Basic Principles of PHARMACEUTICAL QUALITY SYSTEM (PQS)-ICH Q10

Basic Principles of PHARMACEUTICAL QUALITY SYSTEM (PQS)-ICH Q10
Pharm (Mrs). Uche Sonny-Afoekelu, M.Sc.(PH), MPCPharm Assistant Director, Compliance Division Drug Evaluation and Research Directorate, NAFDAC US-A

OUTLINE Introduction- What is quality?
Relationship between different levels of quality What is ICH Q10? Philosophy and essential elements of the quality system in pharmaceutical manufacturing Objectives of Pharmaceutical Quality System (PQS) Applications of PQS US-A

INTRODUCTION What is Quality?
Degree to which a set of inherent characteristics fulfills requirements- ISO Degree- refers to a level which a product or service satisfies. So depending on the level of satisfaction, a product may be termed as excellent, good or poor quality product US-A

INTRODUCTION…..2 Inherent characteristics: Those features that are a part of the product and are responsible for achieving satisfaction Requirements: Refers to the needs of the customer, needs of the organization, and those of other interested parties eg Regulatory Bodies US-A

INTRODUCTION…..3 Examples of quality components
AREA Airlines Healthcare Food services Pharmaceutical Quality System QUALITY COMPONENTS On-time, comfortable, low-cost service Correct diagnosis, minimum wait time, low cost Good taste, free from contamination, fast delivery, good environment ???????????? US-A

INTRODUCTION….4 Every Pharmaceutical product has established identity, strength, purity and other quality characteristics designed to ensure the required levels of safety and effectiveness. In this Presentation, achieving quality means achieving these characteristics for a product. US-A

Relationship between different levels of quality
Quality management, defining the overall policy of the organization towards quality, is over everything else. Next comes quality assurance, which is the concept that ensures the policy is achieved. GMP is part of quality assurance. It deals with the risks that cannot be tested. It builds quality into the product. Quality control is a part of GMP. It is that part of GMP that is focused on testing of the environment and facilities, as well as the testing of the materials, components and product in accordance with standards. US-A

Quality relationships
World Health Organization 18 November, 2017 Quality relationships Quality Management / PQS Quality Assurance GMP Production and Quality Control It is worthwhile repeating the relationships between the different levels of quality management. We have a cascade arrangement: Quality management, defining the overall policy of the organization towards quality, is over everything else. Next comes quality assurance, which is the concept that ensures the policy is achieved. GMP is part of quality assurance. It deals with the risks that cannot be tested. It builds quality into the product. Quality control is a part of GMP. It is that part of GMP that is focused on testing of the environment and facilities, as well as the testing of the materials, components and product in accordance with the standard.

GMP – PICs Guide QUALITY MANAGEMENT QUALITY UNIT PEOPLE PRODUCTION
PRODUCTS & MATERIALS FACILITIES QUALITY UNIT EQUIPMENT PRODUCTION MANAGEMENT PEOPLE QUALITY MANAGEMENT

FDA – 6 Systems Approach of PQS
Quality System Production System Facilities & Equipment System Laboratory Controls Materials System Packaging & Labeling

New Era With New Challenges
World Health Organization New Era With New Challenges 18 November, 2017 “risk-based” concepts and principles of ICH Q8 Q9 Q10 Ref: ICH

How did ICH Q10 Originate? ICH Q10 was created from aspects of regional GMPs, ICH Q7 “GMP Guide for APIs”, and ISO 9000 (and related guidelines). ICH Q10 augments GMP by describing specific quality system elements and management responsibilities. ICH Q10 provides a harmonized model for a pharmaceutical quality system throughout the product lifecycle and is intended to be used together with regional GMP requirements. GMPs don’t explicitly address all stages of product lifecycle (e.g. Development). The quality system elements and management responsibilities described in Q10 promote the use of science and risk based approaches at each lifecycle stage, thereby encouraging continual improvement across the entire product lifecycle.

to IHow did ICH Q10 Originate?......2CH Q10 Conti...
ICH Q10 describes a comprehensive approach to Pharmaceutical Quality System It includes Good Manufacturing Practice (GMP) regulations It is harmonized with ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management” It allows Industry & Regulatory to enhance the Quality and Availability of medicines around the Globe in the interest of Public Health 19

What is ICH Q10? ICH Q10 is not intended to create any new regulatory requirements It only helps in maintaining product quality and compliance at all stages of product life cycle It helps innovation and continual improvement in pharmaceutical manufacturing GMPs do not explicitly address all stages of the product life cycle (e.g., development) and ICH Q10 is intended to encourage the use of science and risk based approaches at each lifecycle stage thereby promoting continual improvement across the entire product life cycle.

