensure that the controls are scientifically sound and appropria adhering to, measuring, and documen ting specifications and process parameters is to objectively assess whether an operation is meeting its desi gn and product performanc e objectives. In a rols should be designed to ensure that the robust quality system, production and process cont tity, strength, quality, finished products have the iden and purity they purpor t or are represented to possess (see, e.g., § 211.100(a)). In a modern quality system, a design concept established during product development typically odification. matures into a commercial design after process experimentation and progressive m Risk manageme nt can help identify areas of pro cess weakness or higher risk and factors that can ibutes that should receive incr eased scrutiny. The FDA recommends influence critical quality attr trate that a fundamentally sound design has been that scale-up studies be used to help demons fully realized. A sufficiently robust manuf acturing process should be in place prior to to transfer commercial production. With proper design (see IV.C .1.) and reliable mechanisms process knowledge from development to commercial production, a manufacturer should be able 14 to validate the ma nufacturing process. Conformance batches provide initial proof that the design of the process produces the intended product quality. Sufficient testing data will provide essential information on performance of the new process, as well as a mechanism for continual improvement. Modern equipment with the potent ial for continual monitoring and control can further enhance this knowledge base. Although in itial commercial batches can provide evidence 15 should be the entire product life cycle ity and consistency of the process, to support the valid 16 the quality system. provement mechanisms in addressed by the establishment of continual im approach, process validation is not a one-time Thus, in accordance with the quality systems event, but an activity that cont inues throughout a product’s life. As experience is gained in commercial pr oduction, opportunities for pr ocess improvements ma y become evident. (CGMP regulations § 211.180 require the review and evaluation of records to determine the need for any change. These reco rds contain data and in formation from production control systems should provide a that provide insight into the product’s state of control. Change 14 See Reference #5. 15 Even with good design and development work, initial conformance batches will provide confidence that future batches will meet specifications only if the process is repeated within defined operating parameters, equipment tolerances, personnel practices, environmental attributes, and material quality. 16 See Reference #6. 17

22 Contains Nonbinding Recommendations tation of technically sound manufacturing dependable mechanism for prompt implemen improvements.) Under a quality system, written procedures a ollowed and deviations from them are justified re f and documented (CGMP requires th is; see § 211.100(b)) to ensure that the manufacturer can trace the history of the product, as appropriate, concerning personnel, materials, equipment, and chronology and that processes for product release are complete and recorded. Both the CGMP regulations (§ 211.110) and qual ity systems models call for the monitoring of critical processes that may be responsible for causing variability during production. For exam ple: • rson (§ 211.188). Process steps can also be Process steps must be verified by a second pe using a validated computer sy stem. Batch production records must be performed prepared contemporaneously with each phase of production (§ 211.100(b)). Although time limits for production can be established when they are important to the quality of the § 211.111), the manufacturer should have the finished product (CGMP addresses this; see ability to establish production controls us ing in-process parameters that are based on desired process endpoints measured using real time testing or monitoring apparatus (e.g., blend until mixed vs. blend for 10 minutes). • Procedures must be in place to prevent objectionable microorganisms in finished products not required to be st erile and to preven t microbial contamination of finished ust be validated for sterile drugs products purported to be sterile . Sterilization processes m 17 (§ 211.113(b)). Manufacturing processes must c onsistently meet their parame ters, and in-process materials must meet acceptance criteria or limits (§ 211.11 0(b) and (c)) so that, ultimately, finished pharmaceutical products will meet their acceptan ce criteria. Under a quality system, selected data are used to evaluate the quality of a pro cess or product. In addi tion, data collection can provide a means to encourage and analyze potential suggestions for improvement. A quality systems approach calls for the manufacturer to develop procedures that monitor, measure, and analyze the operations (incl uding analytical methods and/ or statistical techniques). Monitoring of the process is important due to the limitations of testing. Knowledge continues to accumulate from development through the entire commercial life of a product. Significant unanticipated variables should be detected by a well-managed quality system and revisited as needed to refine operational adjustments implemented. Procedures should be experience and helps design based on new knowledge. Process understanding increases with tinual improvement. When implementing data identify when change will lead to con collection procedures, consider the following: • Are data collection methods documented? • will the data be collected? When in the product life cycle • How and to whom will measurement and monitoring activities be assigned? • atory data be performed? When should analysis and evaluation (e.g. trending) of labor (see IV.D.1) 17 See Reference #7. 18

