sapraa march 2013 validation. presentation what will be covered in this presentation….. why do we...

SAPRAAMarch 2013

Validation

Presentation

What will be covered in this presentation….. Why do we validate? What do we validate? Approach to validation Qualification Process validation – a look at the FDA guidelines

Purpose of Validation

GMP Guide Chapter 5, Annex 11, Annex 15 In compliance

Dossier submission

Ever look at those files…..

Factors affecting quality

Raw Materials

Personnel

ProceduresValidated processes

Equipment

PremisesEnvironment

Packing Materials

OR

Validation

Change Control

FDA Warning Letters

Why do we validate

Manufacturers must assume responsibility for the quality of products & ensure they are: o fit for useo comply with registered requirementso do not place patients at risk

Why do we validate

Validation establishes & provides documented evidence that premises, utilities and equipment:o are designed in accordance with GMPo are installed in compliance with design criteriao operate in accordance with design criteria

Validation establishes that a specific process will consistently produce a product meeting its pre-determined specification

Validation Validation a requirement not an option Is validation a ‘tick box’? Validation documentation always checked in GMP

inspection (the ‘action of proving..’) MCC and PIC/S….. design, installation, operational

and performance…. qualification MCC and PIC/s…. validation of processes, cleaning

and analytical methods…. validation A system or equipment must be qualified in order to

operate in a validated process Process validation protocols required for dossier

submission

Validation / Qualification

Validation:Proving procedures, processes, equipment, materials, activities, systems lead to the expected results

Qualification:Proving and documenting premises, systems, equipment properly installed and/or work correctly & lead to the expected resultsQualification often initial stage of validation, individual steps alone do not constitute process validation

What gets validated

Facilities Utilities / Services / Systems Equipment Computer systems Analytical methods Cleaning methods Processes

Facilities, systems and equipment qualified prior to process validation being completed

What gets validated

Utilities / Services / Systems Critical systems with direct impact e.g.

Purified Water HVAC Compressed air (in contact with product or

primary containers) Steam (if used for cleaning product contact

surfaces)

What gets validated

Processes Non-sterile manufacturing Sterile manufacturing – media fills Sterilizing loads Waste

Sequencing of Validation Stages

Validation Master Plan

Design Qualification

User Requirement Specification

Installation Qualification

Operational Qualification

Performance Qualification

Site Master File

Overall Validation Master Plan

Documents that are required to be in place and are routinely updated

Process ValidationValidation SOP

Approach to Validation

Validation requires:

Collaboration between the all relevant parties (validation, QA, production, engineering, consultants, contractors)

Resources – time, budget, people Planning (including defining scope of

work) and control

Approach to ValidationPlanning

Risk-based approach to validation; not all components need to be validated

Avoids making validation unnecessarily complex A Risk Assessment or Impact Assessment

determines which components are critical and non-critical, or have a direct impact or indirect impact on product quality

Critical Process Parameters & Critical Quality Attributes

These decisions have implications on the extent, cost and time of the qualification process

ISPE Commissioning and Qualification

Fig. 1.1ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification Vol. 5 March 2001

Impact Spectrum

Fig. 2.1ISPE Pharmaceutical Engineering Baseline Guide: Commissioning and Qualification Vol. 5 March 2001

Qualification Requirements

Direct Impact Systems Direct impact on product

quality Designed &

commissioned in line with GEP

Also subject to qualification

Indirect Impact Systems No direct impact on

product quality Designed &

commissioned in line with GEP

No qualification required

Impact Assessment Indicators

Direct Impact Systems Direct contact with product

(e.g. air) Produces an excipient /

ingredient (e.g. WFI) Used in cleaning / sterilizing -

malfunction could result in failure which poses risk

Controls a risk to the product (e.g. Nitrogen blanket)

Produces data used to accept / reject product

Produces identification information (e.g. expiry date)

Direct Impact Components

Used to demonstrate compliance with registered process (e.g. hardness tester)

Has a direct effect on product quality (e.g. blister embossing)

Failure or alarm of component having a direct effect on product quality (e.g. in-line TOC)

Information from component recorded as part of batch record (e.g. drying temperature)

Has direct contact with product

Approach to ValidationVerification and GEP

Verification and GEP – processes that function within the engineering environment

Support the validation effort Operate continually, not only at one point in

time Based on quality management principles e.g.

documentation control, change management, authorization processes, deviations / discrepancies

Approach to ValidationEngineering Risk-based Verification

Risk Management applied - identifies critical aspects for product quality & patient safety

