Quality Assurance,: A Systemic Approach For Effective Compliance

Quality Assurance,
A Systemic Approach for Effective Compliance.
DGM QA (Unit IV)
Hemanth Panasa
Agenda
Basics of GMP Pharmaceutical Quality systems Qualifications/ Validations Quality Risk Management (QRM) Corrective & Preventive Actions (CAPA) RA/ Investigation Tools Case Study Moving Forward
Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011
Agenda
QualityMeans to Public
Efficient/ Effective / Above average performance Flawless / nearly flawless The best of what you get Something we / I can depend on Some thing that will last Good workmanship Lives up to promise Tried and true / good reputation Really listening / responding / caring/ respecting Better than other Reliable/long lasting/ standard / better
Qualitydefined by ISO
The totality of features and characteristics of a product or service that bears on it the ability to satisfy stated or implied need.
Quality is TO COMPLY WITH SPECIFICATIONS
GMPs
Good Manufacturing Practices (GMPs) are regulations (Law) that describe the methods, equipment, facilities and controls required for producing drugs. To ensures that a drug... Is SAFE Is correctly IDENTIFIED Is of the right STRENGHT Has the PURITY it claims
Has the overall QUALITY it claims
GMPs
The language of GMPs are sometimes very broad, with terms such as adequate, without providing details as to what is specifically required.
GMPs have evolved over time and are still evolving. As the industry adopts these improvements, they become the current industry standard. Judges in court decide their cases frequently based on the interpretation of regulations relying both on the intent of the regulations and the current common industry practices in meeting the GMP requirements.
CGMPs
The regulations are called Current Good Manufacturing Practices
'Current' is to emphasize that the expectations are Dynamic'.
The terms Current Good Manufacturing Practices (CGMPs) and Good Manufacturing Practices (GMPs) are interchangeable.
Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011 8
Origin of GMP
Concept of quality: Segregation between good and bad Concept of quality: Testing of finished products Lead to more failures and less consistent quality product
Generation of need of quality building in the product (QA/ QBD)
Birth to GMP (First written GMP : USA, 1963)

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Across the World

UK US Europe India Brazil SA Japan
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Regulatory Agencies
USFDA The USA MHRA The UK MCC South Africa TGA Australia ANVISA Brazil CDSCO India WHO EMEA
ICH PDA PIC/S ISPE
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Requirements of GMPs
At high level, GMPs of various nations are very similar. Most require things like, Equipment and facilities being properly designed, maintained and cleaned. Standard Operating procedures (SOPs) be written and approved. An independent quality unit (Quality Assurance/ Control). Well trained personnel and management. Validated process/ practices.
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10 Commandments of GMP
Principle # 1 Writing detailed step-by-step procedures (SOPs) that provide a roadmap for controlled and consistent performance. Principle # 2 Carefully following written procedures to prevent contamination, mix-ups and errors. Principle # 3 Promptly and accurately documenting work for compliance and traceability.
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Principle # 4 Proving that systems do what they are designed to do by validating work. Principle # 5 Integrating productivity, product quality, and employee safety into the design and construction of facilities and equipment. Principle # 6 Properly maintaining facilities and equipment. Principle # 7 Clearly defining, developing and demonstrating job competence.
Principle # 8 Protecting products against contamination by making cleanliness a daily habit. Principle # 9 Building quality into products by systematically controlling our components and product related processes such as manufacturing, packaging and labeling, testing, distribution, and marketing. Principle # 10 Conducting planned and periodic audits for compliance and performance.
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CGMPs Exist
To protect patients from dangerous, adulterated or misbranded products. Adulterated product: Product that has not been manufactured according to CGMPs, even it meets all specifications. Misbranded product: Not labeled properly or making a false claim. GMPs describes What to do, Not How to do.
Agenda
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Quality System
System is a network of interdependent components that work together to try and accomplish aim of the system. Quality System is a network, by which an organization manages its quality aspects in a systematic and organized manner . It provides a framework/ procedures for planning, implementation and assessment of its aim (i.e. quality) of a product/ service of an organization. It can also describe the methodology on how to achieve compliance to regulations. Hence, GMPs are part of the Quality System.
Quality System
Quality System ensures that, products are consistently produced and controlled to the standards appropriate to their intended use. Unlike buildings and equipments, quality systems are relative and indicator of compliance to GMPs. Hence, quality system is the number one issue for regulatory inspectors, who will look how the Quality is Systematically addressed through out the company.
Implementation of robust Pharmaceutical Quality System is a key to comply with CGMPs