23 Contains Nonbinding Recommendations What records should be collected? • warranted when data analysis A modern quality system approach indicates that change control is nt. Changes to an established process must ation reveals an area fo r improveme or other inform be controlled and documented to ensure that desire d attributes for the finished product will be met (§ 211.100(a)). Change control with regard to pharmaceuticals is addressed in more detail in the CGMP When developing a pr ocess change, it is important to keep the process design and regulations. scientific knowledge of the product in mind. If major design issues are encountered through process experien ce, a firm may want to revisit th e adequacy of the design of the manufacturing facility (§ 211.42), the design of (§ 211.63), the design of the the manufacturing equipment the design of laborator production and control procedures (§ 211.100), or y controls (§ 211.160). When implementing a change, its effect shoul d be determined by monitoring and evaluating those specific elements that may be affected based on an understanding of the process. This approach allows the steps taken to implement a change and the effects of the change on the ation of risk analysis process to be considered systematically. Applic may facilitate evaluating the potential effect of the change. Evaluating the e ffects of a change can en tail additional tests or examinations of subsequent batches (e.g., additional in-process testing or additional stability studies). The quality system elements identified in this guidance, if implemented and maintained, will help a manufacturer manage change and implement continual improvement in manufacturing. approach, procedures should be in place to ensure the accuracy of test Under a quality systems of specification may be due to results. Test results that are out testing problems or manufacturing problems and should be investigated. Any invalidation of a test re sult should be scientifically sound and justified. at prior to completion of manufacturing, the To maintain quality, the Agency recommends th anufacturer should consider stor age and shipment requirements to meet special handling needs m (in th e case of pharmaceuticals, one example might be refrigeration). Under a quality system, trends should be continually identified and evaluated. One way of accomplishing this is the use of statistical process control. The information from trend analyses before they become onitor quality, id entify potential variances can be used to continually m problems, bolster data already collected for the annual review, and facilitate improvement ability assessment can serve as a basis for throughout the product life cycle. Process cap determining the need for changes that can resu lt in process improvements and efficiency (see IV.D.1.). 4. Address Nonconformities quality system is handling nonconformities and/or deviations. The A key component in any investigation, conclusion, and follow-up must be documented (§ 211.192). To ensure that a product conforms to requirements and expectations, it is important to measure the process and the product attributes (e.g., speci fied control parameters, streng th) as planned. Discrepancies may be detected during any stage of the process or during qualit y control activities. Not all discrepancies will result in product defects; how ever, it is important to document and handle 19

24 Contains Nonbinding Recommendations critical when a discrepancy screpancy investigation process is discrepancies appropriately. A di is found that affects product qual ity (CGMP also requires this; see § 211.192). In a quality system, it is important to devel op and docum ent procedures that define who is recording non-conformities, investigating responsible for halting and resuming operations, r a quality system, if a product or process does discrepancies, and taking remedial action. Unde not meet requirements, it is essential to identif y and/or segregate the pr oduct so that it is not action can include any of the following: distributed to the customer. Remedial • Correct the non-conformity • to proceed with ju With proper authorization, allow the product stification of the conclusions regarding the problem’s impact • Use the product for another application where the deficiency does not affect the products’ quality Reject the product • The corrected product or process should also be re-examined for conformance and assessed for ity is the significance of the non- conformity (see, e.g., § 211.115). If the non-conform significant, based on consequences to process co ntrol, p rocess efficiency, product quality, safety, it is important to evaluate ho efficacy, and product availability, w to prevent recurrence (see meet requirements has been released, the product IV.D.4.). If an individual product that does not 18 can be recalled. Customer complaints must be reviewed and then investigated if a discrepancy is identified (§ 211.198). The following table shows how the CGMP regulati ons correlate to specific elements in the quality system s model. Manufacturers should always refer to the specific regulations to ensure that they are complying with all regulations. 18 See 21 CFR Part 7. 20