Scope of ICH Q10 Development Stage Technology Transfer Stage
ICH Q10 can be implemented throughout the different stages of a product lifecycle. Development Stage Technology Transfer Stage Manufacturing Stage Discontinuation Stage

ICH Q10 I(PQS GMP 33 Investigational products
Commercial Manufacturing Discontinuation Technology Transfer Management Responsibilities Process Performance & Product Quality Monitoring System Corrective Action / Preventive Action (CAPA) System Change Management System Management Review Knowledge Management Quality Risk Management Pharmaceutical Development Investigational products PQS elements Enablers 33

Objectives of PQS Achieve Product Realization: To establish, implement & maintain a system that allows the delivery of products with quality attributes appropriate to meet the needs of patient & other stake holders. (2) Establish & Maintain a State of Control: To develop & use effective monitoring & control systems for process performance & product quality, thereby providing assurance of continued suitability and capability of processes. Quality Risk Management (QRM) can be useful in identifying the monitoring and control systems (3) Facilitate Continual Improvement: To identify and implement appropriate product quality improvements, process improvements, variability reduction, innovation & quality system enhancements, thereby increasing the ability to fulfill quality needs consistently. QRM can be useful for identifying & prioritizing areas for continual improvement.

Development + Tech transfer + Commercial + Discontinuation
Objectives of PQS What is the Objective of any System? (Using ICH Q10 as an example) Product Realization State of Control Continual Improvement Compliance ORGANIZATIONAL OPTIMIZATION Development + Tech transfer + Commercial + Discontinuation System Boundaries ie full Life Cycle “Quality is a side effect of a system that is running well”

GMPs without a Modern Framework will Limit Improvements
GMPs provide guidance on the manufacturing and control of pharmaceutical product GMPs do not drive lifecycle approach to quality GMPs do not specifically address proactive continual improvement GMPs only briefly mention management responsibility GMPs are reactive, PQS is more proactive

Philosophy of the Quality System in Pharmaceutical manufacturing
The overarching philosophy is that Quality should be built into the product, and testing alone cannot be relied on to ensure product quality ! Implies QUALITY BY DESIGN (QbD) (Build Quality into your products, design risk out of your processes)! US-A

Philosophy of the PQS…2 The PQS (formerly referred to as Quality management system) is described in ICH Q10 It is based on ISO (International Organization for Standardization ) quality concepts. It includes the concepts of QA, GMP, QC, QRM- which are interrelated aspects of Quality Management. US-A

Philosophy of the PQS…3 Quality Management is a management function
It determines and implements the quality policy which is the overall intention and direction of an organization regarding quality It is formally expressed and authorized by top (senior) management Senior management has the ultimate responsibility to ensure an effective PQS US-A

Philosophy of the PQS…4 Quality Manual
A quality manual should be established and should contain the description of the PQS. The description should include: The quality policy Scope of the PQS Identification of the PQS system processes, their linkages and interdependencies. Process maps and flow charts can be useful. Management responsibilities within the PQS US-A

Philosophy of the PQS…5 Paradigm shift in Quality
(ICH Q8, ICH Q9, and ICH Q10) ICH Q10 is a model for a Pharmaceutical Quality System that can be implemented throughout the different stages of a product life cycle. US-A

Philosophy of the PQS…6 Implementation of ICH Q10 throughout product life cycle should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities US-A

Product lifecycle Pharmaceutical Development:
Goal: To design a product and its manufacturing process to consistently deliver the intended performance and meet the needs of the patients, healthcare professionals, regulatory authorities. Drug Substance development Formulation Development Manufacture of investigational products Delivery system development Manufacturing process development and scale up Analytical method development US-A

Product Lifecycle… 2 Technology transfer
Goal: To transfer Product and Process knowledge Between development and manufacturing, Within manufacturing sites Between manufacturing sites ……. to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and on-going continual improvement US-A

Product Lifecycle…3 Commercial manufacturing
Goal: To achieve product realization, establish and maintain a state of control and facilitate continual improvement Acquisition and control of materials Provision of facilities, utilities, and equipment Production (including packaging and labeling) Quality control and assurance Release Storage Distribution US-A

Product lifecycle…. 4 Product discontinuation
Goal: To manage the terminal stage of the product life cycle effectively. Retention of Documentation Sample Retention Continued product assessment (complaints handling and stability) Reporting in accordance with Regulatory requirements US-A

ELEMENTS OF THE PQS 1) Process performance and product quality monitoring system 2) Corrective action and preventive action system 3) Change management system 4) Management review of process performance and product quality US-A