Pharma. Quality System

International Conference on Harmonization (ICH), which is a consortium of US, EU and Japan with participation of Regulatory and Industry, released a guidance (ICH Q10) on Pharmaceutical Quality System (PQS). Implementation of PQS should achieve three main objectives: Achieve Product Realization. Establish and Maintain a state of control. Facilitate Continual Improvement
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The PQS is based on the concepts of Quality by Design (QbD). Implementation (developing a new system or modifying an existing one) of PQS should consider; Scope of the system to various stages of life cycle, i.e. Pharmaceutical Development Technology Transfer Commercial Manufacture Product Discontinuation
The size and complexity of organization, i.e. across the site and/ or multiple sites/ countries etc.
Enablers of PQS
Knowledge Management: Knowledge management is a systematic approach to acquiring, analyzing, storing and disseminating information related to products, manufacturing processes and components. Sources of knowledge include, but are not limited to: Prior knowledge (public domain or internally documented). Pharmaceutical development studies. Technology transfer activities. Process validation studies over the product lifecycle. Manufacturing experience. Innovation, Continual improvement and Change management activities.
Enablers of PQS
Quality Risk Management: Quality Risk Management (QRM) is integral to an effective pharmaceutical quality system. It can provide a proactive approach to identifying, scientifically evaluating and controlling potential risks to quality. It facilitates continual improvement of process performance and product quality throughout the product lifecycle. ICH Q9 provides principles and examples of tools for QRM (e.g. FMEA) that can be applied to different aspects of pharmaceutical quality.
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Management Responsibility
Management Commitment Quality Policy Quality Planning Resource Management Internal Communication Management Review Control on Outsourcing/ Purchase Managing Change in Ownership
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Continuous Improvement
Of Process Performance and Product Quality
Life Cycle Stage Goals: Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation PQS Elements: Process performance and product quality monitoring system. Corrective action and preventive action (CAPA) system. Change management system Management review of process performance and product quality.
Continuous Improvement
Of the Pharmaceutical Quality System
Management Review of the Pharmaceutical Quality System. Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality System. Outcomes of Management Review and Monitoring
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Pharmaceutical Manufacture
USFDAs Six Systems Model, An inspections approach.

Manufacturing Systems
Facilities & Equipment: Describes the methods for controlled premises, facility and equipment. Laboratory Systems: Describes the methods for laboratory controls for starting material, in-process/ finished products. Material Systems: Describes the methods for material controls, i.e. receipt, handling, storage and dispensing. Packaging & Labeling Systems: Describes the methods for handling of finished products with required packing & Labeling. Production Systems: Describes the methods for formula, process and practices during production, by using the supporting systems.
Quality System
Quality is everyones responsibility, typically monitored by QA through Qualifications/ Validations In-Process Checks and Batch Release Documentation Control QMS tracking & Quality Metrics Training, Audits & Compliance
ensure the state of control in 5 Ps of manufacturing systems.
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5 Ps and QA Controls
Premises
(Includes Facility and Equipment)
Approval of Design and Qualifications/ Validations Training and Qualifications Approval, Distribution, Change controls and Training Training, BR checks, Validations and Audits QC testing and control of other Ps (Premises, Personnel, Procedures and Practices)
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Personnel Procedures Practices

(Includes Process)
Products
(Includes starting material, in-process and final product)
Agenda
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Definitions
Validation: Establishing documented evidence, which provides a high degree of assurance, that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. Qualification: All the actions, with a documented evidence, that an equipment is designed and commissioned, and is consistently performing, to meet the intended requirements. The word validation is sometimes widened to incorporate the concept of qualification. Process Validation: Process validation is establishing documented evidence, which provides a high degree of assurance, that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics.
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Definitions
Prospective Validation: Is the establishment of documented evidence, with high degree of assurance, that a process, procedure, system, equipment or mechanism used in manufacture does what it purports to do based on a pre-planned validation protocol.
Concurrent Validation: Establishment of documented evidence that a process does what it purports to do, based on information generated during actual implementation of the process. Retrospective Validation: A process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data.
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Definitions
As per the Guidance for Industry by USFDA Process Validation: General Principles and Practices, effective from January 2011 Process Qualification: Conforming that the manufacturing process as designed is capable of reproducible commercial manufacturing. Process Validation: The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. This certainly challenge our philosophy & practices, wrt qualifications/ validations, we have adopted as on date!
New Approach
This approach is based on the understanding that, Quality, Safety and Efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished product inspection or testing. This approach describes Process Validation (PV) activities in three stages; Process Design Process Qualification Continued Process Verification
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PV Stages
Process Design: Building and Capturing Process Knowledge and Understanding. Establishing a strategy for process control (CPPs & CQAs). Process Qualification: Design of a Facility and Qualification of Utility and Equipment Process Performance Qualification. Continued Process Verification: Trend Analysis & Quality Metrics Review of Key Performance Indicators (KPIs). All regulatory agencies expects that, the principles of Quality Risk Management (QRM) are integrated into qualifications/ validations.
VALIDATION LIFE CYCLE