List of critical aspects approved by QA Acceptance criteria specified for the critical

aspects Non-critical aspects may be included (do not

require same level of involvement by QA) Acceptance and release must provide

documented confirmation of fitness for intended use

Approach to ValidationVerification Execution

Verification confirms critical aspects meet acceptance criteria

Extent of verification commensurate to risk to product quality

Execution: Design review Factory Acceptance Test (FAT) Site Acceptance Test (SAT) Installation testing Functional testing Performance testing Handling of discrepancies, change management Acceptance and release

Good Engineering Practice

Focus on practices that add value - providing evidence of fitness for use & proper performance

GEP is expected in pharmaceutical enterprises; it is not required by GxP regulations

However value of effective GEP is supported by regulatory and engineering guidance / standards

Qualification Approaches

International regulations: facilities, equipment & systems qualified and automation systems validated

ISPE Guide: ensures facilities, equipment, systems, and associated automation are ‘fit for intended use’

ISPE Guide: states critical aspects, and the installation & operational acceptance criteria documented in the final risk assessment / design review could be labeled as the IQ / OQ

Emphasis on ensuring fitness for use through verification activities during the life cycle rather than ‘incidents’ that represent qualification

Life Cycle

Fig. 2.2ISPE Guide: Science and Risk-Based Approach for the Delivery of Facilities, Systems and Equipment (2011)

Sequencing of Validation Stages

Validation Master Plan

Design Qualification

User Requirement Specification

Installation Qualification

Operational Qualification

Performance Qualification

Site Master File

Overall Validation Master Plan

Documents that are required to be in place and are routinely updated

Process ValidationValidation SOP

User Requirement Specification (URS)

Details of requirements from an operational and GMP perspectiveOne of the most important documents but usually drafted as an after thought!

Examples: Speed e.g. 200 bottles per minute Temperature e.g. drying temperature range 50 to 80ºC Finishes e.g. SS304 Safety features e.g. guards Documentation required e.g. manuals

Design Qualification(DQ)

Verification that what is to be supplied is in line with the requirements specified in the URS and will meet GMP requirements

Does the design incorporate sufficient provisions to control all risks to the end user?

Examples: Speed e.g. 50 to 200 bottles per minute Temperature e.g. drying temperature range 35 to 90ºC Finishes e.g. mild steel (does not meet requirements) Safety features e.g. guards present Documentation required e.g. manuals available

Installation Qualification (IQ)

Installation complies with design specification and manufacturer’s recommendations

Examples: Correct make / model installed All components present Connections made Instruments calibrated As-built drawings available and correct Materials of construction correct

Installation Qualification (IQ)

A thoroughly executed IQ process ensures: A fully verified installation that complies with the

documented design All deviations and changes recorded, assessed and

approved Accurate ‘as built’ drawings available and verified Calibration of measuring instruments completed Materials of construction verified

Operational Qualification (OQ)

Installation performs as intended throughout the anticipated operating ranges

Examples: Test, for example, speeds / temperatures / fill volumes

through full operating range & comparable load (inert material used if required)

Test alarms Test safety mechanisms Test interventions, stoppages, start-up etc. Operational and maintenance procedures available PPM and calibration schedules are drafted SOPs are compiled & authorized Training performed & documented

Operational Qualification (OQ)

A thoroughly executed OQ process ensures: Formal commissioning reports available Ability of systems to maintain set points in all operational

modes demonstrated Correct functioning of the control system demonstrated All alarms verified as functioning correctly Operational ranges, specific alert and action limits

identified Operational and Maintenance manuals available PPM and calibration schedules available SOPs available and authorized Personnel training successfully completed

Performance Qualification (PQ)

Effective and reproducible performance, based on the approved process method and product specification

Does the qualification provide assurance that the system / equipment is fit for use and any deviations from specification have been identified and evaluated?

Examples: Performance of filling equipment:

Consistent fill volume within registered specification using placebo product

Performance of Purified Water system: Microbial contamination within specification

Performance of HVAC: Non-viable particle count within specification

Performance Qualification (PQ)

A thoroughly executed PQ process ensures: Demonstration of consistent delivery of process /

product specification Demonstration that the systems have been

successfully validated and will not contribute any risk to the quality of products routinely produced

Re-validation criteria, where required, have been formalized

Process Validation

FDA

Guidance for Industry

Process Validation: General Principles and Practices

January 2011 Revision 1 ‘…aligns process validation activities with a

product lifecycle concept…’ ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System

Process ValidationFDA Process Validation: General Principles and Practices

‘The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production.’