Elements of the PQS….2 These elements should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognizing the differences among the stages and the different goals of each stage US-A

1) Process performance and product quality monitoring
Pharmaceutical companies should plan and execute a system for the monitoring of process performance and product quality to ensure a state of control is maintained. An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality Identifies areas for continual improvement US-A

Pharmaceutical Development
Application of Process Performance and Product Quality Monitoring System throughout Product Lifecycle Pharmaceutical Development Process and product knowledge generated and process and product monitoring conducted throughout development can be used to establish control strategy for manufacturing US-A

Application of Process Performance and Product Quality Monitoring System throughout Product Lifecycle Technology transfer Monitoring during scale up activities can provide a preliminary indication of process performance and the successful integration into manufacturing Knowledge obtained during transfer and scale- up activities can be useful in further developing the control strategy US-A

Commercial manufacturing
Application of Process Performance and Product Quality Monitoring System throughout Product Lifecycle Commercial manufacturing A well defined system for process performance and product quality monitoring should be applied to assure performance within a state of control and to identify improvement areas US-A

Product discontinuation
Application of Process Performance and Product Quality Monitoring System throughout Product Lifecycle Product discontinuation Once manufacturing ceases, monitoring such as stability testing should continue to completion of the studies. Appropriate action on marketed products should continue to be executed according to regional regulations US-A

2) Corrective Action and Preventive Action System
The Pharmaceutical company should have a system for implementing corrective and preventive actions resulting from the investigation of complaints, product rejections, non conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring US-A

Correction, Corrective and Preventive Action
Correction: Any action taken to eliminate a non-conformity Corrective Action: Action to eliminate the cause of a detected non-conformity or other undesirable situation Note: Corrective action is taken to prevent recurrence whereas preventive action is taken to prevent occurrence (ISO 9000:2005) Preventive Action: Action to eliminate the cause of potential non-conformity or other undesirable potential situation Note: Preventive action is taken to prevent occurrence whereas corrective action is taken to prevent recurrence (ISO 9000:2005)

Corrective Action and Preventive Action System…2
A structured approach to the investigation process should be used with the objective of finding the root cause CAPA methodology should result in product and process improvements and enhanced product and process understanding US-A

Application of Corrective Action and Preventive action system throughout the product lifecycle Pharmaceutical Development Product or process variability is explored. CAPA methodology is useful where corrective actions and preventive actions are incorporated into the iterative design and development process US-A

Application of Corrective Action and Preventive action system throughout the product lifecycle
Technology Transfer CAPA can be used as an effective system for feedback, feedforward, and continual improvement. US-A

Commercial Manufacturing
Application of Corrective Action and Preventive action system throughout the product lifecycle Commercial Manufacturing CAPA should be used and the effectiveness of the actions should be evaluated US-A

Product Discontinuation
Application of Corrective Action and Preventive action system throughout the product lifecycle Product Discontinuation CAPA should be continued after the product is discontinued. The impact on product remaining on the market should be considered, as well as other products that might be affected US-A

Change Management Change Management: A systematic approach to proposing, evaluating, approving, implementing & reviewing changes. It Should Include Quality risk management to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk

Change Management….2 Innovation, continual improvement, the output of process performance and product quality monitoring, and CAPA drive change. To evaluate, approve and implement these changes properly, a company should have an effective change management system (CMS) The CMS should provide a high degree of assurance that there are no unintended consequences of the change US-A

Change Management…3 Proposed changes should be evaluated relative to the marketing authorization including design space, to determine whether a change to regulatory filling is required under regional requirements Proposed change should be evaluated by experts in contributing their experience and knowledge

Change Management…4 After implementation, evaluation of change should be under taken to confirm that the change objectives were achieved and there was no deleterious impact on product quality

Application of Change Management System throughout Product Lifecycle
Pharmaceutical Development Change is an inherent part of the development process and should be documented The formality of the change management process should be consistent with the stage of pharmaceutical development US-A

Technology Transfer The change management system should provide management and documentation of adjustments made to the process during technology transfer activities US-A

Commercial Manufacturing A formal CMS should be in place for Commercial Manufacturing. Oversight by the Quality unit should provide assurance of appropriate science and risk- based assessments US-A

Product Discontinuation Any change after product discontinuation should go through an appropriate change management system US-A

Management Review of Process Performance and Product Quality
Management review should provide assurance that process performance and product quality are managed over the lifecycle. Depending on the size and complexity of the company, management review can be a series of reviews at various levels of management and should include a timely and effective communication and escalation process to raise appropriate quality issues to senior levels of management for review. US-A