Validation Master Plan ( VMP)
Impact Assessment
User Requirement Specifications (URS)
Qualification
Change Control
Design Qualification DQ) (
Factory Acceptance Test (FAT)
Installation QualificationIQ) ( Re- Qualification Operational Qualification (OQ) Monitoring / Maintenance / Calibration Performance Qualification (PQ)
Final Qualification Report
Validation
Analytical Method Validation (AMV)
Cleaning Validation(CV)
Process Validation(PV)
Final Validation Report
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Agenda
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Definitions
Risk: The combination of probability of the harm and the severity of that harm. Risk Assessment: A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.
Quality Risk Management (QRM): A systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. Reference: ICH Q9 Quality Risk Management (QRM); Harmonised Tripartite Guideline .
Typical QRM Process

Approach for QRM

The manufacturing and use of a drug product, including its components, necessarily entail some degree of risk. The risk to its quality, in the entire product life cycle, is just one component of the overall risk. The protection of patient by managing the risk to product quality, during its manufacture and/ or distribution, should be considered as prime importance by all the stake holders. QRM is a systematic process designed to coordinate, facilitate and improve science-based decision making with respect to risk.
Approach for QRM

The success of this exercise depends on the involvement of representatives, with the working knowledge of various important areas of product life cycle (e.g. Logistics, Engineering, Manufacturing, QA, QC and RA). A practical approach for QRM is to define the scope for each risk assessment exercise, and conduct training to concerned personnel, where the representatives are able to identify and make informed judgments on threats to the individual process steps. The selection and implementation of improvements then be assigned to individuals and shall be reviewed for effectiveness, post implementation.
Risk Assessment
QRM begins with a well defined problem description or risk in question. Based on the problem/ risk, we shall constitute a team of experts from user and applicable cross functions, to execute the QRM process. When the risk in question is well defined, appropriate risk management tool and the types of information needed to address the risk in question will be more readily identifiable. As an aid to clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often helpful: What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)?
Risk Assessment
Raw Material & Packing Material Suppliers Equipment/ Component Cleaning and Sterilization Storage and Distribution
sp Di e in ns g
Road, Sea, Air
Warehouse of Manufacturing Plant Dispensing Production and Packaging
Road, Sea, Air
Distributor/ Customer
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Risk Assessment
The QRM team shall carry out detailed process mapping of the activity, under scope of risk assessment. Particular attention shall be paid to interfaces along the product life cycle.
In the above process map, every entry and every arrow represents a risk points at which product threat could occur. Each process can be mapped separately and QRM can be effectively applied to all the stages of pharmaceutical manufacture. All the risk areas and product sensitivities, i.e. customer complaints, deviations etc., and all the attributes related to facilities, equipment, personnel, environment, materials and practices/ procedures are considered for identifying the threats which could impact product quality and/ or safety.
Agenda
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Definitions
Deviation: Departure from an approved procedure, process and/ or established standard. This can be an unexpected/ planned event in noncompliance with established standard, system and/ or procedure, at any stage of manufacturing/ its associated activities. Correction: Action refers to repair, rework and/ or adjustment and relates to the disposition of an existing non-conformity. Corrective Action: Action taken to eliminate the causes of an existing non-conformity, defect or other undesirable situation in order to prevent re occurrence. Preventive Action: Action taken to eliminate the cause of a potential non-conformity, defect or other undesirable situation in order to prevent re occurrence.
Terms in Industry
Deviation Planned Deviation Un Planned Deviation Out of Specification (OOS) Out of Limit (OOL) Out of Trend (OOT) Aberration Exception Un Usual Occurrence Incident Something, which is a discrepancy/ abnormal, from the set standard and/ or routine occurrence.
Regulatory Perspective
Reporting & Tracking of all the events in defined quality system framework. Root cause investigation for all the failures/ non-conformances, with adequate impact assessment and CAPA.
Escalation mechanism and management responsibility/ involvement on handling these failures/ non-conformances.
Inspectors really look how well you handle any problems.
Hence, reviewing atypical event (deviations/OOS/ OOL/ OOT) reveals, just how well the quality system is working! (Ref. FDA News on PAIs).
Regulatory Perspective
Top 10 FDA 483 Items
*PAPC Production and Process Controls
Source: QSIT Presentation on CAPA during the workshop.