FDA Guidance for Industry


January 2011 Revision 1


Guidance covers: Human drugs Veterinary drugs Biological and biotechnology products Finished products and APIs/drug substances The drug constituent of a combination (drug &

medical device) product Medical devices, dietary supplements, human

tissues, medicates feeds excludedFDA Guidance for Industry




Products should be produced that are fit for their intended use

Quality, safety and efficacy are built into the product Quality cannot be adequately assured through in-

process and final product inspection and testing





‘… process validation is defined as 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 product…’

Stage 1- Process Design: Commercial manufacturing process defined through development & scale up activities

Stage 2 – Process Qualification: Process design evaluated to verify capability of reproducible commercial manufacturing

Stage 3 – Continued Process Verification: On going assurance during routine production that process remains in state of control





Gain high degree of assurance in performance of manufacturing process before any commercial batch is distributed for use Attributes consistent Identity Strength Quality Purity Potency





Successful validation depends on information / knowledge from product & process development Understand sources of variation Detect presence & degree of variation Understand impact of variation Control variation (commensurate with risk to process

& product)





Focus on qualification without understanding the process and variation may not lead to quality assurance

Continue to maintain state of control during lifecycle regardless of changes (materials / equipment / facilities / personnel)

On-going programs collect and analyze data to evaluate state of control





Stage 1 – Process Design Do not need cGMP conditions Sound scientific methods & principles, good

documentation practices (ICH Q10) Decisions & justification of controls documented and

reviewed – value for use and later adaptation Product development provides key inputs to quality

attributes and manufacturing process Functionality & limitations of commercial manufacturing

equipment consideredFDA Guidance for Industry




Stage 1 – Process Design Predicted variability considered Strategies for process control:

Reduce input variation Adjust for input variation (to reduce impact on output) Both

Process controls address variability → assures quality Controls:

Examination of material quality Equipment monitoring





Stage 2 – Process Qualification Determine capability for reproducible commercial

manufacture Two elements:

Facility design & equipment / utilities qualification Process Performance Qualification

Successful completion before distribution of product (FDA expects concurrent release to be rarely used)





Stage 2 – Process Qualification Qualification: Demonstrate utilities and equipment are

suitable for intended use and perform properly Qualification must precede Process Performance

Qualification (PPQ) PPQ combines facility, utilities, equipment, trained

personnel, commercial manufacturing process, control procedures and materials / components

Successful PPQ required before distributing product





Stage 2 – Process Qualification PPQ has:

Higher level of sampling Additional testing Greater scrutiny of process performance

Above could be extended in certain cases e.g. complexity of process, production volume

Manufacture under normal conditions using routine personnel





Stage 2 – Process Qualification PPQ protocol:

Manufacturing conditions (including operating parameters, processing limits, materials)

Data to be collected (when, how, evaluation) Tests to be performed and acceptance criteria Sampling plan (sampling points, number of samples, frequency

of sampling) Process performance indicators (statistically based) Status of qualification & analytical method validation Process for addressing deviations Review & approval

FDA Guidance for Industry, Process Validation: General Principles and Practices



Stage 3 – Continued Process Verification Objective: Continual assurance that process remains in

a state of control / validated state Managing change Routine monitoring systems, maintenance, calibration Data collection & review (product reviews) Evaluation of process – identify problems, corrective /

preventative actions Statistical process control techniques

FDA Guidance for Industry, Process Validation: General Principles and Practices



Stage 3 – Continued Process Verification Changes include:

API supplier Excipient physical properties Primary packaging material Equipment Process Facility / plant

Changes require documented description, well-justified rationale, implementation plan, QA approval

Concurrent & Retrospective Validation

Concurrent: Validation carried out during routine production of products intended for sale Exceptional cases Justified, documented, approved

Retrospective: Validation based on historical / collected data (manufacturing, testing, control data) Only for well established processes Inappropriate where changes to composition,

equipment & processes made Suggested source data

Challenges / Issues

Timing Generating the protocol for submission Technology transfer from design to commercial PPQ batches manufactured but cannot be released Time for regulatory approval Launch

New sites for existing products - protocol and results Prospective vs. concurrent Availability of design data and initial validation data Risk

Challenges / Issues

Multi-disciplinary teams PPQ performed when equipment / utilities have

not Robust Change Control process Data collection and review

THANK YOU

sapraa march 2013 validation. presentation what will be covered in this presentation….. why do we...

Documents

validation of processes

process validation slide

validation planni

validation documentation

design criteria validation

initial stage of validation

relevant parties validation

risk slide