Management Review of Process Performance and Product Quality
The Management Review should include Results of regulatory inspections, audits, commitments made to regulatory authorities Periodic quality reviews that can include measures of customer satisfaction such as product quality complaints and recalls Any follow-up actions from previous management reviews US-A

Application of Management Review of Process Performance and Product Quality throughout Product Lifecycle Pharmaceutical Development Aspects of Management Review can be performed to ensure adequacy of the product and process design US-A

Application of Management Review of Process Performance and Product Quality throughout Product Lifecycle Technology Transfer Aspects of Management Review should be performed to ensure the developed product and process can be manufactured at commercial scale US-A

Commercial Manufacturing
Application of Management Review of Process Performance and Product Quality throughout Product Lifecycle Commercial Manufacturing Management review should be a structured system, and should support continual improvement US-A

Product Discontinuation
Application of Management Review of Process Performance and Product Quality throughout Product Lifecycle Product Discontinuation Management review should include such items as product stability and product quality complaints US-A

Continual improvement of the PQS
A)Management should have a formal process for reviewing the PQS on a periodic basis. The review should include: Measurement of achievement of the PQS objective US-A

Continual improvement of the PQS…2
Assessment of performance indicators that can be used to monitor the effectiveness of processes within the PQS such as: Complaints, deviations, CAPA, and Change Management processes Feedback on outsourced activities Self assessment processes including risk assessments, trending, and audits US-A

Continual improvement of the PQS…3
B) Monitoring of internal and external factors that can have an impact on PQS Factors monitored by management may include: Emerging regulations, guidelines Innovations that might enhance the PQS Changes in product ownership US-A

Outcomes of management review
Improvements to the PQS Allocation or re-allocation of resources Personnel training Revisions to quality policy and quality objectives Documentation and timely and effective communication of the results of the management review and actions, including escalation of appropriate issues to senior management US-A

ICH Q10: POINTS TO NOTE It introduces the involvement and role of senior management It introduces a product life cycle perspective Quality Risk Management and Knowledge Management are enablers for the PQS Implementation of PQS provides to enhance assurance of product quality

ICH Q10: POINTS TO NOTE ICH Q10 requires an understanding of FDA for the 21st Century, ICH Q8 (Design), ICH Q9 (Risk) as well as ISO 9000 (2005) to maximize benefit ICH Q10 is an ISO SYSTEMS approach to GMP NOT additional to GMP but integral to GMP

ICH Q10: POINTS TO NOTE Covers full life Cycle of a Product
Objectives: Product Realization, Control & improvement Demands Management Team to lead Quality System and which protects public health in respect of product lifecycle.

What are the benefits of implementing a Pharmaceutical Quality System (in accordance with ICH Q10)?
The benefits are: Facilitated robustness of the manufacturing process, through facilitation of continual improvement through science and risk-based post approval change processes;

Consistency in the global pharmaceutical environment across regions; Enable transparency of systems, processes, organizational and management responsibility; Clearer understanding of the application of a Quality System throughout product lifecycle;

Further reducing risk of product failure and incidence of complaints and recalls thereby providing greater assurance of pharmaceutical product consistency and availability (supply) to the patient; Better process performance;

Opportunity to increase understanding between industry and regulators and more optimal use of industry and regulatory resources. Enhance manufacturer’s and regulators’ confidence in product quality; Increased compliance with GMPs, which builds confidence in the regulators and may result in shorter inspections.

How does a company demonstrate implementation of PQS in accordance with ICH Q10?
When implemented, a company will demonstrate the use of an effective PQS through its documentation (e.g., policies, standards), its processes, its training/qualification its management its continual improvement efforts, and its performance against pre-defined Key Performance Indicators.

How does a company demonstrate implementation of PQS in accordance with ICH Q10?
A mechanism should be established to demonstrate at a site how the PQS operates across the product lifecycle, in an easily understandable way for management, staff and regulatory inspectors, e.g., a quality manual, documentation, flowcharts, procedures. Companies can implement a program in which the PQS is routinely audited in-house (i.e., internal audit program) to ensure that the system is functioning at a high level.

What are potential sources of information for Knowledge Management?
Some examples of knowledge sources are: Prior knowledge based on experience obtained from similar processes (internal knowledge, industry scientific and technical publications) and published information (external knowledge: literature and peer-reviewed publications);

Pharmaceutical development studies; Mechanism of action; Structure/function relationships; Technology transfer activities; Process validation studies;

Manufacturing experience e.g.: - Internal and Vendor audits; - Raw material testing data; Change management activities; Stability reports; Product Quality Reviews/Annual Product Reviews;

Technical investigations and/or CAPA reports; Suppliers and Contractors; Product history and /or manufacturing history; Ongoing manufacturing processes information (e.g., trends).