25 Contains Nonbinding Recommendations 21 CFR CGMP Regulations Related to Manufacturing Operations Regulatory Citation Quality System Element 1. Design and Develop Product and Processes Production: § 211.100(a) – 211.94, 211.101, 2. Examine Inputs Materials: §§ 210.3(b), 211.80 211.122, 211.125 3. Perform and Monitor Operations 211.110, 211.111, Production: §§ 211.100, 211.103, 211.113 QC criteria: §§ 211.22(a-c), 211.115(b), 211.160(a), 211.165(d), 211.188 211.22 (a), 211.84(a), 211.87, QC checkpoints: §§ 211.110(c) 4. Address Nonconformities Discrepancy investigation: §§ 211.22(a), 211.100, 211.115, 211.192, 211.198 Recalls: 21 CFR Part 7 D. Evaluation Activities As in the previous section, the elements of a quality system correlate closely with the requirements in the CGMP regulations. See the ta ble at the end of the section for the specifics. 1. Analyze Data for Trends Quality systems call for continually monitoring trends and improving systems. This can be achieved by monitoring data and informati on, identifying and resolving problems, and eventing problems. anticipating and pr Quality systems procedures involve collecting data from monitoring, measurement, complaint handling, or other activities, and tr acking this data over time, as a ppropriate. Analysis of data can provide indications that controls are losing e ffectiveness. The information generated will be essential to achieving problem resoluti on or problem prevention (see IV.D.3.). Although the CGMP regulations (§ 211.180(e)) require product review on at least an annual basis, a quality systems approach calls for tren ding on a more frequent basis as determined by risk. Trending enables the detec tion of potential problems as early as possible to plan corrective and preventive actions. Another important conc ept of modern quality systems is the use of trending to examine processes as a whole; this is consistent with the a nnual review approach. Trending analyses can help focus internal audits (see IV.D.2.). 2. Conduct Internal Audits A quality systems approach calls for audits to be conducted at planned intervals to evaluate effective implementation and maintenance of the quality system and to determine if processes and products meet established parameters and sp ecifications. As with other procedures, audit 21

26 Contains Nonbinding Recommendations ensure that the planned audit schedule takes procedures should be developed and documented to tivities, the results of previous into account the relative risks of the various quality system ac audit the complete syst audits and corrective actions, and the need to em. Procedures should describe how auditors are trained in objective evidence gathering, their responsibilities, and should also define auditing ac auditing procedures. Procedures tivities such as the scope and me rs, and audit conduct (audit plans, opening thodology of the audit, selection of audito meetings, interviews, closing meeting and reports). It is critical to maintain records of audit findings and assign responsibility for follow- up to prevent problems from recurring (see IV.D.3.). The quality systems model calls for m anagers who are responsible for the areas audited to take timely action to resolve audit findings and ensure that follow-up actions are completed, verified, and recorded. (FDA’s policy is to refrain from both reviewing and copying reports or records 19 that result from internal aud its per Compliance Policy Guide 130.300. ) 3. Quality Risk Management Effective decision-making in a quality syst ems environment is based on an informed ing of quality issues. Elements of risk s hould be considered relative to intended use of understand a product, and in the case of pharmaceuticals, patient safety and ensu ring availability of me dically necessary drug products. Management s hould assign priorities to activities or actions obability of occurrence of harm and of based on an assessment of the risk including both the pr the severity of that harm. It is important to engage appropriate pa rties in assessing the risk. Such parties include customers, appropriate manufacturing personnel, and other stakeholders. Implementation of quality risk management in cludes assessing the risks, selecting and implementing risk management controls commensura te with the level of risk, and evaluating the rative process, it should results of the risk management efforts. Since ri sk management is an ite at changes the need for, or nature of, risk be repeated if new information is developed th management. In a manufacturing quality system sk management is used as a tool in the s environment, ri development of product specifications and critical process parameters. Used in conjunction with helps manage and control change. process understanding, quality risk manageme nt 4. Corrective Action Corrective action is a reactive tool for system improvement to ensure that significant problems do not recur. Both quality systems and the CGMP regulations emphasize corrective actions. or procedures to be developed and documented to ensure that Quality systems approaches call f the need for action is evaluated relevant to th e possible consequences, the root cause of the problem is investigated, possible actions are de termined, a selected action is taken within a defined timeframe, and the effectiveness of the action taken is evaluated. It is essential to document corrective actions taken (CGM P also requires this; see § 211.192). will reduce the likelihood of a problem recurring. It is essential to determine what actions Examples of sources that can be used to ga ther such information include the fo llowing: 19 See Reference #8. 22

27 Contains Nonbinding Recommendations • s and rejections Nonconformance report • Returns • Complaints • Internal and external audits • sk assessment related to oper ations and quality system processes Data and ri • Management review decisions 5. Preventive Actions Being proactive is an essential tool in quality systems management. Succession planning, capturing institutiona personnel, policy, and process l knowledge, and planning for training, changes are preventive actions that will help en sure that potential problems and root causes are identified, possible consequences assesse d, and appropriate actions considered. should be The selected preventive action should be eval uated and recorded, and the system oblems can be anticipate monitored for the effectiveness of the action. Pr d and their occurrence prevented by reviewing data and analyzing risks associated with operational and quality system in scientific developments and regulatory processes, and by keeping abreast of changes requirements. 6. Promote Improvement The effectiveness and efficiency of a quality system can be improved through the quality activities described in this guidance. Management ma y choo se to use other improvement activities as appropriate. It is be involved in the evaluation of critical that senior management this improvement process (see IV.D.3.). The following table shows how the CGMP regulati ons correlate to specific elements in the quality systems model for this section. Manufacturers should always refer to the specific to make sure they ar e complying with all regulations. regulations 23