Purpose of Notification
Identify all the unexpected/ atypical events in GMP areas. Acknowledge them as real deviations or whatever!. Thorough investigation to identify the root cause. Evaluate the impact, i.e. quality, regulatory, systemic and business.
Identify the CAPAs, including responsibilities and time lines. Decision on disposition of the batch and/ or move forward with routine operations. Documenting all the events concurrently in a traceable manner.
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Challenge
The biggest challenge in any Quality System of the organization with respective to Deviations is Communication processes that are untimely, inefficient and lacking in ownership lead to identifying the True Root Cause and applying effective Corrective And Preventive Actions (CAPA). Effective investigations for all atypical events, with adequate CAPAs, is an ultimate tool for any organization to comply with Current requirements of GMPs, which ensures continuous improvement.
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True Root Cause

Is the most basic reason, which if eliminated, would Prevent Recurrence. An identified reason for the presence of a defect or problem and/ or the source or origin of an event.
The goal of every deviation investigation is to identify the True Root Cause. This is critical to ensure that the most effective Corrective Action / Preventative Action is implemented.
Root Cause must be; Stated clearly and concisely Is scientifically valid the conclusion is based on the data and/or sound scientific knowledge and principles. Stated with a level of confidence that is appropriate
Problem Solving
Define Generate Description Map the process, Brainstorm for causes, Identify whats changed, organize information Problem analysis and troubleshooting Test hypothesis Drill down to the true root cause; Tools! Evaluate after implementation
Product Impact
At each stage, ask if the problem definition is still correct and complete In practice, the process is rarely sequential
Not uncommon to go back to Generate Description after some level of problem analysis
As significant new information becomes available, evaluate need to revise or update problem definition
Agenda
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The Tools
Flow charts, Check sheets, process mapping Statistical tools, i.e. control charts, histograms, Pareto charts etc., 5 Whys Technique Cause and Effect Diagrams (Ishikawa diagram or fish bone diagram). Failure Mode Effects analysis (FMEA) Failure Mode, Effects and Criticality Analysis (FMECA) Fault Tree Analysis (FTA) Hazard Analysis and Critical Control Points (HACCP) Hazard Operability analysis (HAZOP) Preliminary Hazard analysis (PHA)
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5 Why? Technique
Developed at Toyota and is critical component of the problem solving training in its production system. Method of asking questions to determine the true root cause of the problem and has potential to uncover underlying design, procedure or organization issues. Provides a structured and layered approach to go from the effect to the first cause. Why 5? Not a magic number Rule of thumb! Based on experience, 5 questions are believed to be sufficient to get to the true root cause
5 Why? Technique
Example (Deviation Event Information): During the first lot after shut-down, the temperature of the product in the holding tank exceeded the allowable 2 to 8 C range, triggering an alarm. Operators found that the ball-valve controlling glycol flow to the tank jacket was in the closed position. Valve was opened and the temperature returned to normal.
Cause: Temperature excursion due to closed glycol valve.

Cause Effect Analysis
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FMEA
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FMEA
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FMEA
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FMEA
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Agenda
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Case Study
Group A:
Group B: Group C:
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Agenda
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Driving Force
The driving force for implementation of a robust pharmaceutical quality system, to meet the CGMPs, is an effective Documentation System.
These documents are important To convey the commitments To define/ Implement systems and procedures For Reference during the operation Are legal and can be requested/ subpoenaed by a court of law. Can be used to prove GMP compliance.
be sensitive towards them!

Take Away
Refer to written instructions and Never Assume! Understand your own processes and improve out of box thinking abilities. Data collection should always accompanied with data analysis to make scientifically justified decisions. Notifications are appropriate tools and enable us to comply with CGMPs. Do not scare of them!
Qualification/ Validation of every thing we do/ adopt.

Risk Assessment and CAPAs should be your daily mantras!
Critical Element
GMPs will only work with the cooperation and understanding of the most important element and that is
YOU
THANK YOU
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Quality Assurance,: A Systemic Approach For Effective Compliance

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Quality Assurance,

A Systemic Approach for Effective Compliance.

DGM QA (Unit IV)

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Quality is TO COMPLY WITH SPECIFICATIONS

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Has the overall QUALITY it claims

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

'Current' is to emphasize that the expectations are Dynamic'.

Generation of need of quality building in the product (QA/ QBD)

Birth to GMP (First written GMP : USA, 1963)

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Across the World

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

ICH PDA PIC/S ISPE

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Implementation of robust Pharmaceutical Quality System is a key to comply with CGMPs

Pharma. Quality System

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Pharma. Quality System

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Pharma. Quality System

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

USFDAs Six Systems Model, An inspections approach.

ensure the state of control in 5 Ps of manufacturing systems.

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Personnel Procedures Practices

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

VALIDATION LIFE CYCLE

User Requirement Specifications (URS)

Design Qualification DQ) (

Factory Acceptance Test (FAT)

Final Qualification Report

Analytical Method Validation (AMV)

Final Validation Report

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Typical QRM Process

Approach for QRM

Approach for QRM

Warehouse of Manufacturing Plant Dispensing Production and Packaging

Road, Sea, Air

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

*PAPC Production and Process Controls

Source: QSIT Presentation on CAPA during the workshop.

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

Business Time Managers Workshop at Unit IV; Jul./ Aug. 2011

True Root Cause