Complaint Reports; Adverse event reports (Patient safety); Deviation Reports, Recall Information;

Knowledge Management Example: Quality By Design
Christopher Sinko, Ph.D. Pfizer Global Research & Development Integrity Uniformity Weight Control In vitro Dissolution Chemical Purity API, Excipients, Manufacturing Process API Particle Size Compatibility Degradation Pathway Prediction Material Property Characterization Process Simulation Design Pharmaceutics Profile API Salt Selection

Summary ICH Q10 requires an understanding of FDA for the 21st Century, ICH Q8 (Design), ICH Q9 (Risk) as well as ISO 9000 (2005) to maximize benefit ICH Q10 is an ISO SYSTEMS approach to GMP NOT additional to GMP but integral to GMP Covers full life Cycle of a Product Objectives: Product Realization, Control & Improvement DEMANDS Management Team to lead Quality System Seek compliance only and you will get compliance only The toughest implementation battles are internal so look for internal Allies before going outside for support

References NAFDAC cGMP Regulations 2009
WHO- Quality Assurance of Pharmaceuticals 2015 GMP for the 21st century International Conference on Harmonisation, ICH Q8: Pharmaceutical Development, November International Conference on Harmonisation, ICH Q9: Quality Risk Management, November International Conference on Harmonisation, Draft Consensus Guideline, ICH Q10: Pharmaceutical Quality System, May FDA, Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations, September Dr Onyenoha Chukwumerije- Training slides 2016

THANK YOU QUESTIONS ?? US-A

World Health Organization
18 November, 2017 1. Case study Group session Imagine you are being inspected by NAFDAC for compliance with GMPs. Consider the situations in the next slides which may have impacts on your company’s quality management programme Describe the action(s) you would take in each case to avoid regulatory citations. (CDs) This brings us to our topic for this group session. We want you to identify the influences that the following situations may have on a company’s management system. We would like to know what action you would propose to counter any negative effects. Please use a brainstorming technique to bring out all the possible problems quickly and then start to focus on the most important using your own practical experiences. Your team here will move around the groups, so please use them to help on any difficult issues. Your allocated groups are now up on the board together with the room allocated. Please get there quickly to make maximum use of the time. We will meet here again at _____________.

18 November, 2017 Issues 1 Quality Management manual not established in writing Limited human resources Lack of qualified people Processes not properly validated Poor SOPs or standard batch documentation More consideration to cost than quality Family members in key positions of authority Issues to discuss Imagine that within a company you are inspecting: Quality Management Manual – Senior management will not allow a quality management manual to be created. Limited human Resources – Owners will not recruit sufficient people to undertake the work. Existing staff are harassed and overworked. They are kept under pressure to perform and there are no spare staff with the skills and experience needed. When staff are ill or go on holiday then there are no replacement staff available. Lack of qualified people - Unqualified or inexperienced people are employed in key positions. Processes – Senior staff do not subscribe to the value of validated processes. SOPs – There are few or no SOPs in operation. Those SOPs that do exist are not adhered to. Standard batch documentation – Batch documentation is poor. Different batch sizes are made in inappropriate equipment. Cost is emphasized over quality. The owners of the company do not subscribe to GMP other than the meaning "Get More Product". They see that GMP mean additional costs with no return. They do not subscribe to any moral code in respect of patient health. Any audit is seen as interference with their ability to manage the company the way that they want. Family members play a major part in the company. Inexperienced or unqualified family members are promoted into positions of responsibility for which they are not qualified. Imagine in a company you are inspecting :

18 November, 2017 Issues – II Substandard materials deliberately purchased Technical staff not involved in purchasing Inability to re-export substandard materials Owner insists on selling rejects Corruption No commitment to training Imagine in a company you are inspecting : Substandard materials are purchased because they are cheap. The technical staff are not involved in the purchasing decisions so inappropriate materials are bought. If material is imported at great cost and then rejected, it can be very difficult to re-export that material for replacement or exchange owing to currency regulations. The owner of the company insists on taking inappropriate decisions about the quality of products that are to be sold. Is there corruption concerning product quality? What do you do if you are offered an inducement not to report GMP deficiencies? Because training costs money, the owner is not prepared to make a commitment to training that is needed.

Basic Principles of PHARMACEUTICAL QUALITY SYSTEM (PQS)-ICH Q10

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