28 Contains Nonbinding Recommendations 21 CFR CGMP Regulations Related to Evaluation Activities Quality System Element Regulatory Citation 1. Analyze Data for Trends Annual Review: § 211.180(e) 2. Conduct Internal Audits -- 3. Risk Assessment 4. Corrective Action D iscrepancy investigation: §§ 211.22(a), 211.192 5. Preventive Action — 6. Promote Improvement § 211.110 V. CONCLUSION Implementation of a comprehensive quality systems model for human and veterinary pharmaceutical products, including biological pro ducts, will facilitate compliance with 21 CFR parts 210 and 211. The central goal of a quality system is the consistent production of safe and effective products and ensuring that these activit ies are sustainable. Quality professionals are aware that good intentions alone will not en sure good products. A robust quality system will promote process consistency by integrating eff ective knowledge-building mechanisms into daily operational decisions. Specifically, successf ul quality systems share the following characteristics, each of which ha s been discussed in detail above: • Science-based approaches of the intended use of a product • Decisions based on an understanding Proper identification and control of areas of potential process weakness • Responsive deviation and investigation syst ems that lead to timely remediation • • Sound methods for assessing and reducing risk Well-defined processes and products, st • arting from development and extending throughout the product life cycle • Systems for careful analysis of product quality Supportive management (philosophically and financially) • Both good manufacturing practice and good busine ss practice require a r obust quality system. When fully developed and effectively managed, a quality system will lead to consistent, predictable processes that ensure that pharmaceutic als are safe, effective, and available for the consumer. 24

29 Contains Nonbinding Recommendations USEFUL REFERENCE MATERIALS 1978 Preamble to the Good Manufacturi ng Practice F 1. inal Regulations – Federal Register Docket No. 73N-0339] 2. CPGM 7356.002 Compliance Program – Drug Manufacturing Inspections rd 3. Quality Planning and Analysis, 3 McGraw-Hill, New Ed. by J.M. Juran, F.M. Gryna ( York, N.Y. 1993) ANSI/ISO/ASQ Q9000-2000: Quality management systems – Fundamentals and vocabulary, 4. (American Society for Quality, 2000) 5. Guideline of General Principles of Process Validation , May 1987 – Process Validation Requirements for Drug 6. FDA Compliance Policy Guide 7132c.08 Products and Active Pharmaceutical Ingred ients Subject to Pre-Market Approva l, updated 03-12-2004 – e_ref/cpg/cpgdrg/cpg490-100.html Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing Current 7. – September 2004. See also the draft guidance on Good Manufacturing Practice Out-of-Specification ( OOS) Test Results for Ph armaceutical Production. investigating 8. FDA Compliance Policy Guide Sec. 130.300, FDA Access to Results of Quality Assurance Program Audits and Inspections , (CPG 7151.02) pg/cpggenl/cpg130-300.html Criteria for Performance Excellence, Business 9. (Baldrige National Quality Program, NIST files/2003_Business_Criteria.pdf 2003) 10. Quality management systems – Requirements (American ANSI/ISO/ASQ Q9001-2000: Society for Quality, 2000) 11. Quality management systems – Guidelines for performance ANSI/ISO/ASQ Q9004-2000: improvement (American Society for Quality, 2000) ANSI/ISO 12. 17025-1999: General requirements for the competence of testing an d calibration laboratories (American Society for Quality, 1999) 13. CMMI-SE/SW, V1.1: Capability Maturity Model Integr ation for Systems Engineering and Software Engineering, Staged Representation (Software Engineering Institute, Carnegie ents/02.reports/pdf/02tr002.pdf Mellon University, 2002) The Balanced Scorecard Institute: 14. 15. Guidance for Developing Quality Systems for Environmental Program (EPA QA/G-1, Nov 2002) ity/qs-docs/g1-final.pdf 16. Guidance for Industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (U.S. Department of Health and Human Services/ Food and Drug Administration, August 2001) . 25

30 Contains Nonbinding Recommendations Good Manufacturing Practices for Pharm Products: Main Principles (World Health 17. aceutical port Series, No. 908, 2003) Organization Technical Re ibrary/qsm/trs908/trs908-4.pdf 18. Procedures For The Implementation of Th e Federal Managers’ Fi nancial Integrity Act ; (FMFIA) FDA Staff Manual Guide 2350.1) ( 19. Managing the Risks from Medical Product Use: Creating a Risk Management Framework (U.S. FDA, 1999) 20. Framework for Environmental Health Risk Assessment – Final Report, Vol.1 (Presidential/Congressional Commission on Risk Assessment and Risk Management, 1997) 21. Report on FDA Quality System Framework for Pharmaceutical Product Regulation Activities; (Quality System Framework Subcommittee, December 2003) (Clemson University, 1995) 22. Tutorials for Continuous Quality Improvement 23. Variation Risk Management – Focusing Qua lity Improvement in Product Development and Products by Anna C. Thornton (John Wiley and Sons, Inc.; Hoboken, New Jersey, 2004 24. Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products – 25. Chapter 3, “Quality Management in the American Pharmaceutical Industry,” in Pharmaceutical Quality, Ed. by R. Prince (DHI Pub lishing, River Grove, IL, 2004) 26

31 Contains Nonbinding Recommendations GLOSSARY To gain a common understanding of a quality sy stems approach, the following terms are used throughout the guidance. Annual Rev standards – An evaluation, conducted at least annua lly, that assesses the quality iew of each drug product to determine the need fo r ch anges in drug product specifications or manufacturing or control procedures – Corrective and preventive ac tion: A systematic approach that includes actions needed CAPA to correct (“correction”), prevent recurrence ( “corrective action”), and eliminate the cause of potential nonconforming product and other quali ty problems (preventive action) (21CFR 820.100) Continual Improvement – Ongoing activities to evaluate and positively change products, processes, and the quality system to increase effectiveness – Repair, rework, or adjustment relating to the disposition of an existing discrepancy Correction – Action taken to eliminate the causes Corrective Action of an existing discrepancy or other undesirable situation to prevent recurrence Customer – A person or organization (internal or ex ternal) that receives a product or service anywhere along the pr oduct’s life cycle Discrepancy requirement; may be range; an unfulfilled – Datum or result outside of the expected mity, defect, deviation, out-o f-specification, out-of-limit, out-of-trend called non-confor Dam age to health, including the damage that can occur from the loss of product quality Harm – or availability A deficiency in a characteristic, produc t specification, process parameter, Non-conformity – procedure that rende rs the quality of a product unaccep table, indeterminate, or not record, or according to specified requirements Action taken to eliminate the cause of a potential disc repancy or other – Preventive Action undesirable situation to prev ent such an occurrence Product/Service – The intended results of activities or processes; products/services can be tangible or intangible Quality – A measure of a product’s or se rvice’s ability to satisfy the customer’s stated or im plied needs Quality Assurance – Proactive and retrospective activ ities that provide confidence that requirements are fulfilled 27

32 Contains Nonbinding Recommendations – The steps taken during the Quality Control generation of a product or se rvice to ensure that it uct or service is reproducible meets requirements and that the prod – Accountability for the successful im plementatio Quality Management n of the quality syst em – Specific measurable activities or proc Quality Ob jectives esses to meet the intentions and directions as defined in the quality policy Quality P lan – The documented result of quality planni ng that is disseminated to all relevant levels of the organization quality objectives and defines the anagement activity that sets – A m Quality P lanning operational the resources needed to fulfill the objectives and/or quality system processes and – A statement of intentions and direc tion issued by the highest level of the Quality Po licy organization related to satisfying cus It is similar to a strategic direction that tomer needs. communicates quality expectations that the organization is striving to achieve. Quality Sys tem tices that define management responsibilities for – Formalized business prac , and resources needed to fulfill product/service organizational structure, processes, procedures requirements, customer satisfaction, and continual improvement Quality Unit – A group organized within an organization to promote quality in general practice Risk – The combination of the probab ility of occurrence of harm a nd the severity of that harm Risk Assessment A systematic process for organizing info rmation to support a risk decision – within a risk mana onsists of the identification of that is made gement process. The process c hazards and the analysis and ev aluation of risks associated wi th exposure to those hazards. – T he systematic application of qua lity management policies, procedures, Risk Management and practices to the tasks of assessing, controlling, communicating, and reviewing risk Top management officials in a fi rm who have the authority and Senior Management – responsibility to mobilize resources Stakeholder – An individual or organization having an ownership or interest in the delivery, nts results, and metrics of the quality system framework or business process improveme Verification mation, through th e provision of objective ev idence, that specified – Confir rd requirements have been fulfilled. (Ref he ASQ Auditing Handbook, 3 edition, ASQ erence: T Quality Audit Division, J.P. Russell, Editor) Validation – Confirmation, through the provision of objective eviden ce, that the requirements been fulfilled. (Reference: The ASQ Auditing a specific intended use or application have for rd Handbook, 3 edition, ASQ Quality Audit Di vision, J.P. Russell, Editor) 28

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